Hypothesis about Transdifferentiation As Backbone of Malignancy

Abstract

Background: Cancer is mainly watched through the prism of random mutations and related corruption of signaling pathways. However, it would seem puzzling to explain the tumor organization, pugnacity and steady evolution of the tumorous disease and, moreover, a systematic ascendancy over the healthy tissues, only through stochastic genomic alterations.Malignancy specific properties: Considering the core characteristics of cancer cells, it appears that two major sets of properties are emerging, corresponding to wellidentified physiological phenotypes, i.e., (1) the trophoblastic logistical functions for cell survival, protection, expansion, migration, and host-tissue conditioning for angiogenesis and immune tolerance and (2) the sexual functions for genome maintenance. To explain the resurgence of these trophoblastic and sexual phenotypes, a particular cell reprogramming, to be called "malignant transdifferentiation" in view of its key role in the precancer-to-cancer shift, appears to be a convincing hypothesis.perspectives: The concept of malignant transdifferentiation, in addition to oncogenic mutations, would determine a more rational approach of oncogenesis and would open so far unexplored ways of therapeutic actions. Indeed, the trophoblastic phenotype would be a good candidate for therapeutic purposes because, on the one hand, it covers numerous properties that all are vital for the tumor, and on the other hand, it can be targeted with potentially no risk of affecting the healthy tissues as it is not expressed there after birth.

Tumor cells generate astrocyte-like cells that contribute to SHH-driven medulloblastoma relapse

“…We used Ptch1 -deficient mice (including Ptch1 +/− and Math1-Cre / Ptch1 fl/fl ) that develop MB with no P53 mutations, whereas Ptch1 +/− , P53 −/− mice were used in the study of the Zong group. P53 deficiency could promote the dedifferentiation or transdifferentiation of tumor cells as previously reported ( Piechowski, 2017 ; Rasmussen et al, 2014 ; Tapia and Schöler, 2010 ). Future studies are needed to investigate whether P53 mutations affect the cellular origins of TAs in human MB.…”

<p>Plausibility of trophoblastic-like regulation of cancer tissue</p>

“…A model of cancer development and resilience, matching these features, has been proposed recently. 8 The perennial, necessary element is a stem-like cell (true stem cell, progenitor or uncommonly de-differentiated cell) with selfrenewal capacity. This type of cell can both continuously generate differentiated daughter cells through asymmetric divisions and participate to an extensive increase of the cell population through symmetric divisions.…”

“…This epigenetic reprogramming was called "malignant transdifferentiation" because, in parallel to save the unstable precancer cells it would constitute, in combination with the structural oncogenic genome alterations, the basis of malignancy. 8 Expression of the trophoblastic program is physiologically strictly forbidden after birth because it would determine ectopic, nonhomeostatic tissue implantation. Hence, acquisition of the trophoblastic logistic properties, normally dormant, would explain the invasive behavior of cancer cells and the distinctive hijacking, to their advantage, of the host tissue functions.…”

“…Both trophoblastic and cancer cells have a comprehensive set of pro-survival functions devoted to fast growth of "semiforeign" cells, including: [8][9][10][11][12] • Autocrine growth factors enabling an autonomous growth inside the host organism; • Metabolism with adaptive enzymatic pathways ensuring an optimal balance between synthesis of cell components and energy production whatever the oxygen tension. Aerobic glycolysis 13 (the "Warburg effect") is a distinctive option consisting in nonmitochondrial, oxygen-free ATP production despite normoxic conditions, when the glucose metabolites are mainly used for biosynthesis purposes.…”

The Contributions of Cancer-Testis and Developmental Genes to the Pathogenesis of Keratinocyte Carcinomas

“…Activation of genes that are commonly restricted to prenatal development, including embryonic stem cell and fetal genes, is a hallmark of cancer cell de-differentiation to progenitor-like states and signifies differentiation impairment [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. When lineage-specific genes are expressed ectopically, trans-differentiation to an alternative cell lineage may be observed [ 6 , 7 , 8 , 9 , 10 , 11 ]. Additionally, the functions of ectopically-expressed genes may be recaptured in malignant contexts [ 12 , 13 ].…”