Cancer genes and cancer stem cells in tumorigenesis: Evolutionary deep homology and controversies

Abstract

In the past, contradictory statements have been made about the age of cancer genes. While phylostratigraphic studies suggest that cancer genes emerged during the transitional period from unicellularians (UC) to early metazoans (EM), life cycle studies suggest that they arose earlier. This controversy could not be resolved. Phylostratigraphic methods use data from somatic tumor gene collections containing or lacking polyploidy genes (PGCC genes) and compare them to genes from evolutionary node taxa. I analyze whether the selected taxa are suitable to resolve the above contradiction or not. Both cancer and amoebae life cycles have a reproductive asexual germline that produces germline stem cells (GSCs) and somatic cell lines that cannot. When the germline loses its reproductive function, the soma-to-germ transition forms a new reproductive germline. The reproductive polyploidy of cancer is homologous to the reproductive polyploidy of unicellular cysts. PGCCs repair DNA defects, reorganize the involved genome architecture and produce new GSCs. The present study refutes the dogma of the early metazoan origin of cancer. Cancer has a unicellular life cycle that was adopted by early metazoans to rescue themselves from evolutionary dead ends. Early metazoans controlled the unicellular life cycle through suppressor and anti-suppressor genes that could suspend or reactivate it. They are the archetypes of tumor suppressor genes and oncogenes. Cells of mammalians and humans that reach a similar impasse as early metazoans can reactivate the conserved life cycle of unicellularians.

Keywords: CSCs; Cancer; EMT; Entamoeba; Gene age; Life cycle; PGCC; Polyploidy.

Figure 1

Schematic universal tree updated from Forterre (2015) after Woese et al (1990). Amorpha is the last assemblage descended from the common ancestor LECA (Eukaria domain). It contains the three sister clades Amoebozoa, Metazoa, and Fungi. https://doi.org/10.3389/fmicb.2015.00717; CC BY 2015.

Figure 2

Amoeba model: the deep homologous germline of cancer (aCLS cycle). Under normoxic conditions, the cancer germline performs reproductive polyploid cycles to GSCs, which are the nascent cancer stem cells (CSCs).

Figure 3

Cancer germline evolution. The germline proliferates under both normoxic and hyperoxic living conditions. Under normoxic conditions and asymmetric cell division, the germline undergoes repetitive aCLS cycles by polyploidization (see Fig. 1). aCLS polyploidization is similar to the polyploidization that occurs in inner cyst cells of Entamoeba, which gives rise to multiple daughter cells and forms GSCs. CSCs are the homologous GSCs of cancer. The nascent GSCs/CSCs differentiate new germlines, clones, and somatic populations. Hyperoxia causes DNA DSB defects: The germline loses its reproductive function and stemness and ceases polyploidization and GSC/CSC production. The loss of function triggers soma-to-germ transition (SGT/EMT) and leads to new germlines or clones, and new sCSCs. Damaged germline cells can repair DNA defects and reorganize the genome integrity through multinucleated germline repair structures (MGRSs) or autonomous PGCCs not induced by therapeutics or radiation. pGSC, sGSC, tGSC: primary, secondary and tertiary CSCs. From: Niculescu.

Figure 4

Sponges architecture: choanocytes (red) and amoebocytes/archeocytes (green). From: Ruppert EE, Fox RS, Barnes RD. Invertebrate Zoology, ed. Brooks/Cole. p. 82. ISBN 978-0-03-025982-1 (https://en.wikipedia.org/wiki/Sponge).

Figure 5

Statistical analysis of the cancer datasets using the 19-phylostrata map. From: Domazet-Lošo and Tautz^, (http://www.biomedcentral.com/1741-7007/8/66). CC BY 3.0.

Figure 6

The percentual proportions of gene origins and distribution of bivalent genes (BVG) in the phylostratic tree of life (strata 1–16) and the effect of polyploidy on it and authors statement. The upregulation of bi-valent genes by polyploidy includes strata 1, 2 (unicellularians), stratum 4 (metazoa) and, prominently, stratum 5 (eumetazoa—the appearance of embryo, germ layer, and gastrulation). The phylostrata are as follows: 1—cellular organisms, 2—Eukaryota, 3—Opisthokonta, 4—Metazoa, 5—Eumetazoa, 6—Bilateria, 7—Chordata,8—Euteleostomi, 9—Amniota, 10—Mammalia, 11—Ttheria, 12—Eutheria, 13—Euarchontoglires, 14—Catarrhini, 15—Homininae. From: Anatskaya et al CC BY 4.0.