On the role of polyploid giant cells in oncogenesis and tumorigenesis.

This correspondence is in response to the commentary by Jinsong Liu ( https://doi.org/10.1007/s12032-023-02038-1 ) to my article "The evolutionary cancer gene network theory versus embryogenic hypotheses" published in Medical Oncology (40:114, 2023). Liu's commentary engages head-on with the evolutionary cancer genome theory and defends his more histopathologically-embryogenically oriented theory of 2020. The dispute revolves, among other things, around the role of polyploid giant MGRS/PGCCs structures in oncogenesis and tumorigenesis.

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

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.

aCLS cancers: Genomic and epigenetic changes transform the cell of origin of cancer into a tumorigenic pathogen of unicellular organization and lifestyle.

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.

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.

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.

Growth of Entamoeba invadens in sediments with metabolically repressed bacteria leads to multicellularity and redefinition of the amoebic cell system.

Extracellular signaling and mechanisms of cell differentiation in Entamoeba are misunderstood. The main reason is the popular use of axenic media, which do not correspond to the natural habitats of Entamoeba. The axenic environment lacks the exogenous activators and repressors provided by natural habitats. Absent bacterial commensals understanding of the development of the amoebic cell system remains deficient. The present Aa(Sm) culture method using mixed sediments of antibiotically repressed Aerobacter aerogens and amoebae was developed to model in vitro extracellular signaling that induce multicellularity in cultures of E. invadens. Repressed oxygen consuming sediment bacteria supply E. invadens the hypoxic environment needed for differentiation and development. The amoebae themselves alter the environment by consuming the bacteria by phagocytosis thus reversing hypoxia. Exogenous activators are in this manner down regulated and suppressed. This feedback effect controls amoebic development and differentiation. Co-existing cell types and cell fractions with different life spans and cell cycle length could be identified. Aa(Sm) long term cultures contain continuous and non-continuous self renewing cell lines producing quiescent and terminally differentiated daughter cells (precysts) by asymmetric division. This culturing method helps to understand the intimate relationship between hypoxic environments and the multicellular behaviour of E. invadens and the interrelations existing between the distinct cell types.