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      Precancerous niche (PCN), a product of fibrosis with remodeling by incessant chronic inflammation

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          Abstract

          Fibroblasts are actively involved in the creation of the stroma and the extracellular matrix which are important for cell adhesion, cell–cell communication, and tissue metabolism. The role of fibrosis in carcinogenesis can be examined by analogy to tissues of various cancers. The orchestration of letters in the interplay of manifold components with signaling and crosstalk is incompletely understood but available evidence suggests a hitherto underappreciated role for fibrosis in carcinogenesis. Complex signaling and crosstalk by pathogenic stimuli evoke persistent subclinical inflammation, which in turn, results in a cascade of different cell types, ubiquitous proteins and their corresponding enzymes, cytokine releases, and multiple signaling pathways promoting the onset of fibrosis. There is considerable evidence that the body's attempt to resolve such a modified extracellular environment leads to further disruption of homeostasis and the genesis of the precancerous niche as part of the six-step process that describes carcinogenesis. The precancerous niche is formed and can be understood to develop as a result of (1) pathogenic stimulus, (2) chronic inflammation, and (3) fibrosis with alterations of the extracellular matrix, stromal rigidity, and mechano-transduction. This is why carcinogenesis is not just a process of aberrant cell growth with damaged genetic material but the role of the PCN in its entirety reveals how carcinogenesis can occur without invoking the need for somatic mutations.

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          The mammalian TOR (mTOR) pathway is a key regulator of cell growth and proliferation and increasing evidence suggests that its deregulation is associated with human diseases, including cancer and diabetes. The mTOR pathway integrates signals from nutrients, energy status and growth factors to regulate many processes, including autophagy, ribosome biogenesis and metabolism. Recent work identifying two structurally and functionally distinct mTOR-containing multiprotein complexes and TSC1/2, rheb, and AMPK as upstream regulators of mTOR is beginning to reveal how mTOR can sense diverse signals and produce a myriad of responses.
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            Transcriptional control by the TGF-beta/Smad signaling system.

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              Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy.

              The matrix metalloproteinases (MMPs) mediate homeostasis of the extracellular environment. They have multiple signalling activities that are commonly altered during tumorigenesis and that might serve as intervention points for anticancer drugs. However, there are many criteria to consider in validating MMPs as drug targets and for the development of MMP inhibitors. The inhibition of some MMPs could have pro-tumorigenic effects (making them anti-targets), counterbalancing the benefits of target inhibition. These effects might partially account for the failure of MMP inhibitors in clinical trials. What are the major challenges in MMP target validation and MMP-inhibitor-drug development?
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                Author and article information

                Journal
                fopen
                https://www.4open-sciences.org
                4open
                4open
                EDP Sciences
                2557-0250
                25 April 2019
                25 April 2019
                2019
                : 2
                : ( publisher-idID: fopen/2019/01 )
                Affiliations
                [1 ] Theodor-Billroth-Academy®, , Germany, USA,
                [2 ] INCORE, International Consortium of Research Excellence of the Theodor-Billroth-Academy®,, Germany, USA,
                [3 ] Department of Surgery, Carl-Thiem-Klinikum, , Cottbus, Germany,
                [4 ] Risk-Based Decisions Inc., Sacramento, , CA, USA,
                Author notes
                [* ]Corresponding author: b-bruecher@ 123456gmx.de
                Article
                fopen180011
                10.1051/fopen/2018009
                © B.L.D.M. Brücher and I.S. Jamall, Published by EDP Sciences 2019

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 294, Pages: 21
                Product
                Self URI (journal page): https://www.4open-sciences.org/
                Categories
                Life Sciences - Medicine
                Disruption of homeostasis-induced signaling and crosstalk in the carcinogenesis paradigm “Epistemology of the origin of cancer”
                Review Article
                Custom metadata
                4open 2019, 2, 11
                2019
                2019
                2019

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