The modern paradigm of studying the processes of carcinogenesis and vital activity of tumor tissues implies increased attention to constituents of tumor microenvironment (TME) and their interactions. These interactions between the cells in TME can be mediated via protein junctions of different types. Connexins (Cnxs) are one of the major contributors to intercellular communication. They form gap junctions responsible for the transfer of ions, metabolites, peptides, miRNA, etc. between neighboring tumor cells as well as between tumor and stromal cells. Cnx hemichannels mediate purinergic signaling and bidirectional molecular transport with the extracellular environment. Additionally, Cnxs were reported to localize in tumor-derived exosomes and facilitate the release of their cargo. A large body of evidence implies that the role of connexins in cancer is multifaceted. Pro- or anti-tumorigenic properties of connexins are determined by their abundance, localization and functionality as well as channel assembly and non-channel functions. In this review we have summarized the data on the Cnxs contribution in TME and to the cancer initiation and progression.

Long gone was the time when tumors were thought to be insular masses of cells, residing independently at specific sites in an organ. Now, researchers gradually realize that tumors interact with the extracellular matrix (ECM), blood vessels, connective tissues and immune cells in their environment, which is now known as the tumor microenvironment (TME). It is found that the interactions between tumors and their surrounding promote tumor growth, invasion and metastasis. The dynamics and diversity of TME cause the tumors to be heterogeneous and thus pose a challenge for cancer diagnosis, drug design and therapy. As TME is significant in enhancing tumor progression, it is vital to identify the different components in the TME. This review explores how different factors in the TME supply tumors with the required growth factors and signaling molecules to proliferate, invade and metastasis. We also examine the development of TME-targeted nanotheranostics over the recent years for cancer therapy, diagnosis and anticancer drug delivery system. This review further discusses the limitations and future perspective of nanoparticle based theranostics when used in combination with current imaging modalities like Optical Imaging, Magnetic Resonance Imaging (MRI) and Nuclear Imaging (PET and SPECT).

Classic Hodgkin lymphoma (cHL) is characterized by a few tumor cells surrounded by a protective, immunosuppressive tumor microenvironment composed of normal cells that are an active part of the disease. Hodgkin and Reed-Sternberg (HRS) cells evade the immune system through a variety of different mechanisms. They are invisible to antitumor effector T cells and natural killer cells and promote T cell exhaustion. Using cytokines and extracellular vesicles, they recruit normal cells, induce their proliferation, and “educate” (i.e., reprogram) them to become immunosuppressive and protumorigenic. Therefore, alternative treatment strategies, targeting not only tumor cells but also the tumor microenvironment, are being developed. Here we summarize current knowledge on the ability of HRS cells to build their microenvironment and to educate normal cells to become protective or immunosuppressive. We also describe therapeutic strategies to counteract formation of the tumor microenvironment and related processes leading to T cell exhaustion and repolarization of immunosuppressive tumor-associated macrophages.

The tumor microenvironment plays a pivotal role in the behavior and development of solid tumors as well as shaping the immune response against them. As the tumor cells proliferate, the space they occupy and their physical interactions with the surrounding tissue increases. The growing tumor tissue becomes a complex dynamic structure, containing connective tissue, vascular structures, and extracellular matrix that facilitates stimulation, oxygenation, and nutrition, necessary for its fast growth. Mechanical cues such as stiffness, solid stress, interstitial fluid pressure, matrix density, and microarchitecture influence cellular functions and ultimately tumor progression and metastasis. In this fight, our body is equipped with T cells as its spearhead against tumors. However, the altered biochemical and mechanical environment of the tumor niche affects T cell efficacy and leads to their exhaustion. Understanding the mechanobiological properties of the tumor microenvironment and their effects on T cells is key for developing novel adoptive tumor immunotherapies.

Classic Hodgkin lymphoma (cHL) is a lymphoid neoplasm composed of rare neoplastic Hodgkin and Reed-Sternberg (HRS) cells surrounded by a reactive tumor microenvironment (TME) with suppressive properties against anti-tumor immunity. TME is mainly composed of T-cells (CD4 helper, CD8 cytotoxic and regulatory), and tumor-associated macrophages (TAMs) but the impact of these cells on the natural course of the disease is not absolutely understood. TME contributes to the immune evasion of neoplastic HRS cells through production of various cytokines and/or aberrant expression of immune checkpoint molecules, in ways that have not been fully understood yet. Herein, we present a comprehensive review of findings regarding the cellular components and the molecular features of the immune TME in cHL, its correlation with treatment response and prognosis as well as the potential targeting of the TME with novel therapies. Among all cells, macrophages appear to be a most appealing target for immunomodulatory therapies, based on their functional plasticity and antitumor potency.

Epigenetic alterations are known contributors to cancer development and aggressiveness. Additional to alterations in cancer cells, aberrant epigenetic marks are present in cells of the tumor microenvironment, including lymphocytes and tumor-associated macrophages, which are often overlooked but known to be a contributing factor to a favorable environment for tumor growth. Therefore, the main aim of this review is to give an overview of the epigenetic alterations affecting immune cells in the tumor microenvironment to provoke an immunosuppressive function and contribute to cancer development. Moreover, immunotherapy is briefly discussed in the context of epigenetics, describing both its combination with epigenetic drugs and the need for epigenetic biomarkers to predict response to immune checkpoint blockage. Combining both topics, epigenetic machinery plays a central role in generating an immunosuppressive environment for cancer growth, which creates a barrier for immunotherapy to be successful. Furthermore, epigenetic-directed compounds may not only affect cancer cells but also immune cells in the tumor microenvironment, which could be beneficial for the clinical response to immunotherapy. Thus, modulating epigenetics in combination with immunotherapy might be a promising therapeutic option to improve the success of this therapy. Further studies are necessary to (1) understand in-depth the impact of the epigenetic machinery in the tumor microenvironment; (2) how the epigenetic machinery can be modulated according to tumor type to increase response to immunotherapy and (3) find reliable biomarkers for a better selection of patients eligible to immunotherapy.

Current therapeutic strategies targeting cancer cells within solid tumors have displayed limited success owing to the presence of non-cancer components referred to as the tumor stroma within the tumor microenvironment (TM). These stromal cells, extracellular matrix and blood vessels influence cancer cell response to therapy and play key roles in tumor relapse and resistance. Of the stromal cells present in the TM, a lot of attention has been given to cancer-associated fibroblasts (CAFs) as they are the most abundant and are important in cancer initiation, progression and therapy resistance. In this updated review I emphasize the role of CAFs in the regulation of tumor cell behaviour and reveal how CAF-derived factors and signaling influence tumor cell heterogeneity and development of novel strategies to combat cancer. To investigate the expression of CAF markers in tumor tissues versus normal tissues, transcriptomic data from The Cancer Genome Atlas (TCGA) and the Gene Expression Profiling Interactive Analysis (GEPIA) databases was used. Bioinformatic analysis reveals differential expression of CAF markers in several cancer types, underscoring the need for further multiomics and biochemical studies on CAFs, CAF subsets and markers. Differences in CAF markers’ expression could be due to different cellular origins as well as the effect of cancer-specific tumor microenvironmental effect on CAFs. Lastly, I present recent advances in therapeutic targeting of CAFs and the success of such endeavours or its lack thereof. It is recommended that for patients’ outcomes to improve, cancer treatment be combinatorial in nature, targeting both cancer cells and stromal cells and interactions.

Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis and highlight various ways through which tumor cells reprogram normal cells including into phenotypes that are pro-tumorigenic including cancer associated- fibroblasts, -macrophages and -endothelial cells. Tumor cells secrete numerous factors leading to transformation of a previously anti-tumorigenic environment into a pro-tumorigenic environment. Once formed, solid tumors continue to interact with various stromal cells including local and infiltrating fibroblasts, macrophages, mesenchymal stem cells, endothelial cells, pericytes, and secreted factors and the ECM within the tumor microenvironment (TME). The TME is key to tumorigenesis, drug response and treatment outcome. Importantly, stromal cells and secreted factors can initially be anti-tumorigenic but over time promote tumorigenesis and induce therapy resistance. To counter hypoxia, increased angiogenesis leads to formation of new vascular networks in order to actively promote and sustain tumor growth via supply of oxygen and nutrients whilst removing metabolic waste. Angiogenic vascular network formation aid in tumor cell metastatic dissemination. Successful tumor treatment and novel drug development require the identification and therapeutic targeting of pro-tumorigenic components of the TME including cancer-associated- fibroblasts (CAFs) and -macrophages (CAMs), hypoxia, blocking ECM-receptor interactions, in addition to targeting of tumor cells. Re-programming of stromal cells and the immune response to be anti-tumorigenic is key to therapeutic success. Lastly, this review highlights potential TME- and hypoxia-centred therapies under investigations.

Considering tumors from an evolucionary perspective, successive tumor cells undergo turnover in response to stressful conditions which pressures tumor cells to adapt to a new environment. Tumor cells uses parts of themselves to communicate and share biological information, known as extracellular vesicles (EV) secretion to promote their survival and “survive to each and every metabolic cost”. Tumor microenvironment (TME) is a miscellaneous of cells, factors, extracellular matrix proteins and EVs. EVs include smalls (<160nm, exosomes) and larger (100-1,000nm, microvesicles) lipid bilayer enclosed packages of biomolecules that are shed by tumors to TME. Tumor-derived extracellular vesicles transfer adaptative stress signaling to recipient cells, reprograming these cells. Heat Shock Proteins (HSP) are more prominent stress response regulators found in exosomes. HSP-loaded exosomes actively reprogram tumor and TME cells to acquire mechanisms that contribute to tumor progression and therapy resistance. The intercellular communication mediated by HSP-loaded EVs favors the escape of tumor cells from, endoplasmic reticulum (ER) stress, hypoxia, apoptosis and anti-cancer therapies. Extracellular HSPs activate and deactivate immune response, induce cell differentiation, changes vascular homeostasis, and help to augment the pre-metastatic niche formation. Here we will explore the EV mechanism of HSP transmission among TME cells and the relevance of these intercellular communications for resistance to therapies in cancer.

Background: Recent researches have investigated the biological importance of RNA N1-methyladenosine (m1A) modifications in oncogenesis and progression of head and neck squamous cell carcinoma (HNSCC). However, whether m1A modifications also have latent effect in tumor microenvironment (TME) generation and immune regulation in HNSCC is unknown. Methods: We evaluated the m1A modification patterns and related to these modification patterns with TME cell infiltration features in 1041 HNSCC samples by bioinformatics approach. Results: The m1A score is an independent prognostic indicator. HNSCC patients with low m1A score group with poor overall survival (OS) was mainly characterized by stroma activation, lack of sufficient immune infiltration, and exhibited an immune- desert TME phenotype. Low m1A scores were also correlated with increased tumor mutation burden (TMB), and HNSCC patients with high TMB and low m1A scores had the worst OS. In addition, anti-CTLA-4 combined with anti-PD1 treatment was more effective in the high m1A score subgroup than in the low m1A score subgroup. Conclusions: This study revealed that m1A modifications play a non-negligible role in developing the TME versatility and complexity of HNSCC. Assessing m1A modification patterns in HNSCC helps improve our comprehension of its TME infiltration profile and guides more effective immunotherapeutic approaches.

The tumor microenvironment (TME) plays a critical role in cancer progression and treatment outcomes. Despite advances in cancer research, many therapeutic strategies have failed to provide the desired clinical outcomes. In this integrated review, aimed to explore the role of TME in cancer biology and develop novel therapeutic strategies that target not only cancer cells but also the surrounding microenvironment. Study conducted a comprehensive literature search using PubMed, Embase, and Web of Science databases for articles published between 2016 and 2022. Inclusion of articles that discussed the impact of TME on cancer development and progression, as well as articles that proposed novel therapeutic strategies targeting the TME. The analysis of the literature revealed that the TME plays a crucial role in cancer development and progression by promoting cancer cell survival, angiogenesis, invasion, and metastasis, and by interfering with the efficacy of cancer therapies. The TME is composed of a complex network of non-cancerous cells, extracellular matrix components, and signaling molecules that interact with cancer cells. Several novel therapeutic strategies have been proposed based on the modulation of TME components. One of the most promising approaches is the use of immunotherapy, which aims to enhance the immune system's ability to recognize and attack cancer cells. Immunotherapy drugs such as checkpoint inhibitors, chimeric antigen receptor (CAR) T cells, and immune-stimulatory monoclonal antibodies have been approved for the treatment of different cancer types. These approaches have shown promising results in preclinical studies and clinical trials. The TME plays a critical role in cancer development and progression, and targeting its components represents a promising avenue for cancer therapy. Novel therapeutic strategies such as immunotherapy, extracellular matrix-targeting drugs, and nanoparticle-based therapies have shown promising results in preclinical studies and clinical trials. However, further research is needed to identify the most effective strategies and to overcome the challenges associated with TME targeting.

Uveal melanoma (UM) is the most common primary cancer of the eye and is associated with a high rate of metastatic death. UM can be stratified into two main classes based on metastatic risk, with class 1 UM having a low metastatic risk and class 2 UM having a high metastatic risk. Class 2 UM have a distinctive genomic, transcriptomic, histopathologic, and clinical phenotype characterized by biallelic inactivation of the BAP1 tumor suppressor gene, an immune suppressive microenvironment enriched for M2-polarized macrophages, and poor response to checkpoint inhibitor immunotherapy. To identify potential mechanistic links between BAP1 loss and immune suppression in class 2 UM, we performed an integrated analysis of UM samples, as well as genetically engineered UM cell lines and uveal melanocytes (UMC). Using RNA sequencing (RNA-seq), we found that the most highly up-regulated gene associated with BAP1 loss across these datasets was PROS1, which encodes a ligand that triggers phosphorylation and activation of the immunosuppressive macrophage receptor MERTK. The inverse association between BAP1 and PROS1 in class 2 UM was confirmed by single-cell RNA-seq, which also revealed that MERTK was up-regulated in CD163+ macrophages in class 2 UM. Using ChIP-seq, BAP1 knockdown in UM cells resulted in an accumulation of H3K27ac at the PROS1 locus, suggesting epigenetic regulation of PROS1 by BAP1. Phosphorylation of MERTK in RAW 264.7 monocyte-macrophage cells was increased upon co-culture with BAP1-/- UMCs, and this phosphorylation was blocked by depletion of PROS1 in the UMCs. These findings were corroborated by multi-color immunohistochemistry, where class 2/BAP1-mutant UMs demonstrated increased PROS1 expression in tumor cells and increased MERTK phosphorylation in CD163+ macrophages compared to class 1/BAP1-wildtype UMs. Taken together, these findings provide a mechanistic link between BAP1 loss and suppression of the tumor immune microenvironment in class 2 UMs, and they implicate the PROS1-MERTK pathway as a potential target for immunotherapy in UM.

Background: Cutaneous Melanoma (SKCM) is characterized by significant heterogeneity in its molecular, genomic, and immunologic characteristics. Methods: Whole transcriptome RNAseq data from The Cancer Genome Atlas of SKCM (n=328) was utilized. The immune microenvironment was characterized using CIBERSORTX to identify immune cell type composition. Unsupervised hierarchical clustering was performed based on immune cell type content. Samples were separated into those obtained from the primary tumor site and regional skin or soft tissue (locoregional), or distant metastasis and regional lymph node (metastatic). Analysis of overall survival (OS) was performed using Kaplan-Meier estimates and Cox-regression multivariable analyses. Results: Four immune clusters were identified, largely defined by lymphocyte:monocyte (L:M) ratio, monocyte-enrichment, and M0-macrophage-enrichment (L:MLow, MonocyteHigh, M0High; L:MLow, MonocyteMid, M0Low; L:MMid, MonocyteLow, M0Low; L:MHigh, MonocyteLow, M0Low). The L:MLow, MonocyteHigh, M0High cluster demonstrated significantly worse OS than clusters 2-4 in the locoregional group (HR 2.804, 95% CI 1.262–6.234, p=0.0114). Membership in the L:MLow, MonocyteHigh, M0High cluster was an independently poor prognostic factor for survival (HR 3.03, 95% CI 1.12–8.20, p=0.029). The L:MLow, MonocyteHigh, M0High cluster correlated with higher rates of metastasis and decreased predicted response to immune checkpoint blockade compared to the other clusters as determined by the Tumor Immune Dysfunction and Exclusion tool (TIDE). Conclusion: Distinct tumor immune clusters with a M0-macrophage-enriched, L:M ratio low phenotype in the primary melanoma tumor site independently characterize an aggressive phenotype that may differentially respond to treatment.

Despite great strides being achieved in improving cancer patients’ outcomes through better therapies and combinatorial treatment, several hurdles still remain due to therapy resistance, cancer recurrence and metastasis. Drug resistance, culminating in relapse and metastatic disease continue to be associated with fatal disease. Cancer stem cells (CSCs) are a subpopulation of cancer cells known to be resistant to therapy and cause metastasis. Whilst the debate on whether CSCs are the origins of the primary tumor rages on, CSCs have been further characterised in many cancers with data illustrating that CSCs display great abilities to self-renew, withstand therapies due to enhanced epithelial to mesenchymal (EMT) properties, enhanced expression of ABC membrane transporters, activation of several survival signaling pathways and increased immune evasion DNA repair mechanisms. CSCs also display great heterogeneity with the consequential lack of specific CSC markers presenting a great challenge to their targeting. In this updated review we re-visit CSCs within the tumor microenvironment (TME) and present novel treatment strategies targeting CSCs. These promising strategies include targeting CSCs-specific properties using small molecule inhibitors, immunotherapy, microRNA mediated inhibitors, epigenetic methods as well as targeting CSC niche-microenvironmental factors and differentiation. Lastly, we present recent clinical trials undertaken to try to turn the tide against cancer by targeting CSC-associated drug resistance and metastasis.

Background: Prostate cancer (PCa) is characterized by significant heterogeneity in its molecular, genomic, and immunologic characteristics. Methods: Whole transcriptome RNAseq data from The Cancer Genome Atlas of prostate adenocarcinomas (n=496) was utilized. The immune microenvironment was characterized using the CIBERSORTX tool to identify immune cell type composition. Unsupervised hierarchical clustering was performed based on immune cell type content. Analyses of progression-free survival (PFS), distant metastases, and overall survival (OS) were performed using Kaplan-Meier estimates and Cox-regression multivariable analyses. Results: Four immune clusters were identified, largely defined by plasma cell, CD4+ Memory Resting T Cells (CD4 MR), M0 and M2 macrophage content (CD4 MRHighPlasma CellHighM0LowM2Low, CD4 MRLowPlasma CellHighM0LowM2Low, CD4 MRHighPlasma CellLowM0HighM2Low, and CD4 MRHighPlasma CellLowM0LowM2High). The two macrophage-enriched/plasma cell non-enriched clusters (3&4) demonstrated worse PFS (HR 2.24, 95% CI 1.46–3.45, p=0.0002) than the clusters 1&2. No metastatic events occurred in the non-macrophage-enriched clusters. Comparing clusters 3 vs 4, in patients treated by surgery alone, cluster 3 had zero progression events (p<0.0001). However, cluster 3 patients had worse outcomes after post-operative radiotherapy (p=0.018). Conclusion: Distinct tumor immune clusters with a macrophage-enriched phenotype and reduced plasma cell enrichment independently characterize an aggressive phenotype in localized prostate cancer that may differentially respond to treatment.

Many cellular functions important for tumor initiation and progression are mediated by members of the integrin family, a diverse family of cell adhesion receptors. With recent studies emphasising on the role of the tumor microenvironment (TME) in tumor initiation and progression, it is not surprising that a lot of attention is being given to integrins. Several integrins are under trial with many demonstrating appealing activity in patients with different cancers. A deeper knowledge of the functions of integrins within the tumor microenvironment is still required, and might lead to better inhibitors being discovered. Integrin expression is commonly dysregulated in many tumors with integrins playing key roles in signaling as well as promotion of tumor cell invasion and migration. This review report new data on the differential expression of integrins within solid tumors using two publicly available resources: The Cancer Genomic Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA). In this analysis, I investigated the expression of integrin alpha 2 (ITGα2), ITGα3, ITGβ4 and ITGβ6 in tumor tissues versus adjacent normal tissues. This analysis showed that integrins were differentially expressed in cervical squamous cell carcinoma (CESC), head and neck squamous cell carcinoma (HNSC), esophageal carcinoma (ESCA) and lung adenocarcinoma (LUAD). This analysis showed that ITGα2 and ITGβ6 expression are upregulated in CESC and ESCA, ITGα3 is upregulated in HNSC and ESCA whilst ITGβ4 is highly expressed in CESC, HNSC, ESCA and LUAD tumor tissues compared to adjacent normal tissues. Integrins also play a major role in adhesion of circulating tumor cells to new sites and the resulting formation of secondary tumors. Furthermore, integrins have demonstrated the ability to promoting stem cell-like properties in tumor cells as well as drug resistance. Anti-integrin therapies rely heavily on the doses or concentrations used as these determine whether the drugs act as antagonists or as integrin agonists. This review offers the latest synthesis in terms of current knowledge of integrins functions within the tumor microenvironment and potential targets for different cancers.

The Na+/K+ ATPase is a protein involved in the active transport of ions across the cellular membrane. Ouabain is a cardiotonic glycoside that, by inhibiting the Na+/K+ pump, interferes with cell processes mediated directly by the pump, but also indirectly influences other cellular processes, such as cellular cycle and proliferation, growth, cell differentiation, angiogenesis, migration, adhesion and invasion. We used the SK-BR-3 breast cancer cell line, mesenchymal stem cells (MSCs), and tumor-associated fibroblasts (TAFs) in vitro for determining the changes induced by Ouabain in concentration of 10-5 M, 10-6 M, 10-8 M, 10-9 M on these cellular types, employing specific methods: SEM for morphological evaluation; immunocytochemistry, flowcytometry to assess immunophenotypical markers expression, cell cycle and Annexin V/PI assay for cellular proliferation and viability testing; flowchamber assay to evaluate functional adhesion behavior; RT-PCR for Na+/K+ ATPase subunits molecular expression. Being indicative of the pro-apoptotic and inhibitory effect of Ouabain on tumor invasion and metastasis, the results support the addition of Ouabain to the oncological therapeutic arsenal, trailing the “repurposing drugs” approach.

The central reason behind emergence of clinically-detectable tumors is evasion from immune surveillance due to lack of cancer cells surface membrane expression of tumor-specific peptides in association with MHC class I molecules, concealment of natural killer cells-activating molecules, and absence of inflammation resulting from inefficient stimulation of innate immunity receptors and co-stimulatory molecules. The tumor microenvironment (TME) also contributes to tumor initiation, progression and resistance to therapeutic interventions because of its dense, fibrogenic, barrier-like composition, aberrant vasculature, and production of cytokines and chemokines responsible for recruitment of immune suppressive cells, notably myeloid-derived suppressor cells, M2 macrophages, regulatory T cells, extracellular trap-forming neutrophils, and cancer-associated fibroblasts. We herein show that the relentless efforts and strategies to overcome the TME elusive tumor-promoting impact produced contrasting, opposed, controversial effects, characterized by limited efficacy and proven adversity, and most importantly deterred from attempts to discover and counteract the fundamental inherent mechanisms initiating, and not consequent to, carcinogenesis.

Although most people are infected with Epstein-Barr Virus (EBV) during their lifetime, only a minority of them develop an EBV-associated malignancy. EBV acts in both direct and indirect ways to transform infected cells into tumor cells. There are multiple ways in which the EBV, host, and tumor environment interact to promote malignant transformation. This paper focuses on some of the mechanisms that EBV uses to transform the tumor microenvironment (TME) of EBV-associated gastric cancer (EBVaGC) for its benefit, including overexpression of IDO1, synergism between H pylori and EBV coinfection, and M1 to M2 switch. In this review, we expand on different modalities and combinatorial approaches to therapeutically target this mechanism.

Ral-interacting protein 76 (RLIP76) is a potential factor with vascular endothelial growth factor (VEGF) in the corpus luteum and tumor angiogenesis. RLIP76, VEGF, and hypoxia-inducible factor-1 (HIF-1) are proteins that activate angiogenic functions in tumor and endothelial cells. RLIP76 is a main factor in tumor growth, and VEGF is a major endothelial cell protein for angiogenesis. Also, RLIP76 regulates a small GTPase (R-Ras, oncogene) in cell survival, spreading, and migration. HIF-1 is important in the corpus luteum, tumor angiogenesis, and tumor growth. VEGF and HIF-1 regulate the angiogenic function of RLIP76, and RLIP76 controls vascular growth in endothelial and tumor cells. RLIP76, R-Ras, VEGF, and HIF-1 may be useful in the research of corpus luteum and cancer therapy and the study of mechanisms of tumor angiogenesis. This review will help to elucidate the roles of RLIP76/R-Ras and VEGF via HIF-1 in corpus luteum and tumor angiogenesis, tumorigenesis, and the specific regulation of RLIP76 in luteal, tumor, and endothelial cells. Thus, we reviewed the angiogenesis of the corpus luteum and tumor in the ovarian and tumor microenvironment.

More than 1 million women are diagnosed annually worldwide with a gynecological cancer. Most gynecological cancers are diagnosed at late stage, either because lack of symptoms such as in ovarian cancer or limited accessibility to primary prevention in low-resource countries such as in cervical cancer. Here, we extend the studies of AR2011, a stroma-targeted and tumor microenvironment responsive oncolytic adenovirus (OAdV) whose replication is driven by a triple hybrid promoter. We show that AR2011 was able to replicate and lyse in vitro fresh explants obtained from human ovarian cancer. uterine cancer, and cervical cancer. AR2011 was also able to strongly inhibit the in vitro growth of ovarian malignant cells obtained from human ascites fluid. The virus could synergize in vitro with cisplatin even on ascites-derived cells obtained from patients heavily pretreated with neoadjuvant chemotherapy. AR2011(h404) a dual transcriptionally targeted derived virus armed with hCD40L and h41BBL under the regulation of the hTERT promoter, showed a strong efficacy in vivo both on subcutaneous and intraperitoneally established human ovarian cancer in nude mice. Preliminary studies in an immunocompetent murine tumor model showed that AR2011(m404) expressing the murine cytokines was able to induce an abscopal effect. The present studies suggest that AR2011(h404) is a likely candidate as a novel medicine for intraperitoneal disseminated ovarian cancer.

Tumor dormancy, a clinically undetectable state of cancer, makes a major contribution to the development of multidrug resistance (MDR), minimum residual disease (MRD), tumor outgrowth, cancer relapse, and metastasis. Despite its high incidence, the whole picture of dormancy-regulated molecular programs is far from clear. That is, it is unknown when and which dormant cells will resume proliferation causing late relapse, and which will remain asymptomatic and harmless to their hosts. Thus, identification of dormancy-related culprits and understanding their roles can help predict cancer prognosis and may increase the probability of a timely therapeutic intervention for the desired outcome. Here, we provide a comprehensive review of the dormancy-dictated molecular mechanisms, including an angiogenic switch, immune escape, cancer stem cells, extra cellular matrix (ECM) remodeling, metabolic reprogramming, miRNAs, epigenetic modifications, and stress-induced-p38 signaling pathways. Further, we analyze the possibility of leveraging these dormancy-related molecular cues to outmaneuver cancer, and discuss the implications of such approaches in cancer treatment.

Tumor dormancy, a clinically undetectable state of cancer, makes a major contribution to the development of multidrug resistance (MDR), minimum residual disease (MRD), tumor outgrowth, cancer relapse, and metastasis. Despite its high incidence, the whole picture of dormancy-regulated molecular programs is far from clear. That is, it is unknown when and which dormant cells will resume proliferation causing late relapse, and which will remain asymptomatic and harmless to their hosts. Thus, identification of dormancy-related culprits and understanding their roles can help predict cancer prognosis and may increase the probability of a timely therapeutic intervention for the desired outcome. Here, we provide a comprehensive review of the dormancy-dictated molecular mechanisms, including an angiogenic switch, immune escape, cancer stem cells, extra cellular matrix (ECM) remodeling, metabolic reprogramming, miRNAs, epigenetic modifications, and stress-induced-p38 signaling pathways. Further, we analyze the possibility of leveraging these dormancy-related molecular cues to outmaneuver cancer, and discuss the implications of such approaches in cancer treatment.

The molecular evolution of medulloblastoma is more complex than was previously imagined as emerging evidence suggests that multiples interactions between the tumor cells and components of the tumor microenvironment (TME) are important for tumor promotion and progression. The identification of several molecular networks within the TME, which interact with tumoral cells, has provided new clues to understand the tumorigenic roles of many TME components as well as potential therapeutic targets. In this review, we discuss the most recent studies regarding the roles of astrocytes in supporting the sonic hedgehog (SHH)–activated medulloblastoma molecular subgroup, and provide an overview of medulloblastoma progression through SHH expression and signal transduction mechanisms into the complex tumor microenvironment. In addition, we highlight the associations between tumor and stromal cells as possible prognostic markers and new therapeutic strategies.

Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL), accounting for about 40% of all cases NHL. Analysis of the tumour microenvironment is an important aspect of the assessment of the progression of DLBCL. In this review article, we have analyzed the role of different cellular components of the tumour microenvironment, including mast cells, macrophages, lymphocytes, in tumour progression of DLBCL. We examined several approaches to confront the available pieces of evidence; three key points emerged. DLBCL is a disease of malignant B-cells spreading and accumulating both at nodal and in extranodal sites. Both in patients with nodal and extranodal lesions, the subsequent induction of a cancer-friendly environment appears pivotal. DLBCL cell interaction with mature stromal cells and vessels confers tumour protection and inhibition of immune response while delivering nutrients and oxygen supply. Single cells may also reside and survive in protected niches in the nodal and extranodal sites as a source for residual disease and relapse. This review aims to molecularly and functionally recapitulate the DLBCL-milieu crosstalk, to relate niche and pathological angiogenic constitution and interaction factors to DLBCL progression.

Tumor-associated macrophages (TAMs) play critical roles in the tumor microenvironment (TME), where they are recruited by signals released by cancer cells. Although they have great potential as therapeutic targets for cancer treatment, the dual roles of TAMs in promoting or inhibiting tumor growth, invasion, and metastasis make their function in cancer progression complex. In this review, we provide an overview of the current understanding of TAMs, including their phenotypic diversity, regulatory signaling pathways, and interactions with other cells in the TME. We also discuss the challenges related to the standard isolation protocols of TAMs, inconsistent research results, and translation of TAM knowledge into clinical applications. Additionally, we review the status of clinical trials involving TAMs and potential strategies to overcome the limitations. The future direction of TAM research should focus on developing more targeted therapies that specifically regulate TAM function and non-invasive methods for monitoring TAM activity in cancer patients. A comprehensive understanding of the complex role of TAMs in cancer may lead to the development of more effective treatments and improved outcomes for cancer patients.

Targeted delivery of drugs or other therapeutic agents through internal or external triggers has been used to control and accelerate the release from liposomal carriers in a number of studies, but relatively few utilize energy of therapeutic X-rays as a trigger. We have synthesized liposomes that are triggered by ionizing radiation (RTLs) to release their therapeutic payload. These liposomes are composed of natural egg PE, DSPC, cholesterol, and DSPE-PEG-2000, and the mean size of the RTL was in the range of 114 to 133 nm, as measured by NTA. The trigger mechanism is the organic halogen, chloral hydrate, which is known to generate free protons upon exposure to ionizing radiation. Once protons are liberated, a drop in internal pH of the liposome promotes destabilization of the lipid bilayer and escape of the liposomal contents. In proof of principle studies, we assessed RTL radiation-release of fluorescent tracers upon exposure to a low pH extracellular environment or exposure to X-ray irradiation. Biodistribution imaging before and after irradiation demonstrated a preferential uptake and release of the liposomes and their cargo at the site of local tumor irradiation. Finally, a potent metabolite of the commonly used chemotherapy irinotecan, SN-38, was loaded into RTL along with near infrared (NIR) fluorescent dyes for imaging studies and measuring tumor cell cytotoxicity alone or combined with radiation exposure, in vitro and in vivo. Fully loaded RTLs were found to increase tumor cell killing with radiation in vitro and enhance tumor growth delay in vivo after three i.v. injections combined with three, 5 Gy local tumor radiation exposures compared to either treatment modality alone.

Worldwide, hundreds of thousands of people are diagnosed with kidney cancer and this disease is more common in developed and industrialized countries. Previously, kidney cancer was known as an elderly disease and was seen in people over a certain age; nowadays it is also seen in younger individuals and it is easier to diagnose thanks to new radiological diagnostic methods. A kidney tumor is a type of cancer that is extremely aggressive and needs surgical treatment rapidly. Today, approximately 30% of patients diagnosed with kidney cancer are unfortunately noticed at the stage of metastatic disease (spread to distant organs). The biggest factor that pushes us to this study is that kidney tumors progress unlike other cancer types with little or no symptoms. Therefore, conducting such studies is extremely important for early diagnosis. In this study, we compare the Unet3D models in order to help people who are dealing with difficulties in the diagnosis of kidney cancer. Unet, Unet+ResNet and Unet++ models were compared for image segmentation.

Malignant tumors behave dynamically as cell communities governed by ecological principles. Massive sequencing tools are unveiling the true dimension of the heterogeneity of these communities along their evolution in most human neoplasms, clear cell renal cell carcinomas (CCRCC) included. Although initially thought to be purely stochastic processes, very recent genomic analyses have shown that temporal tumor evolution in CCRCC may follow some deterministic pathways that give rise to different clones and sub-clones randomly spatially distributed across the tumor. This fact makes each case unique, unrepeatable and unpredictable. Precise and complete molecular information is crucial for patients with cancer since it may help in establishing a personalized therapy. Intratumor heterogeneity (ITH) detection relies on the correctness of tumor sampling and this is part of the pathologist’s daily work. International protocols for tumor sampling are insufficient today. They were conceived decades ago, when ITH was not an issue, and have remained unchanged until now. Noteworthy, an alternative and more efficient sampling method for detecting ITH has been developed recently. This new method, called multisite tumor sampling (MSTS), is specifically addressed to large tumors that are impossible to be totally sampled, and represent an opportunity to improve ITH detection without extra costs.

A brain tumor is an abnormal mass of tissue found inside the brain that consists of cells that grow and multiply without any control and unchecked by the mechanisms that regulate normal cell growth. It is one of the leading causes of death in many different regions worldwide, affecting various ages, sex, race, or ethnicities. Besides being a life-threatening condition, it can also disrupt normal brain function leading to severe cognitive morbidity. Additionally, the cost associated with active treatment and palliative care of the brain tumor most often proves to be out of reach for many people. Over the past decades, even though we have several published literature showing the epidemiology and characteristics of brain tumors, up-to-date epidemiological data is yet to be published. This review will provide comparable recent statistics regarding the incidence of brain tumors in 3 different regions; - the USA, the UK, and Australia. Also, a focus will be given to brain tumor’s key characteristics, classifications, and treatment protocol.

Pheochromocytoma is a rare neuroendocrine tumor that affects people in the 4th and 5th decades of life. It can be benign or malignant, and present as isolated tumors or along with other neuroendocrine syndromes. We present a case of an elderly man who underwent laparoscopic adrenalectomy for pheochromocytoma when he was 58 years only to have a recurrence of metastatic malignant pheochromocytoma in his seventies. We also conducted a literature review to understand the epidemiology and presentation of the tumor and to emphasize that there should be a low threshold of suspicion for timely diagnosis and management of recurrent pheochromocytoma.

Glioblastoma is one of the most difficult tumor types to treat with conventional therapy options like tumor debulking, chemo and radiotherapy. Immunotherapeutic agents like oncolytic viruses, immune checkpoint inhibitors and chimeric antigen receptor T cells have revolutionized cancer therapy, but their success in glioblastoma remains limited and further optimization of immunotherapies is needed. Several oncolytic viruses have demonstrated ability to infect tumors and trigger anti-tumor immune responses in malignant glioma patients. Leading the pack, oncolytic herpesvirus, first in its class, awaits an approval for treating malignant glioma from MHLW, the federal authority of Japan. Nevertheless, some major hurdles like the blood brain barrier, immunosuppressive tumor microenvironment, and tumor heterogeneity can engender suboptimal efficacy in malignant glioma. In this review, we discuss the current status of malignant glioma therapies with a focus on oncolytic viruses in clinical trials. Furthermore, we discuss the obstacles faced by oncolytic viruses in malignant glioma patients and strategies that are being used to overcome these limitations to 1) optimize delivery of oncolytic viruses beyond the blood brain barrier; 2) trigger inflammatory immune responses in and around tumors; and 3) use of multimodal therapies in combination to tackle tumor heterogeneity, with an end goal of optimizing the therapeutic outcome of oncolytic virotherapy.

Protein phosphatase 2A (PP2A) is a ubiquitous serine/threonine phosphatase implicated in a wide variety of regulatory cellular functions. PP2A is abundant in the mammalian nervous system and dysregulation of its cellular functions are associated with myriad neurodegenerative disorders. Additionally, PP2A has oncologic implications, recently garnering attention and emerging as a therapeutic target because of the antitumor effects of a potent PP2A inhibitor, LB100. LB100 abrogation of PP2A is believed to exert its inhibitory effects on tumor progression through cellular chemo- and radio-sensitization to adjuvant agents. An updated and unifying review of PP2A biology and inhibition with LB100 as a therapeutic strategy for targeting cancers of the nervous system is needed, as other reviews have mainly covered broader applications of LB100. In this review, we discuss the role of PP2A in normal cells and tumor cells of the nervous system. Further, we summarize current evidence regarding the therapeutic potential of LB100 for treating solid tumors of the nervous system.

Solid tumors are typically associated with unbridled proliferation of malignant cells, accompanied by an immature and dysfunctional tumor-associated vascular network. Consequent impairment in transport of nutrients and oxygen eventually leads to a hypoxic environment wherein cells must adapt to survive and overcome these stresses. Hypoxia inducible factors (HIFs) are central transcription factors in the hypoxia response and drive the expression of a vast number of survival genes in cancer cells and in cells in the tumor microenvironment. HIFs are tightly controlled by a class of oxygen sensors, the HIF-prolyl hydroxylase domain proteins (PHDs), which hydroxylate HIFs, thereby marking them for proteasomal degradation. Remarkable and intense research during the past decade has revealed that, contrary to expectations, PHDs are often overexpressed in many tumor types and that inhibition of PHDs can lead to decreased tumor growth, impaired metastasis and diminished tumor-associated immune-tolerance. Therefore, PHDs represent an attractive therapeutic target in cancer research. Multiple PHD inhibitors have been developed that have either been recently accepted in China as erythropoiesis stimulating agents (ESA) or are currently in phase III trials. We review here the function of HIFs and PHDs in cancer and related therapeutic opportunities.

Circulating tumor cells (CTCs) enumeration is a promising technique to predict cancer prognosis and treatment response. CTCs were evaluated in healthy subjects, cirrhotic controls and hepatocarcinoma (HCC) patients. CTCs were isolated using microfluidic system based on the expression of EpCAM, EGFR and three epithelial to mesenchymal transition (EMT) markers. Patients were stratified according to disease progression and exitus. Although counts of individual CTCs, clustered CTCs and α-fetoprotein (AFP) at basal level in patients with HCC were significantly increased compared with the values obtained in cirrhotic patients and control subjects, only individual CTCs (p=0.027), but not clustered CTCs (p=0.063) and AFP (p=0.072), were independent predictors of HCC development. The univariate regression model showed that basal levels of CTCs46 were related to high risk of HCC (Odds Ratio 3.467, p=0.011). The stratification of our cohort according to disease progression and death showed that basal individual CTCs 76 (Hazard Ratio 5.131, p=0.004) were related to disease progression, as well as the difference of clustered CTCs between 1-month and baseline levels 1.5 were related to death (Hazard Ratio 10.204, p=0.036). In conclusion, the preoperative and 1-month measurements of CTCs in blood constitute useful markers to predict the outcome of patients under TACE treatment.

Although metastasis is the primary cause of death on patients with malignant solid tumors, efficient antimetastatic therapies are not clinically available thus far. Sulfated glycosaminoglycans from marine sources have shown promising pharmacological effects, acting in different steps of the metastatic process. Oversulfated dermatan sulfate from ascidians is effective in preventing metastasis by inhibition of P-selectin, a platelet surface protein involved in the platelet-tumor cell emboli formation. We report in this work that the heparan sulfate isolated from the viscera of the ascidian Phallusia nigra drastically attenuates metastasis of colon carcinoma cells in mice. Our in vitro and in vivo assessments demonstrate that the P. nigra glycan has very low anticoagulant and antithrombotic activities and a reduced hypotension potential, although efficiently preventing metastasis. Therefore, it may be a promising candidate for the development of a novel anti-metastatic drug.

Nowadays molecular and immunological research is essential for the better understanding of tumor cells pathophysiology. The increasing number of neoplasms is taken under ‘the molecular magnifying glass’ therefore it is possible to discover complex relationships between cytophysiology and immune system action. An example could be renal cell carcinoma (RCC) which has deep interactions with immune mediators such as Interleukin 17 (IL-17) - an inflammatory cytokine reacting to tissue damage and external pathogens. RCC is one of the most fatal urological cancer because of its often late diagnosis and poor susceptibility to therapies. IL-17 and its relation with tumors is extremely complex and constitute a recent topic for numerous research. What is worth highlighting is IL-17 dual character in cancer development - it could be pro- as well as antitumorigenic. The aim of this review is to summarize the newest data considering multiple connections between IL-17 and RCC.

Podoplanin (PDPN) is a cell-surface mucin-like glycoprotein that plays a critical role in tumor development and normal development of the lung, kidney, and lymphatic vascular systems. PDPN is overexpressed in several tumors and is involved in their malignancy. PDPN induces platelet aggregation through binding to platelet receptor C-type lectin-like receptor 2. Furthermore, PDPN modulates signal transductions that regulate cell proliferation, differentiation, migration, invasion, epithelial to mesenchymal transition, and stemness, all of which are crucial for the malignant progression of tumor. In the tumor microenvironment (TME), PDPN expression is up-regulated in the tumor stroma, including cancer-associated fibroblasts (CAFs) and immune cells. CAFs play significant roles in the extracellular matrix remodeling and the development of immunosuppressive TME. Additionally, PDPN functions as a co-inhibitory molecule on T cells, indicating the involvement with immune evasion. In this review, we describe the mechanistic basis and diverse roles of PDPN in malignant progression of tumor and discuss the possibility of the clinical application of PDPN-targeted cancer therapy, including cancer-specific monoclonal antibodies, and chimeric antigen receptor T technologies.

Background: transcriptome data provide a valuable resource for the study of cancer molecular mechanisms, but technical biases, samples’ heterogeneity and small sample sizes result in poorly reproducible lists of regulated genes. Additionally, the presence of multiple cellular components contributing to cancer development complicate the interpretation of bulk transcriptomic profiles. Methods: we collected 48 microarray datasets of laser capture microdissected breast tumors, and performed a meta-analysis to identify robust lists of genes differentially expressed in these tumors. We created a database with carefully harmonized metadata to be used as a resource for the research community. Results: combining the results of multiple datasets improved the statistical power, and the analysis of stroma and epithelium separately allows identifying genes with different contribution in each compartment. Conclusions: our database can profitably help biomarkers’ discovery and is readily accessible through a user-friendly web interface (https://aurorasavino.shinyapps.io/metalcm/).

The dominant paradigm holds that spontaneous and therapeutically induced anti-tumor responses are mediated mainly by CD8 T cells and directed against tumor-specific antigens (TSAs). The presence of specific TSAs on cancer cells can only be proven by mass spectrometry analyses. Bioinformatic predictions and reverse immunology studies cannot provide this type of conclusive evidence. Most TSAs are coded by unmutated non-canonical transcripts that arise from cancer-specific epigenetic and splicing aberrations. When searching for TSAs, mass spectrometry analyses must therefore interrogate not only the canonical reading frame of annotated exome but all reading frames of the entire translatome. The majority of aberrantly expressed TSAs (aeTSAs) derive from unstable short-lived proteins that are good substrates for direct MHC I presentation but poor substrates for cross-presentation. This is an important caveat because cancer cells are poor antigen-presenting cells and the immune system therefore depends on cross-presentation by dendritic cells (DCs) to detect the presence of TSAs. We therefore postulate that, in the untreated host, most aeTSAs are undetected by the immune system. We present evidence suggesting that vaccines inducing direct aeTSA presentation by DCs represent an attractive strategy for cancer treatment.

Background/Aim: Patients with uterine sarcoma comprise 2%–5% of all patients with uterine malignancies; however, the morbidity of uterine sarcoma is low compared with that of other gynecological cancers. For many cases, malignant uterine tumors are diagnosed during follow-up of benign uterine leiomyoma. Of the uterine sarcomas, rhabdomyosarcoma is considered a mixed tumor containing components of epithelial cells and mesenchymal cells. Therefore, the onset of primary uterine rhabdomyosarcoma during follow-up of uterine leiomyoma is extremely rare. Rhabdomyosarcoma is a relatively common malignant tumor in children, but rhabdomyosarcoma in adults is extremely rare, accounting for approximately 3% of all patients with soft tissue sarcoma. Rhabdomyosarcoma in children is highly sensitive to chemotherapy and radiation therapy; however, the response to chemotherapy and radiation therapy in adult rhabdomyosarcoma is low and survival in adult rhabdomyosarcoma with metastatic lesions to other organs is approximately 14 months. We experienced a case of polymorphic rhabdomyosarcoma during the follow-up of a uterine leiomyoma. Materials and Methods: We examined the oncological properties of uterine rhabdomyosarcoma in adults using molecular pathological techniques on tissue excised from patients with uterine leiomyoma. Result: A differential diagnosis was made for this case by molecular pathology, which included candidate biomarkers for uterine smooth muscle tumors. The oncological nature of uterine rhabdomyosarcoma was found to be similar to the oncological properties of uterine leiomyosarcoma. However, in uterine rhabdomyosarcoma, LMP2/1i-positive cells were clearly observed. Conclusion: It is expected that establishing a diagnostic and treatment method targeting characteristics of mesenchymal tumor cells will lead to the treatment of malignant tumors with a low risk of recurrence and metastasis.

Gastrointestinal stromal tumors are the mostly seen mesenchymal tumors of the gastrointestinal system. This rare tumor in duodenum is seen 5%. The diagnosis and treatment is hard because of its rarity and location. Case: A 63-year-old man with a solid mass at the third part of the duodenum, and local segmental resection of the tumor was performed. The histopathology was reported as gastrointestinal stromal tumor of the duodenum with negative surgical margins. Discussion: Gastrointestinal stromal tumors at the duodenum are seen rarely. They can be asymptomatic or may involve symptoms of upper GI bleeding and abdominal pain at presentation. Because of the misleading clinical presentation the differential diagnosis may be difficult. Tumors less than 2 cm can be followed by endoscopic ultrasound. Local segmental resection with 1cm clear margin is the treatment choice.

Background and objectives: Primary brain tumors include any tumors arising in the brain whose prognosis is poor due to their histologic characteristics. The aim of this research was to evaluate the frequency of HER2 tumor marker in primary malignant brain tumors. Materials and Methods: This descriptive study was conducted on the samples admitted to the pathology laboratory with diagnosis of primary brain tumor during 2008–2015. Results: From among 107 patients (61.7% males and the rest females) with mean age of 40.4 years, the highest frequency of tumor location was in supratentorial region of the brain (including lobes and ventricles) (63.85% cases). High-grade astrocytoma had the highest prevalence at diagnosis (43.9%), followed by low-grade astrocytoma (37.4%). As for HER2 score, 42.1% of patients were HER2-positive (scores 2 & 3). On the other hand, 5.6% of patients were HER2-negative (-), 40.2% were positive (+), and 54.2% were positive (++). The patients with high-grade astrocytoma had older age (P < 0.001), higher HER2 positivity (P = 0.024) and percentage (P < 0.001) compared to the patients with low-grade astrocytoma. Conclusions: HER2 expression is dependent on the type of brain tumors. High expression of HER2 in high-grade astrocytoma may be useful for therapeutic purposes. The future research is needed to confirm these results with a large number of patients in different areas.

The first FDA-approved drugs were small, chemically-manufactured and highly active molecules with possible off-target effects. After this first successful wave of small drugs, biotechnology allowed the development of protein-based medicines such as antibodies. Conventional antibodies bind a specific protein and are becoming increasingly important in the therapeutic landscape. A very prominent class of biologicals are the anti-TNF drugs that are applied in several inflammatory diseases that are characterized by dysregulated TNF levels. Marketing of TNF inhibitors revolutionized the treatment of diseases such as Crohn’s disease. However, these inhibitors also have undesired effects, some of them directly associated with the inherent nature of this drug class such as immunogenicity, whereas others are linked with their mechanism of action. Recently, researchers tried to design innovative drugs with reduced side effects aiming to make them more effective and safer. Molecules with more specificity e.g. that target one specific TNF format or receptor, or that neutralize the TNF signaling pathway in specific cells, are generated. Alternatively, TNF-directed biologicals without the typical antibody structure are manufactured. Here, we review the complications related to the use of conventional TNF inhibitors, together with the anti-TNF alternatives and the different (neurodegenerative) diseases that might benefit from selective approaches.

Testicular granulosa cell tumors (TGCTs) are rare tumors of sex cord stromal origin. TGCTs can be classified into the adult type and the juvenile type. The adult type is extremely rare with only 93 known cases reported in the literature. We, herein, present a report of a case of a 30 year old male patient who presented with a testicular mass, underwent radical inguinal orchiectomy and the pathology examination revealed an adult type granulosa tumor. We additionally review the literature to summarize the scientific knowledge of an entity barely described worldwide.

Extracellular vesicles (EV), including exosomes and microvesicles, are released from various cells and alter recipient cell phenotypes and fates by their biomolecules. Here we review current knowledge about tumor EVs and how they prompt malignant cell communication with tumor-associated cells, such as cancer-associated fibroblasts, tumor endothelial cells, and immune cells. We delineate the major pathways and molecular players that influence each step of cancer initiation, progression, and resistance. Of note, cancer exosomes involve immunosuppression by tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells. Moreover, tumor exosomes can induce the apoptosis of killer T cells and immune checkpoint of dendritic cells and attenuate natural killer cells. An in-depth understanding of EV biology is essential to ensure the clinical development of exosome/EV-based therapeutic products, which will be of benefit to exosome manipulation in cancer management.

The Wnt pathway plays an essential role in the initiation and progression of various types of cancer. ROR1 and ROR2 are Wnt receptors that are critical for β-catenin-independent (non-canonical) pathways and have been linked to processes driving tumor development and progression, such as cell proliferation, survival, invasion, and therapy resistance. Both receptors have garnered interest as potential therapeutic targets since they are largely absent in adult tissue, are overexpressed in several cancers, and, as members of the receptor tyrosine kinase family, are easier to target than all other components of the pathway. Unlike ROR1 which always promotes tumorigenesis, ROR2 has a very complex role in cancer acting either to promote or inhibit tumor progression in different tumor types. In the present article, we summarize the findings on ROR2 expression in cancer patients and its impact on clinical outcome. Further, we review the biological processes and signaling pathways regulated by ROR2 that explain its dual role in cancer. Finally, we describe the ongoing strategies to target ROR2 in cancer.

Background: Esophageal cancer was hardly diagnosed in early stage, and more potential biomarkers should be found. Methods: 252 patients and normal controls which recruited in Renmin Hospital of Wuhan University, were divided into esophageal carcinoma group (105 cases), disease control group (75 cases) and the control group of healthy people (72 cases). Moreover, TISIDB and GEPIA databases were used to investigate the different expression of EC and normal tissues, and explore the roles of C1q in tumor-immune system interactions in EC. Results: The concentration of serum C1q in EC group is 196.8(180~219.4) mg/L, which is higher than the level of DC [178.10(153.70~200.85) mg/L]and HC [183.00(167.75~201.00) mg/L] (P<0.05). A higher expression level of C1q was observed in Ⅲ and Ⅳ grades [214(192~237.3) mg/ml] than grades Ⅰ and Ⅱ [180.95(172.03~193.85) mg/L] (P<0.05). C1q was positively correlated with eosinophils, active CD8 T cells, myeloid derived suppressor cells, natural killer cells, monocytes and macrophages (r = 0.373; r = 0.659; r = 0.846; r = 0.760; r = 0.499; r = 0.757; P<0.05). Conclusion: The concentrations of C1q increased in EC and related to the severity of EC, which had potential value of diagnosis of EC. There were correlations in C1q and tumor-infiltrating lymphocytes.

There is compelling evidence that the nuclear receptor TRβ, a member of the thyroid hormone receptor (TR) family, is a tumor suppressor in thyroid, breast and other solid tumors. Cell-based and animal studies reveal that the liganded TRβ induces apoptosis, reduces an aggressive phenotype, decreases stem cell populations, and slows tumor growth through modulation of a complex interplay of transcriptional networks. TRβ-driven tumor suppressive transcriptomic signatures include repression of known drivers of proliferation such as PI3K/Akt pathway and activation of novel signaling (JAK1/STAT1) and metabolic reprogramming in both thyroid and breast cancers. The presence of TRβ is also correlated with a positive prognosis and response to therapeutics in BRCA+ and triple-negative breast cancers respectively. Ligand activation of TRβ enhances sensitivity to chemotherapeutics. TRβ co-regulators and bromodomain-containing chromatin remodeling proteins are emergent therapeutic targets. This review considers TRβ as a potential biomolecular diagnostic and therapeutic target.

Gastrointestinal stromal tumors are the mostly seen mesenchymal tumors of the gastrointestinal system and mostly seen at the stomach. We report a case of giant gastrointestinal stromal tumor of the stomach in a 71-year-old woman. The physical examination and radiological findings revealed that a giant mass occupied most of the abdominal cavity. The patient underwent an en-block resection of this giant mass with partial resection of the distal stomach and transverse colon and, reconstruction with gastro-jejunostomy and end-to end colo-colic anatomoses. The histopathologic diagnosis was revealed as gastrointestinal stromal tumor of the stomach. We suggest that complete surgical resection is the only effective radical treatment approach for giant gastrointestinal stromal tumors of the stomach.

Effective biomarkers are essential to the early diagnosis of non-small cell lung cancer (NSCLC). Herein, a retrospective study of 49 newly diagnosed and recurrent NSCLC patients, 31 patients with benign pulmonary disease and 24 healthy volunteers was conducted, to evaluate the diagnostic value of circulating rare cells for NSCLC. The expression of circulating tumor cells (CTCs) and circulating tumor-derived endothelial cells (CTECs) in peripheral blood were measured by subtraction enrichment-immunostaining-fluorescence in situ hybridization (SE-iFISH). The level of CTCs (P＜0.001) and CTECs (P＜0.001) was significantly higher in NSCLC group than that in benign pulmonary disease group. The proportion of small CTCs (P＜0.001) and CTECs (P＜0.0001) significantly increased from benign lung disease individuals to NSCLC patients. The AUC of ROC curves of total CTCs and CTECs were 0.815 (95%CI: 0.722~0.907), 0.739 (95%CI: 0.618~0.860), respectively. The cut-off values for discriminating NSCLC with benign lung disease patients were total CTCs 11.5 units/6ml and total CTECs 10.5 units/6ml, with sensitivity and specificity being 67.3% and 83.9%, 77.6% and 77.4%, respectively. When CTCs and CTECs were combined, predictive value significantly increased to 82.6% as measured by the area under the curve. Small CTCs and triploid CTCs had high positive predictive value (PPV) and positive likelihood ratio (LR+) of the diagnosis of NSCLC in early stage. CTCs and CTECs can not only be used as new biomarkers for the diagnosis of NSCLC, but can also improve diagnostic performance of the early stage NSCLC. Moreover, the combined examination of CTCs and CTECs is be superior to the single.

Skeletal metastases of unknown primary (SMUP) represent a clinical challenge dealing with patients diagnosed with bone metastases. The management have improved significantly in the past years, however fraught with lack of evidences, approach to these patients held out hope for more systematic and tailored treatment—and some patients can achieve impressive gains. Nevertheless, in real-life practice the outlook at the beginning of the take in charge of SMUP is decidedly more somber. An incomplete translational relevance of pathological and clinical data on the mortality and morbidity rate has had unsatisfactory consequences for SMUP patients and their physicians. We examined several approaches to confront the available evidences and highlighted three key points that emerge. The characterization of the SMUP biologic profile is essential to drive clinical decisions, integrating genetic and molecular profile into a multi-step diagnostic work-up. Nonetheless, pragmatic investigation plan and therapy of SMUP cannot follow a single template; it must be adapted to different pathophysiological dynamics and coordinated with efforts of a systematic algorithm and high-quality data derived from statistically powered clinical trials within. This review argues that greater efforts are required to face the unmet need dealing with SMUP patients in oncology. Finally, we provide an original functional network analysis, identifying novel therapeutic targets.

CXCR4 is a chemokine receptor crucial in tumor progression, although the angiogenic role of CXCR4 in oral squamous cell carcinoma (OSCC) has not been investigated. Here we show that CXCR4 is crucial for tumor angiogenesis thereby supports tumor survival in OSCC. Immunohistochemistry on human clinical specimens revealed that CXCR4 and a tumor vasculature marker CD34 were co-distributed in tumor vessels in human OSCC specimens. To ask the effects of CXCR4 inhibition, we treated the OSCC-xenografted mice with AMD3100, so-called plerixafor, an antagonist of CXCR4. Notably, we found a unique pathophysiological structure defined as Tumor Angiogenic Inhibition Triggered Necrosis (TAITN) induced by the CXCR4 antagonism. Treatment with AMD3100 increased necrotic area with the induction of hypoxia-inducible factor-1α in the xenografted tumors, suggesting that AMD3100-induced TAITN was involved in hypoxia and ischemia. Taken together, we demonstrated that CXCR4 plays a crucial role in tumor angiogenesis required for OSCC progression, whereas TAITN induced by CXCR4 antagonism could be an effective anti-angiogenic therapeutic strategy in OSCC treatment.

Cancer diseases lead to the second-highest death rate all over the world. The dynamics of invasion of cancer cells into the human body tissues and metastasis are the main causes of death in patients with cancer. This study deals with theoretical investigation of the dynamics of invasion of cancer cells for tumour growths in human body tissues using discretized Cahn-Hilliard, concentration and reaction-diffusion equations which were solved by Finite Difference Method with the aid of MATLAB computer software. A Crank-Nicolson numerical scheme was developed for the discretized model equations. The numerical result obtained was used to describe the dynamics of cancer invasion of tissues with respect to cancer cells density on tumour growth, turbulence and mobility and equilibrium between charge and discharge of cancer cells. The results of the study provide new insights into combating cancer disease by providing mitigating and intervention measures to this major health problem.

Chronic inflammation may have a detrimental impact on human health as it tends to result in cancer. In addition, it is often linked to different steps that participate in tumorigenesis, including cellular transformation, survival, promotion, invasion, proliferation, angiogenesis, and metastasis. Hence, inflammation predisposes cancer development and plays a vital role in promoting all tumorigenesis stages. Inflammation is caused by many factors, such as bacterial and viral infections, tobacco smoking, autoimmune diseases, obesity, asbestos exposure, and many others, increasing cancer risk. Moreover, cancer can be enhanced by mutations that proceed to cancer progression. Consequently, it leads to immunosuppression and provides a favorable background for tumor development. Although many studies address the question of relationships between inflammation and cancer development, little attention is paid to the link between inflammation and blood cancer. Therefore, the current study reviews the role of inflammation in cancer development, particularly in blood cancer. A meta-analysis research approach meets the research objective and answers the research question. The review results indicate that chronic inflammation directly relates to the development of many cancer types, blood cancer in particular.

(1) Background: The present study was carried out to provide new information about the relation between angiogenesis, tumor stage Oral squamous cell carcinoma (OSCC); (2) Materials and methods: Thirty formalin-fixed paraffin embedded blocks were used, 10 of them were previously diagnosed as well differentiated OSCC, 10 moderate differentiated OSCC and 10 poorly differentiated OSCC. To determine the expression of CD31 and D2-40 proteins, streptavidin-biotin immunoperoxidase staining technique was used. The areas with the most vascular density (hot spots) were determined. The stained vessels were counted independently in intratumoral and peritumoral stroma in five areas of hot spot at ×400 magnification; (3) Results: Immunohistochemical staining using CD 31 protein showed that CD31-positive vessels in the peritumoral and intratumoral stroma subjacent to the malignant invading nests which was recorded highest values in poor differentiated OSSC followed by moderate differentiated OSSC then well differentiated OSSC. D2-40 expression was positive in lymphatic vessel in the peritumoral and intratumoral stroma subjacent to the malignant invading nests. Poorly differentiated OSSC tissue sections recorded the highest vessels count followed by moderate differentiated OSSC then well differentiated OSSC. There was statistically significant difference found between the three studied groups regarding CD31 and D2-40 levels. Also there was statistically significant positive correlation found between CD31 level and D2-40 level and vice versa; (4) Conclusion: CD31 and D2-40 are related to stage of OSCC and are consistent with angiogenesis in tumor progression.

Neuroendocrine tumors develop from systemic endocrine and nerve cells, and their occurrence has increased recently. Since these tumors are heterogeneous, pathological classification has been based on the affected organ. In 2019, the World Health Organization introduced a change that is expected to influence neuroendocrine tumor research, as gastroenteropancreatic neuroendocrine tumors are now included within a unified classification. In this retrospective study, we aimed to investigate the characteristics (e.g., lymph node metastases, all other metastases) of gastroenteropancreatic neuroendocrine tumors using this new classification in 50 cases. Tumor size, depth, MIB-1 index, lymphatic invasion, venous invasion, and neuroendocrine tumor grade were significantly correlated with lymph node metastasis and all other metastases. Venous invasion was more strongly correlated with lymph node metastasis and all other types of metastasis than with lymphatic invasion. Identification rates for lymphatic invasion were considered lower because of structural problems such as lymphatic vessels being much thinner than veins. However, venous invasion was considered effective in compensating for the low rate of identification in cases of lymphatic invasion. In future research, a unified classification and standardized framework for assessment will be important when analyzing the characteristics of neuroendocrine tumors, and large-scale studies are required.

Epigenetic mechanisms, including post-translational modifications of DNA and histones that influence chromatin structure, regulate gene expression during normal development, and are also involved in carcinogenesis and cancer progression. The histone methyltransferase G9a (euchromatic histone lysine methyltransferase 2, EHMT2), which mostly mediates mono- and dimethylation by histone H3 lysine 9 (H3K9), influences gene expression involved in embryonic development and tissue differentiation. Overexpression of G9a has been observed in several cancer types, and different classes of G9a inhibitors have been developed as potential anticancer agents. Here, we review the emerging evidence suggesting the involvement of changes in G9a activity in brain tumors, namely glioblastoma (GBM), the main type of primary malignant brain cancer in adults, and medulloblastoma (MB), the most common type of malignant brain cancer in children. We also discuss the role of G9a in neuroblastoma (NB) and the drug development of G9a inhibitors.

Although pancreatic neuroendocrine neoplasms (PNENs) are relatively rare tumors, their number is increasing with advances in diagnostic imaging modalities. Even small lesions that are difficult to detect using computed tomography or magnetic resonance imaging can be detected with endoscopic ultrasound (EUS). Contrast-enhanced EUS is useful, and not only diagnosis but also malignancy detection have become possible by evaluating the vascularity of tumors. Pathological diagnosis using EUS with fine-needle aspiration (EUS-FNA) is useful when diagnostic imaging is difficult. EUS-FNA can also evaluate the grade of malignancy. Pooling the data of the studies which compared the PNENs grading between EUS-FNA samples and surgical specimen, the concordance rate was 77.5% (κ-statistic: 0.65, 95% confidence interval = 0.59 - 0.71, P< 0.01). EUS is a particularly important modality for the treatment of PNENs.

Glioma tumors are one of the most devastating cancer types. Of the different glioma tumors, glioblastoma is the most advanced stage with the worst prognosis. Current therapies are still unable to provide an effective cure. Recent advantages in oncolytic immunotherapy have generated great expectations in the cancer therapy field. The use of oncolytic viruses (OV) in cancer treatment is one of those immune-therapeutic alternatives. OV have a double oncolytic action by both, directly destroying the cancer cells, sparing the patient’s life, and stimulating a tumor specific immune response to revert the ability of tumors to escape the control of the immune system. OV are one promising alternative to conventional therapies in glioma tumor treatment. Several clinical trials have proven the feasibility to use some viruses to specifically infect tumors eluding undesired toxic effects in the patient. Here we have revisited the literature in order to describe the main OV proposed so far as therapeutic alternatives to destroy glioma cells in vitro and trigger tumor destruction in vivo. Some clinical trials are exploring the use of this therapy as an alternative were other approaches provide limited hope.

The use of circulating cell-free (cf) DNA to monitor cancer progression and response to therapy has significant potential but there is only limited data on whether this technique can detect the presence of low frequency subclones that may ultimately confer therapy resistance. In this study, we sought to evaluate whether whole-exome sequencing of cfDNA can accurately profile the mutation landscape of metastatic melanoma. We used whole-exome sequencing (WES) to identify variants in matched tumor-derived genomic (g) DNA and plasma-derived cfDNA isolated from a cohort of 10 metastatic cutaneous melanoma patients. WES parameters such as sequencing coverage and total sequencing reads were comparable between gDNA and cfDNA. There was significant concordance between gDNA and cfDNA based on the total number of variants identified and the degree of overlap in variants which was independent of the site of tumor biopsy. The mutant allele frequency of common single nucleotide variants was lower in cfDNA reflecting lower read depth and dilution of circulating tumor DNA in the circulation by other cfDNA species. In addition to known melanoma driver mutations, several other melanoma-associated mutations were found to be concordant between matched gDNA and cfDNA. This study highlights that WES of cfDNA can capture clinically-relevant mutations present in melanoma metastases, but does not appear to provide any additional unique information on tumor heterogeneity. Targeted deep sequencing may be required to detect low frequency genomic aberrations known for predicting therapy resistance.

Endothelial cells form a powerful interface between tissues and immune cells. In fact, one of the underappreciated roles of endothelial cells is to orchestrate immune attention to specific sites. Tumor endothelial cells have a unique ability to dampen the immune responses and thereby maintain an immunosuppressive microenvironment. Recent approaches to trigger immune responses in cancers have focused on activating nucleic acid sensors such as cGAS/STING in combination with immunotherapies. In this review, we present a case for targeting nucleic acid sensing pathways within the tumor vasculature to invigorate tumor immune responses. We introduce two specific nucleic acid sensors, the DNA sensor TREX1 and the RNA sensor RIG-I and discuss their functional roles in the vasculature. Finally, we present perspectives on how these nucleic acid sensors in the tumor endothelium can be targeted in an antiangiogenic and immune activation context. We believe understanding the role of nucleic acid sensing in the tumor vasculature can enhance our ability to design more effective therapies targeting the tumor microenvironment.

Caribbean sponges of the genus Smenospongia are a prolific source of chlorinated secondary metabolites. The use of molecular networking as a powerful dereplication tool revealed the presence in the metabolome of S. aurea of two new members of the smenamide family, namely smenamide F (1) and G (2). The structure of smenamide F (1) and G (2) was determined by spectroscopic analysis (NMR, MS, ECD). The relative and the absolute configuration at C-13, C-15, and C-16 was determined on the basis of the conformational rigidity of a 1,3-disubstituted alkyl chain system (i.e. the C-12/C-18 segment of compound 1). Smenamide F (1) and G (2) were shown to exert a selective moderate antiproliferative activity against cancer cell lines MCF-7 and MDA-MB-231, while being inactive against MG-63.

Macrophages and dendritic cells (DCs) acquire functionally distinct properties in response to various environmental stimuli; the interaction of these cells with myeloid-derived suppressor cells (MDSCs) in tumor microenvironments regulates cancer progression. Immunodeficient mice lacking T cells are less likely to reject human cancer cells because of major histocompatibility complex (MHC) mismatches. The xenograft tumor microenvironment, comprising human cancer and mouse host cells, exhibits more complex bidirectional signaling and function than a syngeneic tumor microenvironment. Here human and mouse colorectal cancer cells were transplanted into nude mice to elucidate differences in macrophage, DC, and MDSC functions in human xenograft and mouse allograft tumor models. Plasma interferon-γ and interleukin-18 concentrations in the former model after intraperitoneal lipopolysaccharide (LPS) administration were significantly higher than those in the latter model and non-transplanted control group. Splenic MHC class I, II, and CD80 expression increased in CD11b+ and MDSC populations after LPS administration in only the xenograft tumor model. The number of CD80- and MRC1-expressing cells decreased upon LPS administration in only the xenograft tumor. These results suggxest that macrophages and DCs function normally in xenograft tumor models, whereas their functions in response to LPS administration vary in allograft tumor models.

It has been proposed that tumourigenicity was an intrinsic feature of embryonic/germ cell developmental axis as well as embryonic/germ cell-related genes play a crucial role in tumourigenicity. Our previous studies indicated that primordial germ cell (PGC)-like potential could be reactivated in tumourigenesis. In this study, 4T1, 168FARN and 67NR cells which originated from the same mouse breast cancer were studied and the results indicated that the acquisition of embryonic/germ cell-like state is essential for tumourigenicity. We further demonstrated that somatic to PGC-like transformation (SPLT) was activated in 4T1 cells and that inhibition of PGC-like cell formation by depleting pluripotency and/or PGC specification-related genes markedly repressed SPLT and the tumourigenicity. Collectively, our findings reveal that tumourigenicity is linked to the acquisition of PGC-like state through SPLT in 4T1 cells, provide new insight into deeper understanding the biological nature of tumours and novel therapeutical strategies for cancer targeting.

This review systematically examines the multifaceted relationship between the tumor microenvironment, stromal interactions, and colorectal cancer (CRC) progression and metastasis. The analysis begins by assessing the gut microbiome's influence on CRC development, emphasizing its association with gut-associated lymphoid tissue (GALT). The role of the Wnt signaling pathway in CRC tumor stroma is scrutinized, elucidating its impact on disease progression. Tumor budding, its effect on tumor stroma, and implications for patient prognosis are investigated. The review also identifies conserved oncogenic signatures (COS) within CRC stroma and explores their potential as therapeutic targets. Lastly, the seed and soil hypothesis is employed to contextualize metastasis, accentuating the significance of both tumor cells and the surrounding stroma in metastatic propensity. In summary, this review highlights the intricate interdependence between CRC cells and their microenvironment, providing valuable insights into prospective therapeutic approaches targeting tumor-stroma interactions.

Neutrophils are the most abundant immune cells and make up about 70% of white blood cells in human blood and play a critical role as the first line of defense in the innate immune response. They also help regulate the inflammatory environment to promote tissue repair. However, in cancer, neutrophils can be manipulated by tumors to either promote or hinder tumor growth depending on the cytokine pool. Studies have shown that tumor-bearing mice have increased levels of neutrophils in peripheral circulation, and that neutrophil-derived exosomes can deliver various cargos, including lncRNA and miRNA, which contribute to tumor growth and degradation of extracellular matrix. Exosomes derived from immune cells generally possess anti-tumor activities and induce tumor-cell apoptosis by delivering cytotoxic proteins, ROS generation, H2O2 or activation of Fas-mediated apoptosis in target cells. Engineered exosome-like nanovesicles have been developed to deliver chemotherapeutic drugs precisely to tumor cells. However, tumor-derived exosomes can aggravate cancer-associated thrombosis through the formation of neutrophil extracellular traps. Despite the advancements in neutrophil-related research, a detailed understanding of tumor-neutrophil crosstalk is still lacking and remains a major barrier in developing neutrophil-based or targeted therapy. This review will focus on the communication pathways between tumors and neutrophils, and the role of neutrophil-derived exosomes (NDEs) in tumor growth. Additionally, potential strategies to manipulate NDEs for therapeutic purposes will be discussed.

Immune checkpoint inhibition therapy (ICIT) is an emerging field in oncology especially opening new horizons to chemotherapy refractory patients. This paper provides deep insight into immune related adverse events (irAEs) posing a major challenge and drawback to ICIT, and presents right management strategies for very complex complications. Moreover, for the first time in literature, a non-linear mathematical model is introduced to measure the ICIT success rate and to decide about the optimum ICIT duration. Furthermore, a strategy is presented to overcome or to delay the progression after initial good response in a subset of patients.

MicroRNAs (miRNAs) are single-stranded, noncoding RNA molecules that regulate gene expression post-transcriptionally by binding to messenger RNAs. miRNAs are important regulators of gene expression, and their dysregulation is implicated in many human and dog diseases. Most cancers tested, to date, have been shown to express altered miRNA levels, which indicates their potential importance in the oncogenic process. Based on this evidence, numerous miRNAs have been suggested as potential cancer biomarkers for both diagnosis and prognosis. miRNA-based therapies have also been tested in different cancers and have provided measurable clinical benefits to patients. In addition, understanding miRNA biogenesis and regulatory mechanisms in cancer can provide important knowledge about resistance to chemotherapies, leading to more personalized cancer treatment. In this review, we have comprehensively summarized the importance of miRNA in human and dog cancer research. We have discussed the current state of development and potential for miRNA as both a diagnostic marker and a therapeutic target.

Liquid biopsy has been developed to diagnose and monitor cancer. Despite the recent advances in investigating early cancer detection and diagnosis strategies, there is still a lack of improvements in capturing (CTCs). To archive this, we developed an efficient CTC detection system by integrating gold nanoparticles and a microfluidic platform, which can achieve CTC capture within 120 min. The microdevice was functionalized by immobilizing antibodies specific to the target cells. The method was tested with spiked tumor cells in whole human blood with three pancreatic cancer cell lines and compared with purified cancer cells suspended in a phosphate buffer solution. Our results captured pancreatic cancer cells spiked in blood samples with efficiency (90±3.2)% and were used to isolate CTCs from patients with metastatic pancreatic cancer. This methodology will enable the production of functionalized, patterned surfaces that interact with tumor cells, enhancing the selective capture of CTCs from biological assays.

Brain tumors are abnormal cells growth in the brain tissues that can be cancerous, or not. In any case, they could be a very aggressive disease that should be detected as early as possible. Usually, magnetic resonance imaging (MRI) is the main tool commonly adopted by neurologists and radiologists to identify and classify any possible anomalies present in the brain anatomy. In the present work, an automatic unsupervised method called Z2-$\gamma$, based on the use of adaptive finite-elements and suitable pre-processing and post-processing techniques, is introduced. In particular, the proposed methodology is able to automatically classify whether a given MR image represents a healthy or a diseased brain and in this latter case, is able to locate the tumor area.

Extensive growth in the volume of irregular brain cells is known as brain tumor. Human brain is surrounded by stiff skull. There are various issues that occur due to the growth of any tumor inside this restricted space. The malignant and benign are two main categories of the brain tumor. The skull is pressurized to enlarge from inside in case of growth of any benign or malignant tumor. This tumor leads to harm in brain and it may be dangerous to life also. The brain tumor is divided into two kinds - primary or secondary. The brain tumor detection techniques have various phases. In this paper, comparative study of CNN with GLCM approach and superpixel based spectral clustering is done tumor. This work takes into account metrics like accuracy, sensitivity and specificity for drawing the comparison between both the techniques.

Segmentation of brain tumor images is a major research topic in medical imaging to have a refined detection and understanding of abnormal masses in the brain. This paper proposes a new segmentation method, consisting of three main steps, to detect brain lesions using magnetic resonance imaging (MRI). In the first step, the parts of the image delineating the skull bone are removed to exclude insignificant data. In the second step, which is the main contribution of this study, the particle swarm optimization (PSO) technique is applied to detect the block that contains the brain lesions. The fitness function, used to determine the best block among all candidate blocks, is based on a two-way fixed-effects analysis of variance (ANOVA). In the last step of the algorithm, the K-means segmentation method is used in the lesion block to classify it as tumor or not. A thorough evaluation of the proposed algorithm is performed using the MRI database provided by the Kouba imaging center in Algiers, Algeria. Estimates of the selected fitness function are first compared to those based on the sum-of-absolute-differences (SAD) dissimilarity criterion and demonstrate the efficiency and robustness of the ANOVA. The performance of the optimized brain tumor segmentation algorithm is then compared to the results of several state-of-the-art techniques, including fuzzy C-means, K-means, Otsu thresholding, local thresholding, and watershed segmentation. The results obtained using Dice coefficient, Jaccard distance, correlation coefficient, and root mean square error (RMSE) measurements demonstrate the superiority of the proposed optimized segmentation algorithm over equivalent techniques.

The development of a fast and accurate intraoperative method that enables the differentiation and stratification of cancerous lesions is still a challenging problem in laboratory medicine. Therefore, it is important to find and optimize a simple and effective analytical method that enables the selection of distinctive metabolites. This study aims to assess the usefulness of solid-phase microextraction (SPME) probes as a sampling method for the lipidomic analysis of brain tumors. To this end, SPME was applied to sample brain tumors immediately after excision, followed by lipidomic analysis via liquid chromatography-high resolution mass spectrometry (LC-HRMS). The results showed that long fibers were a good option for extracting analytes from an entire lesion to obtain an average lipidomic profile. Moreover, significant differences between tumors of different histological origin were observed. In-depth investigation of the glioma samples revealed that malignancy grade and isocitrate dehydrogenase (IDH) mutation status impact the lipidomic composition of the tumor, whereas 1p/19q co-deletion did not appear to alter the lipid profile. This first on-site lipidomic analysis of intact tumors proved that chemical biopsy with SPME is a promising tool for the simple and fast extraction of lipid markers in neurooncology.

Liquid biopsy via isolation of circulating tumour cells (CTCs) represents a promising diagnostic tool capable of supplementing state-of-the-art for prostate cancer (PC) prognosis. Unfortunately, most of CTC technologies, such as AdnaTest or Cellsearch, critically rely on the Epithelial-Cell-Adhesion-Molecule (EpCAM) marker, limiting the possibility of detecting stem-like cells (CSCs) and mesenchymal-like cells (EMT-CTCs) that are present during PC progression. In this tontext, dielectrophoresis (DEP) is an epCAM independent, label-free, enrichment system, separating rare cells simply on the basis of their specific electrical properties. As compared to other technollgies, DEP represents a superior technique in terms of running costs, cells yield and specificity, but due to its higher complexity, requires still further technical as well as clinical development. Interestingly, DEP can be improved by the use of microfluid, nanostructured materials and fluoroimaging in order to increase its potential applications. In the context of PC, the utility of DEP can be translated in its capacity to detect CTC in the bloodstream in their epithelial, mesenchymal, or epithelial-mesenchymal phenotypes, which should be taken into account when choosing CTC enrichment and analysis methods for PC prognosis and early diagnosis.

Metastasis is the leading cause of cancer death and can be realized through the phenomenon of tumor cell fusion. The fusion of tumor cells with other tumor or normal cells leads to the appearance of tumor hybrid cells (THCs) exhibiting novel properties such as increased proliferation and migration, drug resistance, decreased apoptosis rate and avoiding immune surveillance. Experimental studies showed the association of THCs with a high frequency of cancer metastasis; however, the underlying mechanisms remain unclear. Many other questions also remain to be answered: the role of genetic alterations in tumor cell fusion, the molecular landscape of cells after fusion, the lifetime and fate of different THCs, and the specific markers of THCs, and their correlation with various cancers and clinicopathological parameters. In this review, we discuss the factors and potential mechanisms involved in the occurrence of THCs, the types of THCs, and their role in cancer drug resistance and metastasis, as well as potential therapeutic approaches for the prevention and targeting of tumor cell fusion. In conclusion, we emphasize the current knowledge gaps in the biology of THCs that should be addressed to develop highly effective therapeutics and strategies for metastasis suppression.

Background/Aim: Uterine leiomyoma, also known as fibroids, is the most common benign neoplasm of the female genital tract. Leiomyoma, including its subtypes, is the most common uterine tumor. The subtypes account for approximately 10% of leiomyomas. Intravenous leiomyomatosis, a uterine leiomyoma subtype, is an intravascular growth of benign smooth muscle cells, occasionally with pelvic or extrapelvic extension. Uterine leiomyosarcoma, a malignant tumor, tends to metastasize hematogenously, and distant metastasis to the lungs and liver is common. Therefore, this intravenous leiomyomatosis’ oncological features resemble those of the malignant tumor uterine leiomyosarcoma. Cancer stem cells migrate to distant organs via intravascular infiltration, leading to micrometastases. Materials and Methods: We examined the oncological properties of intravenous leiomyomatosis using molecular pathological techniques on tissue excised from patients with uterine leiomyoma. Result: CD44-positive mesenchymal tumor stem-like cells were detected in both intravenous leiomyomatosis and uterine leiomyosarcoma. The oncological nature of intravenous leiomyomatosis was found to be similar to the oncological properties of uterine leiomyosarcoma. However, in intravenous leiomyomatosis, Cyclin E and Ki-67-positive cells were rare, and no pathological findings suspected to be malignant were observed. Conclusion: It is expected that establishing a treatment method targeting cancer stem cells will lead to the treatment of malignant tumors with a low risk of recurrence and metastasis.

: Increased glucose and choline uptake are hallmarks of cancer. We investigated if the uptake and conversion of [2H9]choline alone and together with that of [6,6’ 2H2]glucose can be assessed in subcutaneous tumors by deuterium metabolic imaging (DMI) after bolus administration of these compounds. Therefore tumors with human renal carcinoma cells were grown subcutaneously in mice up to ~0.5 cm3. Mice were anesthetized with isoflurane and IV infused in the MR magnet for ~20 sec with ~0.2 ml solutions containing either [2H9]choline (0.05g/kg) alone or together with [6,6’ 2H2]glucose (1.3g/kg). 2H MR was performed on a 11.7T MR system with a home-built 2H/1H coil using a 900 excitation pulse and 400ms repetition time. 3D DMI was recorded at high resolution (2x2x2mm) in 37 min or at low resolution (3.7x3.7x3.7mm) in 2:24 min. Absolute tissue concentrations were calculate assuming initial [HOD]=13.7mM. Within 5 minutes after [2H9]choline infusion its signal appeared in tumor spectra representing concentration increasing up to 0.3–1.2 mM and then slowly decreased or remained constant over 100 minutes. In plasma [2H9]choline disappeared within 15 minutes post-infusion implying that its tumor signal arises from tissue and not blood. After infusing a mixture of [2H9]choline and [6,6’ 2H2]glucose their signals were observed separately in tumor 2H spectra. Over time the [2H9]choline signal broadened, possibly due to conversion to other choline compounds, [[6,6’ 2H2]glucose] declined, [HOD] increased and a lactate signal appeared, reflecting glycolysis. Metabolic maps of all 2H compounds were reconstructed from high resolution DMIs. As choline infusion and glucose DMI is feasible in patients, their simultaneous detection has clinical potential for tumor characterization.

Breast cancer, although the most frequently diagnosed malignant tumour in humans, has a less clear aetiology compared to other frequent cancer types. Mouse-mammary tumour virus (MMTV) is involved in breast cancer in mice and dogs and might play a role in the aetiology of some breast cancers in humans, since it has been identified in 20-40% of breast cancer samples in Western Europe, USA, Australia and some other parts of the world population. The purpose of our study was to identify MMTV DNA sequences in breast tissue samples from breast cancer patients operated in our regional centre from Romania. We have selected 75 patients with non-metastatic breast cancer treated with curative intent and searched with PCR the MMTV-like DNA sequence in the breast cancer tissue and normal breast tissue obtained from the same patients. Since none of the examined samples was positive for MMTV-like target sequences on PCR we could not prove that MMTV plays a role in the aetiology of breast cancer in our patient group. This finding is similar to publications of other geographically related research groups and might be due to the fact that only the Mus musculus domesticus mouse species was proven to carry infectious MMTV, but not the Mus musculus musculus species, which is specific to South-Eastern Europe (including Romania) and some parts of Asia.

Tumor microenvironment (TME) represents a complex network between tumor cells and a variety of components including immune, stromal and vascular endothelial cells as well as extracellular matrix. A wide panel of signals and interactions here take place, resulting in a bi-directional modulation of cellular functions. Many stimuli, on one hand, induce tumor growth and spread of metastatic cells and, on the other hand, contribute to the establishment of an immunosuppressive environment. The latter feature is achieved by soothing immune effector cells, mainly cytotoxic T lymphocytes, B and NK cells, and/or through expansion of regulatory cell populations, including regulatory T and B cells, tumor-associated macrophages and myeloid-derived suppressor cells. In this context, immune checkpoints (IC) are key players in the control of T cell activation and anti-cancer activities, leading to the inhibition of tumor cell lysis and of pro-inflammatory cytokine production. Thus, these pathways represent promising targets for the development of effective and innovative therapies both in adults and childhood. Here we address the role of different cell populations homing the TME and of well-known and recently characterized IC in the context of pediatric solid tumors. We also discuss preclinical and clinical data available using IC inhibitors alone, in combination each other or administered with standard therapies.

Proper and timely segregation of cellular genome is an important and a prime requirement of all cell division programmes. Mis-segregation of chromosomes and resulting aneuploidy leads to several clinical consequences. Over the years, shugoshin emerges as a key protein factor involved in the segregation of genetic material in dividing cells. Deletion or altered level of shugoshin is reported in several human malignancies, as a result, shugoshin now emerges as an important tumour associated gene and a possible target for cancer therapy. Apart from the role in cancer, recent studies also showed the involvement of shugoshin in several other clinical disorders. Through this review, we tried to highlight the clinical relevance of shugoshin.

In the last few decades, the dynamics of tumor cells and their growths are presented via clinical, experimental, and theoretical approaches, which leads to the development of the new idea of multiple cancer therapies to control and reduce the death rate for earlier detection. In this paper, we discussed the dynamics of tumor cell growth and its treatment process. We analyzed some simple mathematical models and generalized the study to understand the growth of tumor cells. The main proposed model is a system of ordinary differential equations which combines interactions among natural killer cells, dendritic cells and cytotoxic CD8+ T cells. The model is solved numerically to explain how the tumor cells spread and become more dangerous as well as the treatment process of cancer. It is also studied that how the cell behaves in the presence of different therapy and drugs. The optimal control of chemotherapy has been discussed. It has also been explained how much the model is effective in reducing tumor cells over time. Finally, a couple of spatially distributed models are discussed for tumor cell growth.

The lymphocyte function–associated antigen-1 (LFA-1) (also CD11a/CD18 and αLβ2), is just one of many integrins in the human body, but its significance derives from its exclusive presence in leukocytes. In this review, we summarize the studies relating LFA-1 and its major ligand ICAM-1 (CD54) with cancer, through the function of lymphocytes and myeloid cells on tumor cells. We consider how LFA-1 mediates the interaction of leukocytes with tumors and the role of ICAM-1 in tumor dynamics, which can be independent of its interaction with LFA-1. A more detailed examination of LFA’s role within B-cell chronic lymphocytic leukemia is made. Finally, we discuss the role of LFA-1-harboring exosomes in tumor growth and metastasis.

MicroRNAs (miRNAs) are a kind of conserved small non-coding RNAs that participate in regulating gene expression by targeting multiple molecules. Early studies have shown that the expression of miRNAs changes significantly in different tumor tissues and cancer cell lines. It is well acknowledged that such variation is involved in almost all biological processes, including cell proliferation, mobility, survival and differentiation. Increasing experimental data indicate that miRNA dysregulation is a biomarker of several pathological conditions including cancer, and that miRNA can exert a causal role, as oncogenes or tumor suppressor genes, in different steps of the tumorigenic process. Anticancer therapies based on miRNAs are currently being developed with a goal to improve outcomes of cancer treatment. In our present study, we review the function of miRNAs in tumorigenesis and development, and discuss the latest clinical applications and strategies of therapy targeting miRNAs in cancer.

An emerging picture in cancer biology is that, paradoxically, chemotherapy can actively induce changes that favor cancer progression. These pro-cancer changes can be either inside (intrinsic) or outside (extrinsic) the cancer cells. In this review, we will discuss the extrinsic pro-cancer effect of chemotherapy; that is, the effect of chemotherapy on the non-cancer host cells to promote cancer progression. We will focus on metastasis, and will first discuss recent data from mouse models of breast cancer. Intriguingly, despite reducing the size of primary tumors, chemotherapy changes the tumor microenvironment, resulting in an increased escape of cancer cells into the blood stream. Furthermore, chemotherapry changes the tissue microenvironment at the distant sites, making it more hospitable to cancer cells upon their arrival. We will then discuss the idea and evidence that these devastating pro-metastatic effects of chemotherapy can be explained in the context of stress response. At the end, we will discuss the potential relevance of these mouse data to human breast cancer and their implication on chemotherapy in the clinic.

Alkaloids are the most diversified nitrogen-containing secondary metabolites having antioxi-dant, and antimicrobial properties and are extensively used in pharmaceuticals to treat different types of cancer. Nicotiana serves as a reservoir of anticancer alkaloids and is also used as a model plant for the de novo synthesis of various anti-cancer molecules through genetic engineering. Up to 4% of the total dry weight of Nicotiana was found to be composed of alkaloids where nicotine, nornicotine, anatabine, and anabasine are reported as the dominant alkaloids. And, among the alkaloids present in Nicotiana, β-carboline (Harmane and Norharmane), Kynurenines are found to show anti-tumor effects, especially in the case of colon and breast cancer. Creating new or shunting of existing biosynthesis pathways in different species of Nicotiana resulted in de novo or increased synthesis of different anti-tumor molecules or their derivatives or precursors includ-ing Taxadiane (~22.5 µg/g), Artemisinin (~120 μg/g), Parthenolide (~2.05 ng/g), Costunolide (~60 ng/g), Etoposide (~1 mg/g), Crocin (~400 µg/g), Catharanthine (~60 ng/g), Tabersonine (~10 ng/g), Strictosidine (~0.23 mg/g), etc. Enrich precursor pool especially Dimethylallyl Diphos-phate (DMAPP) and down-regulating of other bi-product pathways, compartmentalization or metabolic shunting, or organelle-specific reconstitution of the precursor pool might trigger the enhanced accumulation of the targeted anticancer alkaloid in Nicotiana.

Background: About 10% of Wilms Tumor (WT) patients have a malformation or cancer predisposition syndrome (CPS) with causative germline genetic or epigenetic variants. Knowledge on CPS is essential for genetic counselling. Methods: This retrospective analysis focused on 2927 consecutive patients with WTs registered between 1989 and 2017 in the SIOP/GPOH studies. Results: (GU, N=66, 2,3%), Beckwith-Wiedemann spectrum (BWS, N=32, 1,1%), isolated hemihypertrophy (IHH, N=29, 1,0%), Denys-Drash syndrome (DDS, N=24, 0,8%) and WAGR syndrome (N=20, 0,7%) were reported most frequently. Compared to others, these patients were younger at WT diagnosis (median age 24,5 months vs. 39,0 months), had smaller tumors (334,8mL vs. 496,9mL), less often metastasis (8,2% vs. 18%), but more often nephroblastomatosis (12,9% vs. 1,9%). WT with IHH was associated with blastemal WT and DDS with stromal subtype. Bilateral WTs were common in WAGR (30%), DDS (29%) and BWS (31%). Chemotherapy induced reduction in tumor volume was poor in DDS (7,7% increase) and favorable in BWS (84,6% reduction). The event-free survival (EFS) of patients with BWS was significantly (p=0,002) worse than in others. Conclusions: CPS should be considered in WTs with specific clinical features resulting in referral to a geneticist. Their outcome was not always favorable.

Meningioma (MGM) is the most common type of intracranial tumor in adults. The validation of novel prognostic biomarkers to better inform tumor stratification and clinical prognosis is urgently needed. Many molecular and cellular alterations have been described in MGM tumors over the past few years, providing a rational basis for the identification of biomarkers and therapeutic targets. The role of receptor tyrosine kinase (RTKs), including those of the ErbB family of receptors, as oncogenes has been well established in several cancer types. Here, we review histological, molecular, and clinical evidence suggesting that RTKs, including the epidermal growth factor receptor (EGFR, ErbB 1), as well as other members of the ErbB family, may be useful as biomarkers in MGM.

Several treatment guidelines for sporadic, nonmetastatic nonfunctioning neuroendocrine tumors of the pancreas (NF-pNETs) have recommended resection, however, tumors ≤ 2 cm do not necessarily need surgery. This study aimed to establish a surgical treatment plan for NF-pNETs ≤ 2 cm. From 2000 to 2017, 483 patients who underwent resection for NF-pNETs ≤ 2cm in 18 institutions from Korea and China were enrolled and their medical records were reviewed. Median age was 56 (range 16- 80) years. The 10-year overall survival rate (10Y-OS) and recurrence-free survival rate (10Y-RFS) were 89.8 and 93.1%, respectively. In multivariable analysis, tumor size (> 1.5cm; p = 0.001) and nodal metastasis (p = 0.013) were independent adverse prognostic factors for OS. Perineural invasion (p = 0.008) and high Ki-67 index (≥3%; p < 0.001) were independent prognostic factors for poor RFS. NF-pNETs ≤ 2 cm showed unfavorable prognosis after resection when the tumor was larger than 1.5cm, Ki-67 index ≥ 3%, or nodal metastasis was present. NF-pNET patients with tumors ≤ 1.5cm can be observed if the preoperative Ki-67 index is under 3%, and if nodal metastasis is not suspected in preoperative radiologic studies. These findings support the clinical use to make decision about small NF-pNETs.

In this paper, we propose methods for brain tumor detection in MRI images based on ensemble learning. We build upon prior research on ensemble methods by testing the concatenation of pre-trained models: features extracted via transfer learning are merged and segmented by classification algorithms or a stacked ensemble of those algorithms. The proposed approach achieved accuracy scores of 0.98 , outperforming a benchmark VGG-16 model. Considerations to granular computing are given in the paper as well.

A surgical microscope is large in size, which makes it impossible to be portable. The distance between the surgical microscope and the observation tissue is 15–30 cm, and the adjustment range of the right and left of the camera is a maximum of 30°. Therefore, the surgical microscope is generated attenuation (above 58%) of irradiation optical source owing to the long working distance. Moreover, the observation of tissue is affected because of dazzling by ambient light as the optical source power is strong (55 to 160 mW/cm2). Further, observation blind spot phenomena will occur due to the limitations in adjusting the right and left of the camera. Therefore, it is difficult to clearly observe the tumor. In this study, a compact pen-type probe with a portable surgical microscope is presented. The proposed surgical microscope comprises a small and portable pen-type probe that can adjust the working distance between the probe and the observed tissue. In addition, it allows the adjustment of the viewing angle and fluorescence brightness. The proposed probe has no blind spots or optical density loss.

A surgical microscope is large in size, making portability impossible. The distance between the surgical microscope and the observation tissue is 15 to 30 cm, while the maximum adjustment range of the camera to the right and left is 30°. Therefore, surgical microscopes cause attenuation (above 58%) of the irradiation optical source owing to the long working distance. Moreover, the observation of tissue was dazzled with ambient light because the optical power source was strong (50 to 160 mW/cm2). Owing to the limited ability to adjust the camera to the right and left, a blind spot occurs with a surgical microscope. Therefore, it is difficult to clearly observe a tumor. In this study, a compact pen-type probe with a portable surgical microscope is proposed. The pen-type probe is small with a portable shape, and is capable of adjusting the working distance between itself and the observed tissue. It is also possible to adjust the viewing angle and fluorescence brightness. The proposed pen-type probe has no blind spots or optical density loss.

The heterogeneity of tumor infiltrating lymphocytes is not well characterized in brain metastasis. To address this, we performed a targeted analysis of immune cell subsets in brain metastasis tissues to test which immunosuppressive routes are involved in brain metastasis. We performed multiplex immunofluorescence (mIF), using commercially available validated antibodies on twenty formalin-fixed paraffin embedded whole sections. We quantitated the subsets of immune cells utilizing a targeted panel of proteins including PanCK, CD8, CD4, VISTA and Iba1, and analyzed an average of 15000 cells per sample. We classified tumours as either high (>30%) or low (<30%) tumour infiltrating lymphocytes (TILs) and found that increased TILs density correlated with survival. We next sought out to phenotype these TILs using mIF. The tumours with low TILs (n=9) had significantly higher expression of the immune-checkpoint molecule VISTA in tumor cells (p<0.01) as well as in their microenvironment (p<0.001). Contrastingly, the brain metastatic tumours with high TILs (n=8) displayed higher levels of activated microglia, as measured by Iba1 expression. Low TILs-tumours displayed CD8+ T-cells that co-express VISTA (p<0.01) significantly more compared to high TILs group, where CD8+ T-cells significantly co-express Iba1 (p<0.05). Interestingly, no definite phenotypes of CD4+ subsets were observed. These results were supported by RNA analysis of a publicly available, independent cohort. In conclusion, our work contributes to a growing understanding of the immune surveillance escape routes active in brain metastasis.

Several studies have suggested that pre and/or postdiagnosis physical activity can reduce the risk of recurrence in breast cancer patients, however its effect according to follow-up time has not yet been investigated. We analyzed recurrence and mortality dynamics in randomized clinical trials (RCTs) from Australia and Canada. The combined Australian RCTs evaluated, at median follow-up of 8.3 years, an 8-month pragmatic exercise intervention in 337 women with newly diagnosed breast cancer, while the Canadian RCT evaluated, at median follow-up of 7.4 years, supervised aerobic or resistance exercise during chemotherapy in 242 patients. For each RCT, the control arm consisted of patients undergoing usual care. We estimated the event dynamics by the discrete hazard function, through flexible regression of yearly conditional event probabilities with generalized additive models. In the considered RCTs, the recurrence and mortality risk of patients enrolled in the physical activity arm was stably reduced at medium/long term after five year of follow-up. In the Australian RCTs where patients were recruited by urban versus rural area, the latter group did not display benefit from physical activity. Estimated Odds Ratios (95% Confidence Intervals) for Disease Free Survival (DFS) in urban women were 0.63 (0.22-1.85); 0.27 (0.079-0.90); 0.11 (0.013-0.96) at the 3rd, 5th and 7th year of follow-up, respectively. For rural women, DFS patterns were overlapping with ORs approximating 1 at the different years of follow-up. Although not reaching statistical evidence, the estimates in the Canadian trial were in line with the results from the Australian urban women with ORs (95% CI) forDFS of 0.70 (0.33-1.50); 0.47 (0.19-1.18); 0.32 (0.077-1.29) at 3rd, 5th, 7th follow-up year, respectively. While we acknowledge that the analyzed RCTs were not designed for investigating disease recurrence over time, these results support the evidence that physical activity reduces the risk of developing medium/long-term metastases. Additional translational research is needed to clarify the mechanisms underlying these observations.

In the present era, infertility is one of the major issues which restricts many couples to have their own kids. Infertility is the inability to achieve a clinical pregnancy after regular unprotected sexual intercourse for the period of one year or more. Various factors including defective male or female germ cell development, unhealthy and improper lifestyles, diseases like cancer and associated chemo-or-radiation therapies, congenital disorders etc. may be responsible for infertility. Therefore, it is highly important to understand the basic concepts of germ cell development including primordial germ cell (PGC) formation, specification, migration, entry to genital ridges and their molecular mechanisms, activated pathways, paracrine and autocrine signaling, along with possible alteration which can hamper germ cell development and can cause adversities like cancer progression and infertility. Knowing all these aspects in a proper way can be very much helpful in improving our understanding about gametogenesis and finding possible ways to cure related disorders. Here in this review, various aspects of gametogenesis especially female gametes and relevant factors causing functional impairment have been thoroughly discussed.

There are many theories of carcinogenesis arguing against the orthodox mutation theory, debating on such as “epigenetic alteration” that is inheritable and yet, theoretically, reversible. Our integrated theory describes that any extracellular, intracellular, or intranuclear stressors, mutagenic or not, can initiate a lengthy tumorigenesis to engender a benign or malignant tumor, but the aberrations directly establishing cellular immortality and autonomy may be epigenetic or genetic alterations in the genomic DNA. A neoplasm is considered a semi-new organism with autonomy; it therefore should have genetic mutations to be “new”. We may be able to direct cancer cells towards differentiation as a remedy, because the extracellular milieu may control the phenotype of a cell and the tissue or organ made of the cell’s progenies, and the cytoplasm of a cell may override the nucleus in the phenotypic control. However, the nucleus retains the capacity to manifest itself if allowed by the microenvironment, which then allows the already reversed cells to revert back to tumor cells again. Neoplasms are malignant if they bear epigenetic or genetic anomalies in mutator genes defined as those whose alterations allow or accelerate alterations to occur in other genes, whereas neoplasms are benign if they bear epigenetic or genetic aberrations only in non-mutator genes. It is imperative to identify the immediate tumor-causing cellular alterations defined as those directly responsible for immortality and autonomy, and for treatment purposes to identify the extracellular and intracellular factors that control the phenotype of cancer cells.

Stem cells are currently being used in many clinical trials for regenerative purposes. These are promising results for stem cells in the treatment of several diseases, including cancer. Nevertheless, there are still many variables which should be addressed before the application of stem cells for cancer treatment. One approach should be to establish well-characterized therapeutic stem cell banks to minimize the variation in results from different clinical trials and facilitate their effective use in basic and translational research.

Silencing of tumor suppressor genes (TSGs) by DNA promoter hypermethylation is an earlyevent in carcinogenesis; Hence TSGs may serve as early tumor biomarkers. We determinedthe promoter methylation levels of p16INK4a, RASSF1A, TIMP3 and PCQAP/MED15 TSGs in salivary DNA from oral cancer (OC), and oropharyngeal cancer (OPC) patients, using methylation specific PCR coupled with densitometry analysis. We assessed the association between DNA methylation of individual TSGs with OC and OPC risk factors. We evaluated the performance and the clinical validity of this quadruple methylation marker panel in discriminating OC and OPC patients from healthy controls using CombiROC web tool. Our study reported that RASSF1A, TIMP3 and PCQAP/MED15 TSGs were significantly hypermethylated in OC and OPC cases compared to healthy controls. We found that DNA methylation levels of TSGs were significantly augmented by smoking, alcohol use and betel quid chewing by indicating that the fact that frequent exposure to risk factors may drive oral and oropharyngeal carcinogenesis through TSG promoter hypermethylation. Also, this quadruple-methylation marker panel of p16INK4a, RASSF1A, TIMP3 and PCQAP/MED15 TSGs demonstrated excellent diagnostic accuracy in the early detection of OC at 91.7% sensitivity and 92.3% specificity, and OPC at 99.8% sensitivity and 92.1% specificity, from healthy controls.

Development of novel anti-cancer peptides requires a rapid screening process which can be accelerated by using appropriate in vitro tumor models. Breast carcinoma tissue is a three dimensional (3D) microenvironment, which contains a hypoxic center surrounded by dense proliferative tissue. Biochemical clues provided by such 3D cell mass cannot be recapitulated in conventional 2D culture systems. In this experiment, we evaluate the efficacy of the sandalwood peptide, cyclosaplin on established in vitro 3D silk breast cancer model using invasive MDA-MB-231 cell line. The anti-proliferative effect of the peptide on 3D silk tumor model is monitored by alamar blue assay, with conventional 2D culture as control. The proliferation rate, glucose consumed, LDH, and MMP-9 activity of Human breast cancer cells are higher in 3D constructs compared to 2D. A higher concentration of drug is required to achieve 50% cell death in 3D culture than 2D cultures. The cyclosaplin treated MDA-MB-231 cells showed significant decrease in MMP-9 activity in 3D constructs. Microscopic analysis revealed the formation of cell clusters evenly distributed in the scaffolds. The drug treated cells were less in number, smaller and showed unusual morphology. Overall, these findings indicate the role of cyclosaplin as a promising anti-cancer therapeutics.

In the present study, we have systematically examined the clinical significance of Nectin-4 (encoded by the PVRL-4 gene), a marker for breast cancer stem cells (CSCs), in cancer metastasis and angiogenesis using a variety of human specimens, including invasive duct carcinoma (IDC) with multiple grades, several types of primary tumors to local and distant relapses, lymph node metastases and circulating tumor cells (CTCs). Nectin-4 was overexpressed in more than 92% of samples with 65.2% Nectin-4 positive cells. The level of expression was increased with increasing tumor grade (GI-III) and size (T1-4) of IDC specimens. More induction of Nectin-4 was noted in relapsed samples from a variety of tumors (colon, tongue, liver, kidney, ovary, buccal mucosa) in comparison to primary tumors, while paired adjacent normal tissues do not express any Nectin-4. A high expression of Nectin-4 along with other representative markers in CTCs and lymph node metastasis was also observed in cancer specimens. An increased level of Nectin-4 along with representative metastatic (CD-44, Sca1, ALDH1, Nanog) and angiogenic (Ang-I, Ang-II, VEGF) markers was noted in metastatic tumors (local and distant) in comparison to primary tumors that were correlated with different grades of tumor progression. In addition, greater expression of Nectin-4 was observed in secondary tumors (distant metastasis, e.g., breast to liver or stomach to gallbladder) in comparison to primary tumors. Nectin-4 was overexpressed at all stages of metastasis and angiogenesis, thus appearing to play a major role in tumor relapse through the PI3K-Akt-NFκβ pathway.