Understanding cancer from an evolutionary perspective: high-risk reprogramming of genome-damaged stem cells

Abstract

Background: One of the most astounding discoveries of recent times is the recognition that cancer embodies a transition from a higher level of metazoan cell organization to a more foundational premetazoic state. This shift is steered by genes housed within the ancestral genome compartment, pervasive across all metazoan genomes, encompassing humans, and governed by a premetazoic ancestral gene regulatory network. This work aims to highlight the emerging field of evolutionary cancer cell biology (ECCB), which points to the deep homology between cancer and protist life cycles tracing back to the common ancestor of amoebozoans, metazoans, and fungi (AMF). The ECCB analysis reveals the essence of the non-gametogenic germline of the AMF ancestor, which serves as a blueprint for all metazoan germlines and stem cell lineages and controls the life cycle of cancer. Every germ and stem cell lineage of humans and metazoans traces its lineage back to this Urgermline, transmitting crucial processes such as asymmetric cell cycling, differentiation, stemness, and phenomena like germ-to-soma GST and soma-to-germ transition (aka epithelial-mesenchymal transition EMT and MET) to their subsequent evolutionary descendants. Oxygen-sensitive germline and stem cells suffer DNA doublestrand breaks due to stress and oxygen ranges reminiscent of ancestral hyperoxia, leading to cell senescence. Cells that can overcome senescence can proliferate as defective symmetric cell division, paving the way for malignancy and polyploid giant cancer cell cancers. Conclusions: Understanding cancer from its evolutionary origins may help break some of the logjams in cancer prevention and open up new therapeutic pathways.

The enigma of cancer polyploidy as deciphered by evolutionary cancer stem cell biology (ECCB)

“…Human DSCDs can enter a state of transient quiescence or slow cycling within their niche. However, they can exit the quiescence niche and continue to proliferate through aberrant symmetric cell cycles [9][10][11]. Environmental changes inside the niche or exposure to more oxygenated regions can induce increased proliferation, causing DSCD progeny to become fusible and form cell aggregates (MGRS).…”

“…Thus, DNA damage repair and genome reprogramming proceed in a unicellular manner under the control of the ancient gene regulatory network (aGRN) that transforms the precancerous high-risk tetraploid DSCD phenotype into a cancerous asymmetric cell division (ACD) phenotype, with stemness, differentiation potential, and the ability to initiate germ and soma (G+S) life cycles of pre-metazoan imprinting. The NG germline of cancer contains all the hallmarks of the ancestral Urgermline, producing naive CSCs as GSCs [9][10][11].…”

“…At least 90% of undifferentiated colorectal carcinoma and glioblastoma have polyploid giant cancer cells (PGCCs) as genome repair structures [12]. PGCCs are responsible for oncogenic transformation and the generation of CSCs [10].…”

“…Evolutionary cancer cell biology (ECCB), recently introduced as a significant advancement in the field of carcinogenic and tumorigenic cancer cell biology [9][10][11]13], is based on the recognition that human cancer represents a shift to a lower level of cell organization that evolved hundreds of millions of years ago in the common ancestor of amoebozoan, metazoan, and fungi (AMF). Amoebozoa has recently been classified within the stable Amorphea group and recognized as one of the eight eukaryotic supergroups [14].…”

The Enigma of Cancer Polyploidy as Deciphered by Evolutionary Cancer Cell Biology (ECCB)

“…In tumors, metastases, and recurrences, PGCCs function as mechanisms for genome repair (reprogramming) and serve as reproductive entities for the generation of CSCs. 10. PGCCs serve as an overarching term encompassing hyperpolyploidization through both cell and nuclear fusion (MGRS-like) and defective lower polyploidization processes such as tetraploidization and aneuploidization.…”