Cell of Origin in Cancer

The present work substantiates the atavistic hypothesis of cancer and considers that cancer initiation starts from a mitotic- blocked precursor cell (protoprecur-sor) that escape death by a process of polyploidisation/ depolyploidisation analogous to the encystment/ excystment process of invasive pathogenic amoebae. The protoprecursor cell down regulates its multicelular genes, up regulating unicellular gene networks of the dark genome; it primes a carcinogenic immortal self sufficient stem and progenitor cell lineage (caSPCL) developed and controlled by basic mechanisms of the common eukaryotic ancestor. The primitive cancer life cycle contains reproductive cyst-like structures (aCLS, PGCCs) protected by a more or less characteristic envelope. aCLS’s microcell progeny forms an atavistic stem cell line capable to convert in two antagonistic sublines: one is the neotic more hypoxic aCLS+ progenitor subline that differentiates multiple generations of reproductive aCLSs by asymmetric cell division, and the other is the more oxygenic vegetative/ somatic aCLS-/siCLS+ subline that do not form aCLSs in cultures however, may express differentiation potential in conditions of stress and genotoxic insults forming stress induced siCLS respectively gCLS. In primitive eukaryotes such as invasive, pathogenic amoebae, progenitor sublines for cycling encystment may transdifferentiate to further vegetative/ somatic sublines; vegetative sublines and clones may change the genotype. We redefine neosis as the atavistic reproductive life cycle of cancer that forms microcells (aCLS progeny) capable of stemness and caSPCL renewal. The aCLS+ subline is the neotic/carcinogenic subline: it generates the atavistic family of stem and progenitor cells (aCSCs). 

Keywords:  cancer, neosis, atavistic stemness, primitive cell lineages, Entamoeba, genotoxic agents, DNA repair

At least 1/3 of all acquired solid cancers produce unusual cyst-like structures  (CLSs , PGCCs) with simultaneous loss of p53 function. However, p53 deficiency or accumulated mutations are not the causes of aCLS cancers. The cause is the reversal to unicellularity of a metabolic stressed cell by activating silenced transition switches and ancestral gene networks inherited from early Metazoans. After reprogramming and transformation the cell-of-origin of cancer bypasses mitosis and forms the polyploid pCLS, the homemade pathogen of aCLS cancers. pCLS's daughter cells (microcells) generate the pretumorigenic cancer stem cell pool (pCSCs) that start in turn the unicellular cancer cell lineage containing reproductive and somatic sublines. While the reproductive subline gives rise to new autonomous aCLSs by asymmetric division and cyclic differentiation, the somatic subline grows aCLS free.  In the course of cancer evolution, some of the somatic mutants convert to stem cell precursors (SCPs). Somatic SCPs transfer part of somatic mutations and epimutations to the genome of newly formed reproductive clones. In this way, subsequent generations of tumorigenic and metastatic CSCs are being produced. aCLS cancer development is neither chaotic nor deregulated it follows unicellular development patterns. The unicellular program is controlled by mechanisms from early eukaryotic evolution.

Prolongation of ovarian epithelial cancer survival depends on early detection or improved responses to chemotherapy. Gains in either have been modest at best. Understanding the diverse pathogenesis of this disease is critical to early intervention or prevention. This review addresses six important variables, including (i) cell of origin, (ii) site of origin, (iii) initial genotoxic events, (iv) risks imposed by hereditary and other promoting conditions, (v) subsequent factors that promote different patterns of metastatic spread, and (vi) prospects for intervention. This review proposes two distinct pathways to pelvic epithelial cancer. The first initiates in ovarian surface epithelium (OSE), Mullerian inclusions or endometriosis in the ovary. The second arises from the endosalpinx and encompasses a subset of serous carcinomas. The serous carcinogenic sequence in the distal fallopian tube is described and contrasted with lower grade serous tumors based on tumour location, earliest genetic change and ability (or lack of) to undergo terminal (ciliated) differentiation. Ultimately, a clear understanding of tumour origin and the mechanism(s) leading to the earliest phases of the serous and endometrioid carcinogenic sequences may hold the greatest promise for designing prevention strategies and/or developing new therapies.

The present work proposes a single-cell development model for cancer based on recent insights into protist germ and stem cell biology and the analogy of the two
systems. Germ stem cells (GSCs) were produced in cancer by a germline of unicellular imprinting that performs reproductive aCLS cycles consisting of self-renewing
progenitor cells, committed aCLS precursor cells, aCLS polyploid cells (mother cells) and daughter germ stem cells, inherits stemness from one cell generation to
the next. The highlights of this theory are:
1. The cell-of-origin of cancer activates an ancient silent single-cell genome, which can differentiate germ and soma of unicellular imprinting;
2. Germline and soma cell have differential stress resistance (DSR);
3. Hyperoxia damages the germline, which loses the ability to perform reproductive aCLS cycles and GSCs (loss-of-function), but not the proliferation capacity;
4. DNA damage signalling cells of the defective germline induce an EMT-like soma-to-germ cell transition (SGT) that increases the fitness of the CSC pool;
5. The hyperoxic damaged genome must be repaired by multinucleated genome repair structures (MGRSs) better known as “pre-existing” PGCCs;
6. Germline evolution occurs by alternating normoxic and hyperoxic damaged phenotypes; genome reorganization increases the fitness and invasiveness of CSCs;
7. Genotoxically induced PGCCs are not identical to “pre-existing” PGCCs.