Life Entrapped in a Network of Atavistic Attractors: How to Find a Rescue

Abstract

In view of unified cell bioenergetics, cell bioenergetic problems related to cell overenergization can cause excessive disturbances in current cell fate and, as a result, lead to a change of cell-fate. At the onset of the problem, cell overenergization of multicellular organisms (especially overenergization of mitochondria) is solved inter alia by activation and then stimulation of the reversible Crabtree effect by cells. Unfortunately, this apparently good solution can also lead to a much bigger problem when, despite the activation of the Crabtree effect, cell overenergization persists for a long time. In such a case, cancer transformation, along with the Warburg effect, may occur to further reduce or stop the charging of mitochondria by high-energy molecules. Understanding the phenomena of cancer transformation and cancer development has become a real challenge for humanity. To date, many models have been developed to understand cancer-related mechanisms. Nowadays, combining all these models into one coherent universal model of cancer transformation and development can be considered a new challenge. In this light, the aim of this article is to present such a potentially universal model supported by a proposed new model of cellular functionality evolution. The methods of fighting cancer resulting from unified cell bioenergetics and the two presented models are also considered.

What Are the Reasons for Continuing Failures in Cancer Therapy? Are Misleading/Inappropriate Preclinical Assays to Be Blamed? Might Some Modern Therapies Cause More Harm than Benefit?

“…The mechanisms underlying the creation of increasingly aggressive “monsters” are multifactorial, extremely complex, but fairly well studied (as was briefly discussed in Section 2 ). These include the interplay between various manifestations of genome chaos (e.g., chromothripsis, polyploidy, multinucleation, micronucleation) [ 122 ], repeated loss of synchronization between circadian rhythms and cell cycle regulation [ 123 , 124 ], and reversal of cancer cells to an atavistic form of life, resulting in activation of resistance genes [ 54 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 ].…”

“…The blog was posted in 2014, and presented a dispute between two accomplished oncologists, Frank Arguello (Cd Juárez, Chih, Mexico; former Senior Scientist, Division of Cancer Treatment & Diagnosis, National Cancer Institute, NIH, Frederick, MD, USA) and David Gorski (Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA), on the atavistic model of cancer [ 134 ]. (Since 2014 there has been significant progress in this field of research; see, e.g., [ 54 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 ]). What we found particularly fascinating in this blog concerns the life expectancy of patients with a given solid tumor nearly a century ago as compared to that in the modern era.…”

Polyploidy and Myc Proto-Oncogenes Promote Stress Adaptation via Epigenetic Plasticity and Gene Regulatory Network Rewiring

“…Under normoxia, polyploidy is usually accompanied by enhanced glycolysis, glutaminolysis, hypertranscription, active protein synthesis, and ribosome biogenesis, which are also manifestations of embryonality [ 2 , 6 , 71 , 79 , 186 , 187 ]. All these features of metabostemness have also been described in endopolyploid cells of Drosophila in development and wound healing, in cancer polyploid cells, and in cells of normal mammalian tissues [ 7 , 57 , 178 , 184 , 188 ].…”

“…Similarly to pluripotent stem cells, polyploid cells can simultaneously derive energy from pathways that are incompatible with differentiated cells, promoting adaptation to stress associated with energy deprivation [ 49 , 72 , 176 , 177 , 178 , 179 , 180 , 181 , 182 ]. Recent data obtained from polyploid cells from normal tissues of animals and plants, various tumors, and yeasts indicate that these cells possess energetically flexible metabolism combining glycolysis glutaminolysis and oxidative phosphorylation [ 43 , 57 , 72 , 183 , 184 , 185 ]. Thus, in addition to stem cells, polyploid cells can adjust their energy metabolism to the environment, which is impossible for differentiated cells.…”

“…Ploidy-associated cell protection from DNA instability is provided by additional genomes buffering DNA damage and by an efficient but error-prone DNA repair system, which is a characteristic of unicellular organisms [ 214 , 215 ]. Additional energy is provided by the activation of pathways of glycolysis, glutaminolysis, and NADH production, as well as by the induction of Warburg and Crabtree effects [ 72 , 183 , 184 , 185 ]. All three features enabling rapid identification of attractors are also related to ancient, unicellular organisms, confirming a tight link between polyploidy and recapitulation of evolutionarily ancient programs [ 200 , 201 ].…”