Cancer is a complex and devastating disease that has engaged scientists and researchers for decades. Despite tremendous efforts, previous hypotheses about cancer development have not achieved significant breakthroughs. Evolutionary Cancer Cell Biology (ECCB) is a novel and emerging branch of oncological science that provides an evolutionary perspective on the origin of cancer. It reveals that the cancer genome evolved hundreds of millions of years ago, long before multicellular organisms such as metazoans and humans emerged. ECCB aims to unify all evolutionary insights, hypotheses, and theories into a cohesive framework. It investigates the intricate relationship between cancer genomics and ancient pre-metazoan genes that emerge when normal cells transform into cancer cells. It challenges the conventional wisdom of cancer research by suggesting that cancer could arise through intrinsic cellular mechanisms without genetic alterations and mutations. Furthermore, it postulates that somatic mutations are only secondary, downstream events in the process of oncogenesis.

The evolutionary cancer cell biology ECCB explains the deep homology existent between the life cycle of cancer and protists. Due to their origin and sensitivity to oxygen, all non-gametogenic germ lines and germ stem cells (GSCs), including human adult stem cells (ASCs) and cancer stem cells (CSCs), suffer severe DNADSB damage when exposed to stress oxygen content above 6.0% O2 (Urgermline hyperoxia) as occurring in tissue and bloodstream. As a result, GSCs/ASCs/ CSCs lose their stemness potential and convert from a functional asymmetric cyclic phenotype (ACD phenotype) to a dysfunctional symmetric phenotype capable of defective symmetric proliferation (DSCD) that is, however, unable to repair genomic degradation. Genome reconstruction occurs through evolutionary mechanisms evolved by the common ancestor of amoebozoans, metazoans, and fungi. They complete the cycle by removing the damage, reconstructing the functional genome, and reinstating the ASC phenotype. The stemness life cycle acts not only during carcinogenesis, tumorigenesis, and recurrence but also in the life cycle of protists.

Recent successes in the field of evolutionary cancer cell biology (ECCB) have brought to a head two of the most important controversies regarding cancer origin. The first concerns the question of whether carcinogenesis is initiated only by genetic alterations, mutations, and driver genes, as the mutational theory teaches. The ECCB, claims that a large number of polyploidy-related cancers (PGCC cancers) are not due to mutations, but rather to inadequate ancient repair mechanisms used by DNA-damaged stem cells for their repair. Somatic mutations are merely secondary. The second controversy, described in the previous article, concerns the non-mutational theory itself: Are non-mutational polyploid cancers an atavism - as previously thought - or rather the effect of an ancient gene regulatory network aGRN that controls genome reprogramming in precancerous DNA-damaged cells as well in the transformed cells. Finally, the unicellular gene module of cancer, of which the aGRN is a part, has evolved along with the multicellular genome during the last 1000 My of evolution. and non-mutated cancer cell systems are under the control of the aGRN. The atavistic theory relies on phylostratigraphic evidence to determine the age of cancer genes. It states that most cancer-like genes arose during the transition period from unicellularity to multicellularity, but also during the early metazoan era. In our opinion, the atavistic theory is flawed and suffers from many misunderstandings. It provides little insight into the origin and coevolution of the cancer cell system and its control by the ancient gene regulatory network aGRN.

Evolutionary Cancer Cell Biology (ECCB) reveals that the majority of cancer hallmarks trace their origins back to the premetazoic era, approximately 2300 to 1750 million years ago. These cancer hallmarks share deep homology with the oxygen-sensitive non-gametogenic NG (Urgermline), which evolved from the common ancestor of Amoebozoan, Metazoan, and Fungi (AMF). The genes, gene modules, and gene regulatory networks of the premetazoic cell system are preserved in the ancestral genome compartment of metazoans and humans. The Urgermline serves as a blueprint for all germ and stem cell lineages, including parasitic amoebae. As observed in amoebae, DNA double-strand breaks (DSBs) manifest in the homologous recombination (HR) genes of NG germlines and stem cell lineages when exposed to specific hyperoxic conditions, referred to as AMF hyperoxia, characterized by an oxygen content exceeding 6.0%. The cells lose their stemness and differentiation potential but persist in proliferation as low-grade polyploids (4n) through defective symmetric cell division (DSCD phenotype). Genomic integrity can be restored through homotypic cell and nuclear fusion, resulting in the formation of high-grade polyploids known as multinuclear genome repair syncytia (MGRSs), or by inductive hyperpolyploidization of more than 64n, as observed in single-celled polyploid giant cancer cells (PGCCs). Interestingly, low-, middle-, and high-grade polyploidization are not exclusive to cancer. Therefore, we investigate (i) functional polyploidies that occur in healthy cells, including humans, mammals, and protists, (ii) dysfunctional polyploidies that occur in cells with impaired homologous recombination (HR) and irreparable DNA DSB defects, and (iii) the restoration of genome integrity through cyst-like and high-grade polyploidization events. Additionally, we explore dysfunction in aging stem cells, hepatocytes, and cardiomyocytes