Molecular and Cell Biological Considerations in the Initiation and Development of Sporadic Non-Hereditary Solid Cancers

This paper reviews the state of cancer research in the post-mutation era. It presents cancer as a highly complex disease viewed differently by scientists from various research fields. Histopathologists considered cancer as a disease of cell differentiation, cancer cell biologists overestimated the causal role of accumulated DNA mutations. More recently molecular biologists have focused on driver genes and driver mutations, regulatory gene networks and deregulation of the genomic balance between unicellular and multicellular gene sets (UG/MG balance). From a developmental biological standpoint, there is a clear analogy between the reproductive life cycles of cancer and protists. The key player of both analogous life cycles is the polyploid cyst, the atavistic cyst-like structure aCLS (PGCC). In the analogy to protists, we assume that the first aCLS initiating cancer originates from a mitoticly blocked cell (cell of origin of cancer, protoprecursor) that escapes death entering an atavistic reproductive process of polyploidisation and depolyploidisation; it forms the atavistic cyst-like structure aCLS and numerous daughter cells (microcells). The microcell progeny develops a multi-lined cell lineage containing stem cells as well as somatic and reproductive cells and clones. Subsequent aCLSs are formed sequentially by committed daughter cells or occasionally by stressed somatic cells. Accordingly, cancer initiation occurs by genomic changes leading to the amitotic cell state and reactivation of an atavistic life cycle. In humans, atavistic life cycles and hyperpolyploidisation (n >16) are mostly repressed by stable gene regulatory networks – but not in cancer. The permanent UG/MG gene conflict and robust ancient surveillance mechanisms trigger a cascade of molecular lesions leading to genomic heterogeneity and aberrant cancer cell states. DOI : 10.14302/issn.2572-3030.jcgb-18-2183 Corresponding author: Vladimir F. Niculescu, Cell Biologist, Germany, Kirschenweg 1, 86420 Diedorf, Email: vladimir.niculescu@yahoo.com


Introduction
The origin of cancer is not definitively understood. In the past histopathologists understand cancer as a disease of progressive cell dedifferentiation.
Later, DNA mutations were thought to be the cause of cancer and cancer was regarded as a genetic disease caused by acquired or parental mutations. The discovery of cancer stem cells later led to the assumption that a deregulated normal human stem cell (hSC) generates spontaneously CSCs that give rise to tumors. More recently, molecular biologists understand cancer as a disease associated with regulatory changes of non coding DNA sequences [1][2][3][4] however, it is still not clear whether mutations are causes or rather consequences of cancer. The number of mutated genes identified in cancer increased in the meantime to about 2% of the human genome [5]. In 2007 Erenpreisa and Craig [13] introduced the term cancer life cycle as an evolutionary conserved cycle of life, analogous to the life cycles of certain unicellular organisms, supporting the older statements of Sundaram et al. [14] and Rajaraman et al [15] from 2004/2006 that rightly consider stemness as a cyclic property afforded by depolyploidisation of cysts-like structures, later named aCLSs [16][17][18] or PGCCs [19][20][21][22][23]. variants (a/TP53) [24,25]. Switching to primitive a/TP53 variants such as Ehp53 of amoebae [26] and Dp53 of Drosopihla [27] could explain why "mutated" TP53 of cancer repairs in a Dp53 manner only DNA damages of the reproductive cells but not the genotoxic DNA damage occurring in irradiated somatic cells.

Aberrant Cell Phenotypes in Tumors
Histopathologists still differentiate between well-differentiated low-grade tumors -early stages of cancer whose cells look almost normal -and poorly or undifferentiated tumors (late cancer stages) whose   cell into a cancer cell [77].

Specific Cancer Driver Modules
Previously efforts were made to detect genes with significantly higher mutation rates [81,91] namely gene mutations that are enough to perturb a relevant genetic pathway [92,93]. Since it is known that genes with driver mutations work together in regulatory pathways [92,94] researchers believe that searching driver modules (driver gene sets) will lead to a better understanding of carcinogenesis at the pathway level. genomic sites that affect p53 suppression function [96].
Participants to the ENCODE project consider that 10-20% of the non-coding genome has a function that if disrupted, may be significantly perturb the cell [4]. In the light of these findings Polak et al. [97] consider cancer as a "regulatory and epigenetic program that is superimposed on a cell and the result is the development of genetic and genomic instability" In the last decade, cancer has been suggested to result from an atavistic process whereby the activation of primitive highly conserved programs lead to molecular phenotypes and population dynamics similar to unicellular organisms [56,[98][99][100]. Similarly it was suggested that the expression of highly conserved genes is a feature of drug resistance in tumor cells [101]. Trigos et al. [2] show patterns of co-expression between highly inter-connected cellular processes that are disrupted in tumors. The findings suggest that deeper understanding of the differences in the expression and regulation of ancient UC genes and more recently evolved MC genes will be crucial for uncovering the molecular basis of cancer initiation and providing of new therapeutic strategies.

Life Cycles in Cancer and Protists
Noone has observed directly the cell taking the PGCCs) whose role in the past was poorly understood.
We believe that the better understanding of ancient cell lineages conserved in protists may be helpful to understand the mechanisms of cancer initiation.

Hypoxic Stem Cells, Environmental Oxygen and Autonomous Cyclic Differentiation (ACD)
Briefly described, the life cycle of protists begins in the small intestine with cysts hatching and microcell dissemination [6]. The eight totipotent microcells In the course of the disease (amoebiasis), early somatic clones change to more invasive and virulent genotypes capable of invading the liver and other organs [16][17][18].

Differentiation Potential and Differentiation Switch (DS)
We believe that the decision of whether a cell commits for differentiation or not, or becomes a self-renewing pre-differentiated cell (such as MAS cells) depends on a molecular switches. We assume that

Cancer's Life Cycle and its Atavistic Stem Cell Family
The life cycle of cancer is quite similar. In recent

Concluding Remarks
Using the analogy with ancient reproductive life cycles and primitive protist SPCL lineages, we consider that cancer is triggered from a dysregulated mitotic cell blocked in a state of G1 or G0/G1 [6,7,12]