Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Targeting M2-TAM via STAT3/NF-kB/AKT Signaling Pathway With Oxaliplatin, Retinoic Acid, and Libidibia ferrea -Loaded Extracellular Vesicles From Macrophages 1 Down-Regulates Murine Colon Cancer Metastasis

Version 1 : Received: 24 May 2023 / Approved: 25 May 2023 / Online: 25 May 2023 (10:48:17 CEST)

How to cite: De Carvalho, T.G.; Lara, P.; Jorquera-Cordero, C.; Schomann, T.; Aragão, C.F.S.; Oliveira, A.D.S.; Garcia, V.B.; Souza, S.V.D.P.; Marques, I.D.L.; Lira Soares, L.A.; Guedes, P.M.D.M.; De Araújo-Júnior, R.F. Targeting M2-TAM via STAT3/NF-kB/AKT Signaling Pathway With Oxaliplatin, Retinoic Acid, and Libidibia ferrea -Loaded Extracellular Vesicles From Macrophages 1 Down-Regulates Murine Colon Cancer Metastasis. Preprints 2023, 2023051804. https://doi.org/10.20944/preprints202305.1804.v1 De Carvalho, T.G.; Lara, P.; Jorquera-Cordero, C.; Schomann, T.; Aragão, C.F.S.; Oliveira, A.D.S.; Garcia, V.B.; Souza, S.V.D.P.; Marques, I.D.L.; Lira Soares, L.A.; Guedes, P.M.D.M.; De Araújo-Júnior, R.F. Targeting M2-TAM via STAT3/NF-kB/AKT Signaling Pathway With Oxaliplatin, Retinoic Acid, and Libidibia ferrea -Loaded Extracellular Vesicles From Macrophages 1 Down-Regulates Murine Colon Cancer Metastasis. Preprints 2023, 2023051804. https://doi.org/10.20944/preprints202305.1804.v1

Abstract

Despite the numerous advances in target therapy for the treatment of colorectal cancer, aggressive colorectal cancer remains an incurable disease whose negative modulation of the immune system in the tumor microenvironment is still critical for improving the patient's prognosis. Extracellular vesicles (EVs) have received attention for their use as cell-membrane-camouflaged nanoparticles and drug delivery systems in nanomedicine derived by nearly all cell types for intercellular communication and regulation in the tumor microenvironment (TME). In this study, M1 Macrophage EVs (M1EVs) were used as nanocarriers of oxaliplatin (M1EV1) associated with retinoic acid (M1EV2) and Libidibia ferrea (M1EV3), or combined together with retinoic acid and Libidibia ferrea (M1EV4) to evaluate their antiproliferative and immunomodulatory potential on CT-26 and MC-38 colorectal cancer cell lines, as well as their capacity to prevent metastases in mouse models of colorectal cancer such as allographic and peritoneal. Tumors were evaluated by qRT-PCR and immunohistochemistry. The cell death profile and epithelial-mesenchymal transition process (EMT) were analyzed in vitro in colorectal cancer cell lines. Polarization of murine macrophages (RAW264.7 cells) was also carried out. M1EV2 and M1EV3 used alone or especially combined (M1EV4) downregulated the tumor progression by TME immunomodulation, leading to a decrease in primary tumor size and metastases in peritoneum, liver and lungs. STAT3, NF-kB and AKT were the major genes downregulated by systems of M1EVs. Tumor-associated macrophages (TAM) switched M2 phenotype (CD163) towards M1 (CD68) reducing levels of IL-10, TGF-β and CCL22. Furthermore, malignant cells showed overexpression of FADD, APAF-1, caspase-3, and E-cadherin, and decreased expression of MDR-1, survivin, vimentin, CXCR4, and PD-L1 after treatment with systems of M1EVs. The results obtained in this study provided evidence that EVs from M1 antitumor macrophages can transport drugs and increase their immunomodulatory and antitumor activity by stimulating activation or blockage of pathways involved in cell proliferation, migration, cell survival, and drug resistance processes.

Keywords

EVs; Macrophages 1; STAT3, AKT; NF-κB; metastasis; colorectal cancer.

Subject

Medicine and Pharmacology, Oncology and Oncogenics

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