The reproductive life cycle of cancer: Hypotheses of cell of origin, TP53 drivers and stem cell conversions in the light of the atavistic cancer cell theory

Abstract

Polyploid giant cancer cells (PGCCs) found in different solid cancers are reproductive cyst-like structures surrounded by an actin envelop. They give rise by hyper-polyploidisation to numerous progeny (microcells, neotic cells) that start a primitive multi-lined lineage and generate subsequent PGCCs by asymmetric cell division and cyclic differentiation. This cancer cell life cycle has multiple similarities with the life cycle of lower eukaryotes (protists) substantiating the atavistic theory of cancer. The primitive cancer life cycle contains several cell types including primary cancer stem cells, somatic cells, as well as reproductive cells, that differentiate new atavistic cyst like structures (aCLSs, PGCCs). Accordingly, cancer stem cells are not transformed normal stem cells (hSCs). Similarities between CSCs and normal hSCs arise from the evolutionary common origin of primitive eukaryotes and more highly evolved eukaryotic cells (stemness evolution). The cell of origin of cancer, as postulated here is a deregulated human cell that has lost, not only relevant control mechanisms and mitotic capacity, but also its normal human p53 network becoming useless for the atavistic life cycle. We believe that this protoprecursor of cancer reactivates an ancient primitive TP53 network originating from the common eukaryotic ancestor. This atavistic p53 helpes to repair genotoxic DNA damages of reproductive cancer cells including CSCs but not DNA damages of somatic cancer cells exposed to genotoxic stress.