The Origin of Tumor Cell Heterogeneity

The main problems with cancers are: (1) they seem to have unlimited division potential; and (2) they display intra-tumor heterogeneity. We discuss three different hypotheses that attempt to explain the origin and continuous growth of tumors: (a) the clonal evolution (CE) hypothesis, (b) the cancer stem cell (CSC) hypothesis, and (c) the neosis paradigm of carcinogenesis (NPC). The CE hypothesis assumes that any cell with defective DNA can give rise to cancer cell by mitosis and when this abnormal cell proliferates, it accumulates random additional mutations and the dominant clone will be selected against others. According to the CSC hypothesis, only tissue-specific stem cells or adult stem cells (ASCs) or the progenitor cells with mutation (the CSCs) can initiate the tumor growth. It was assumed that like stem cells, the CSCs have unlimited division potential and that by asymmetric mitosis, CSCs give rise to one CSC and the other cell undergoes transit amplification and defective differentiation to form tumor tissue contributing to tumor cell heterogeneity. Like normal differentiated cells, tumor cell do not have the potential to divide and therefore do not have the capacity to form tumors. From the beginning, the CSC hypothesis was plagued by the possible isolation method-induced artifacts, which have turned out to be true according recent reports. Both the CE and CSC hypotheses do not explain the mode of origin of heterogeneity and of the evolution of malignancy. NPC hypothesis is based on video documentation and the fact that senescence is a tumor suppressor mechanism. The cells defective in the senescent checkpoint pathway escape senescence induced mitotic catastrophe via neosis by suppressing spindle checkpoint and executing karyokinesis by nuclear budding to yield Tumor Initiating Raju Cells (TIRCs), with transient progenitor stem cell-like properties. The neosis mother cell dies after yielding several Raju cells. Video documentation proves that cancer cells are mortal and when they reach senescence, they escape death due to transformation via neosis, thus producing the next generation of Tumor Repopulating Raju Cells (TRRCs). Exposure of cancer cells to genotoxins induce premature senescence and senescent cells escape cell death via neosis by yielding resistant offspring. Neosis executes epigenetic genome modulation via Epithelial- Mesenchymal Transition (EMT), and the tumor cells go through several EMTs and the reverse process of Mesenchymal-Epithelial Transitions during growth. This explains the mode of introduction of heterogeneity in the tumor cell population, which is subject to natural selection. The NPC incorporates the transient stem cell properties in Raju cells, which, at the end of their extended symmetric, MLS, will repeat the cycle of polyploidization followed by EMT executed by neosis yielding diploid (near diploid or aneuploid) cell population of TRRCs, again and again. The scientific community is neglecting this mode of cell division to the peril of humanity.