Metformin alters signaling induced crosstalk and homeostasis in the carcinogenesis paradigm “Epistemology of the origin of cancer”

Abstract

The anti-hyperglycemic drug, Metformin, is effective in treating early stages of diabetes and has been associated with a 37% decrease in cancer incidence. While the precise mechanisms for the anti-cancer effects of Metformin remain to be elucidated, this review shows the multiplicity of its effects on interdicting signaling and crosstalk, anti-inflammatory effects and in restoring homeostasis, which, taken together, go beyond its well-known anti-hyperglycemic effect that serves as the basis for its use in type 2 diabetes. Metformin is much more than a one-trick pony. The recent discovery of several signaling pathways influenced by Metformin appears to have potential value in cancer therapy. Based on what we know at present, Metformin promotes beneficial effects attributed to its anti-inflammatory and anti-fibrotic effects largely demonstrated in vitro. Metformin activates or upregulates while it simultaneously inhibits or downregulates multiple signaling pathways of cell-cycle arrest and apoptosis accompanied by oxidative stress, which are in accordance with the 6-step sequence of carcinogenesis. Furthermore, in vivo studies in laboratory animals and in cancer patients are beginning to address the magnitude of the anti-cancer effects and delineate its anti-cancer effects. In this context, results from prior pancreatic and non-pancreatic cancer trials, which contained a significant proportion of the patient population treated with Metformin, will have to be reexamined in light of the observed anti-cancerous effects to gain additional insights. The detailed exploration of Metformin in the context of the “Disruption of signaling homeostasis induced crosstalk in the carcinogenesis paradigm Epistemology of the origin of cancer” can provide helpful insights into the anti-proliferative mechanisms and could play a relevant role in anti-cancer therapy in the future.

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.…”

“…The PCN promotes ongoing chronic cell matrix stress resulting in the normal cell-to-cancer cell transition [111]. This sequence is influenced by the microbiome [147], its modulation by Metformin [148] as well as the metabolism of eicosanoids [149] and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-jB) signaling [150] all of which have been described in considerable detail in this Special Issue.…”

“…This figure was published as original illustration in paper 3 of this Special Issue -Disruption of homeostasis-induced signaling and crosstalk in the carcinogenesis paradigm "Epistemology of the origin of cancer" entitled "Chronic inflammation evoked by pathogenic stimulus during carcinogenesis" [145]. Furthermore, we point out, that to the complexity of the content of the Special Issue the original and/or modified version of the original illustration was republished within the following papers of the Special Issue: paper 5 "Microbiome and morbid obesity increase pathogenic stimulus diversity" [147], paper 6 "Precancerous niche (PCN), a product of fibrosis with remodeling by incessant chronic inflammation" [146], paper 7 "Metformin alters signaling homeostasis" [148], paper 8 "Transition from normal to cancerous cell by precancerous niche (PCN) induced chronic cell-matrix stress" [111] and paper 9 "NF-kB signaling and crosstalk during carcinogenesis" [150]. Nomenclature Figure 1: The nomenclature common abbreviations are bold, followed by the common trivial names (if available) and (if available) by the name in accordance to the International Union of Pure and Applied Chemistry (IUPAC): metabolic pathway which the cells (ab)use it for membrane synthesis of cancer cells [265].…”

“…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.…”

NF-κB signaling and crosstalk during carcinogenesis

“…Metformin inhibits inflammatory response and malignant cell transformation [387]. It also inhibits NF-jB in a dose-dependent manner [388]. Metformin decreases both pro-inflammatory cytokines and NF-jB and improves the immune response to cancer cells in colorectal, prostate, pancreatic, renal, cervical, endometrial, gastric, lung, breast, and ovarian cancer (reviewed in [389]).…”