Prelude and premise to the special issue: disruption of homeostasis-induced signaling and crosstalk in the carcinogenesis paradigm “Epistemology of the origin of cancer”

Abstract

The vast majority of anticancer strategies are symptomatic but in order to achieve some tangible progress, we need to identify the cause(s) of the majority of cancers. There is a kind of zeitgeist that findings in genetics, namely somatic mutations, are reflexively viewed as being causative for carcinogenesis, although some 80% of all cancers are presently termed “sporadic” (i.e., with no proven cause). The observation that one inch of cancerous liver tissue can have more than 100 000 000 mutations and an identical mutation can result in different phenotypes, depending on the environment surrounding that mutation, makes it very unlikely that mutations by themselves are causative of most cancers. 4open debuts its Special Issue series with papers that provide strong evidence that carcinogenesis consists of a 6-step sequence (1) a pathogenic stimulus followed by (2) chronic inflammation from which develops (3) fibrosis with associated remodeling of the extracellular microenvironment, and from these changes a (4) precancerous niche (PCN), a product of fibrosis with remodeling by persistent inflammation develops which triggers the deployment of (5) a chronic stress escape strategy and when this fails to be resolved it results in (6) the normal cell to cancerous cell transition. This Special Issue contains separate papers discussing undervalued ubiquitous proteins, chronic inflammation, eicosanoids, microbiome and morbid obesity, PCN, cell transition, followed by altered signaling induced by Metformin, NF-κB signaling and crosstalk during carcinogenesis, and a brief synopsis. In essence, the available evidence, both in vitro and in vivo, lends credence to the proposition that the majority of cancers occur from a disruption of homeostasis-induced signaling and crosstalk in the carcinogenesis paradigm “Epistemology of the origin of cancer”.

Synopsis: Special Issue on “Disruption of signaling homeostasis induced crosstalk in the carcinogenesis paradigmEpistemology of the origin of cancer”

“…Despite the need to be cautious in evaluating these findings, they together with the extensive discussions published here [111,113,[144][145][146][147][148][149][150], provide evidence that a much more nuanced view on carcinogenesis is needed. The sixstep sequence is much more plausible than a mono-causal carcinogenesis paradigm.…”

“…However, we acknowledge that the complexity of various sequences and specific conditions that must be considered [113].…”

“…As reviewed [113], Warburg and Cori observed that lactic acid is produced by cancer cells from the activation of anaerobic glycolysis [114][115][116][117][118]. To better understand how this led to a postulation that the majority of cancers would develop from anaerobic glycolysis we need to take a step back.…”

“…Warburg and Cori's observations were significant to our understanding of biology. However, glycolysis is "known to be common among developing or regenerating tissues, whether normal or neoplastic, and the tricarboxylic acid (TCA) cycle to be basically intact in neoplastic tissues" ( [142] reviewed in [113]).…”

“…This Special Issue "Disruption of signaling homeostasis induced crosstalk in the carcinogenesis paradigm 'Epistemology of the origin of cancer' " [111,113,[144][145][146][147][148][149][150] provides evidence that the six-step sequence [5,6] of events explains carcinogenesis for some 80% of all cancers. This sequences include (1) a pathogenic stimulus followed by (2) chronic inflammation, from which develops (3) fibrosis with associated remodeling in the cellular microenvironment.…”