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

Brücher, Björn L.D.M.; Jamall, Ijaz S.

doi:10.1051/fopen/2019006

Cited by 3 publications

(11 citation statements)

References 160 publications

(163 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

Section: Summary (Figs 3-5)mentioning

confidence: 84%

“…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.…”

Section: Synopsis Of Evidencementioning

confidence: 99%

“…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].…”

Section: Disruption Of Lipid Metabolismmentioning

confidence: 99%

“…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.…”

Section: Summary (Figs 3-5)mentioning

confidence: 99%

See 3 more Smart Citations

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

Brücher

Jamall

2019

4open

Self Cite

View full text Add to dashboard Cite

It is increasingly evident that carcinogenesis, in the vast majority of cancers, cannot be explained simply through an accumulation of somatic mutations, or epigenetics, the stem cell theory, or the Warburg effect. Here, decades of thinking based on incorrect assumptions has resulted in an incorrect hypothesis on the origin of cancer. Many papers studying DNA, genetics, RNA, miRNA, proteomics, and epigenetics have increased our understanding of biology. Our paradigm, though more complex, is more reliable and plausible. It states that cancer originates from a disruption of homeostasis. This essential biological phenomenon, homeostasis, maintains the interrelationships of various signaling pathways and induced crosstalk which modify cellular functions together with the interactions of surrounding cells and structures such that the equilibrium lies towards the optimal health of the organism. This Special Issue “Disruption of signaling homeostasis induced crosstalk in the carcinogenesis paradigm Epistemology of the origin of cancer” provides compelling evidence that carcinogenesis is explained by a six-step sequence of events for the vast majority of cancers. These six steps include, (1) a pathogenic stimulus followed by (2) chronic inflammation, from which develops (3) fibrosis with associated remodeling in the cellular microenvironment. From these changes a (4) pre-cancerous niche develops which triggers the deployment of (5) a chronic stress escape strategy, and when this fails to resolve, and (6) the transition of a normal cell to a cancer cell occurs. This paradigm provides opportunities to move away from a symptom-oriented understanding of cancer and is much closer to a cause-based understanding, which opens the door for early preventative strategies to mitigate cancer as a disease, and to interdict metastases. This is underpinned by the fact that an independent recently published proof of this paradigm showed how a stimulus trigger the proposed multi-sequence cascade of events as abrupt involution-induced chronic inflammation, followed by fibrosis with remodeling, which describes the pre-cancerous niche followed by hyperplasia, metaplasia, and cancer.

show abstract

Section: Summary (Figs 3-5)mentioning

confidence: 84%

Section: Synopsis Of Evidencementioning

confidence: 99%

Section: Disruption Of Lipid Metabolismmentioning

confidence: 99%

Section: Summary (Figs 3-5)mentioning

confidence: 99%

See 2 more Smart Citations

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

Brücher

Jamall

2019

4open

Self Cite

View full text Add to dashboard Cite

show abstract

“…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]).…”

Section: Metforminmentioning

confidence: 99%

NF-κB signaling and crosstalk during carcinogenesis

Brücher

Läng

Jamall

2019

4open

Self Cite

View full text Add to dashboard Cite

Transcription factors (TFs) are proteins that control the transcription of genetic information from DNA to mRNA by binding to specific DNA sequences either on their own or with other proteins as a complex. TFs thus support or suppress the recruitment of the corresponding RNA polymerase. In general, TFs are classified by structure or function. The TF, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), is expressed in all cell types and tissues. NF-κB signaling and crosstalk are involved in several steps of carcinogenesis including in sequences involving pathogenic stimulus, chronic inflammation, fibrosis, establishment of its remodeling to the precancerous niche (PCN) and transition of a normal cell to a cancer cell. Triggered by various inflammatory cytokines, NF-κB is activated along with other TFs with subsequent stimulation of cell proliferation and inhibition of apoptosis. The involvement of NF-κB in carcinogenesis provides an opportunity to develop anti-NF-κB therapies. The complexity of these interactions requires that we elucidate those aspects of NF-κB interactions that play a role in carcinogenesis, the sequence of events leading to cancer.

show abstract

Epistemology of the Origin of Cancer II: Fibroblasts Are the First Cells to Undergo Neoplastic Transformation

2023

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Many questions in cancer biology remain unanswered. Perhaps the most important issues remaining to be addressed focus on the molecular basis of carcinogenesis. Today’s cancer focus lies on genetics and gene expression, which is unlikely to explain the true cause of most cancers or lead to a cure. Methods: Earlier, we provided a plausible mechanism for this process, specifically, that most cancers develop in response to pathogenic stimuli that induce chronic inflammation, fibrosis, and remodeling of the cellular microenvironment. Collectively, these changes generate a precancerous niche (PCN) in which fibrosis and remodeling are ongoing secondary to persistent inflammation, followed by the deployment of a chronic stress escape strategy (CSES). If the CSES is unsuccessful, the cell undergoes a normal cell to cancer cell transformation (NCCT). Results: Here, we highlight the critical role of fibroblasts as the first cells to undergo neoplastic transformation to a cancerous phenotype which is based on several critical findings. First, persistent disruption of homeostatic crosstalk increases lysyl oxidase activity and lysine oxidation which leads to increased collagen stiffness and decreased elasticity. If unresolved, chronic tissue stress will lead to an escape strategy that involves the recruitment of fibroblasts and fibrocytes from the bone marrow as well as cells undergoing an epithelial-mesenchymal transition (EMT). This yields a heterogeneous pool of cells that express both epithelial and mesenchymal markers and that will ultimately differentiate into cancer-associated fibroblasts (CAFs). Finally, CAFs undergo a mesenchymal-epithelial transition (MET) and express epithelial markers that facilitate their integration into the target tissue. Conclusion: Here, we review the published findings that led us to this conclusion which is the most plausible answer to this critical question.

show abstract

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

Cited by 3 publications

References 160 publications

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

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

NF-κB signaling and crosstalk during carcinogenesis

Epistemology of the Origin of Cancer II: Fibroblasts Are the First Cells to Undergo Neoplastic Transformation

Contact Info

Product

Resources

About