Resolution of Complex Issues in Genome Regulation and Cancer Requires Non-Linear and Network-Based Thermodynamics

Abstract

The apparent lack of success in curing cancer that was evidenced in the last four decades of molecular medicine indicates the need for a global re-thinking both its nature and the biological approaches that we are taking in its solution. The reductionist, one gene/one protein method that has served us well until now, and that still dominates in biomedicine, requires complementation with a more systemic/holistic approach, to address the huge problem of cross-talk between more than 20,000 protein-coding genes, about 100,000 protein types, and the multiple layers of biological organization. In this perspective, the relationship between the chromatin network organization and gene expression regulation plays a fundamental role. The elucidation of such a relationship requires a non-linear thermodynamics approach to these biological systems. This change of perspective is a necessary step for developing successful 'tumour-reversion' therapeutic strategies.

Cellular Responses to Platinum-Based Anticancer Drugs and UVC: Role of p53 and Implications for Cancer Therapy

“…Despite such complexities, as recently pointed out by White-Gilbertson and Voelkel-Johnson [142], the field of cancer cell dormancy (e.g., through formation of PGCCs) "is at an exciting moment, when bench-to-bedside research has the potential to make a difference in the lives of many cancer patients." For those who are interested in further reading, we suggest seminal/recent papers on reversible cancer cell polyploidy and senescence [87,88,95,99,100,104,118,142,143] that were discussed herein as well as papers on related topics such as therapy-induced autophagy [95,144,145] and genome chaos/micronucleation [146][147][148] that were beyond the scope of the current review.…”

The Role of the Meiotic Component in Reproduction of B-RAF-Mutated Melanoma: A Review and “Brainstorming” Session

“…The naturally occurring tumors are found already in Hydra [223]. When the organisms were challenged by extinction, they have adapted to it by transient polyploidy, epigenetic plasticity, including pluripotent stemness with its bivalency of genes, intrinsically disordered proteins, and rearrangement of the nuclear architecture domains by phase transitionsthese epigenetic adaptations are by two orders faster than the gene mutationselection-based process would allow [224]. In accord, the expression of stemness genes, early stress response genes, epigenetic master activator CTCFL/BORIS and in particular, CT antigens genes as universal adaptors for reconstruction of the genome functional network-all these epigenetic evolutionary adaptations are found in melanoma, which are highly mortal-risky and treatment resistant in patients.…”

“…At the same time, the tumor pathways are rare evolutionary attractors of the genome multi-dimensional network [225], entrapping cancer cells by the therapy resistance-only a small number of cells, but inevitably survive and repopulate the tumors [56,177]. These rare genome space states can be only chosen by the mechanisms of nonequilibrium thermodynamics, which is by coherating fluctuations, through the method of trial and error [224,226]. Those are inevitably accompanied by a lot of cell death and a lot of aberrant phenotypes, which may persist as transient or axillary to reproductive cancer cell line.…”

Complexity in Biological Organization: Deconstruction (and Subsequent Restating) of Key Concepts

“…The same topology, which gives rise to the same network properties, can result from infinite collections of different elements. Therefore, there is a level of causality and explanation that is purely relational in nature and that does not refer to the objects involved in it [ 39 ]. This means that in organized complex systems, the construction of the networks is neither casual nor arbitrary.…”