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      The role of the myofibroblast in tumor stroma remodeling

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          Abstract

          Since its first description in wound granulation tissue, the myofibroblast has been recognized to be a key actor in the epithelial-mesenchymal cross-talk that plays a crucial role in many physiological and pathological situations, such as regulation of prostate development, ventilation-perfusion in lung alveoli or organ fibrosis. The presence of myofibroblasts in the stroma reaction to epithelial tumors is well established and many data are accumulating which suggest that the stroma compartment is an active participant in tumor onset and/or evolution. In this review we summarize the evidence in favor of this concept, the main mechanisms that regulate myofibroblast differentiation and function, as well as the biophysical and biochemical factors possibly involved in epithelial-stroma interactions, using liver carcinoma as main model, in view of achieving a better understanding of tumor progression mechanisms and of tools directed toward stroma as eventual therapeutic target.

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          Most cited references208

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          Microenvironmental regulation of metastasis.

          Metastasis is a multistage process that requires cancer cells to escape from the primary tumour, survive in the circulation, seed at distant sites and grow. Each of these processes involves rate-limiting steps that are influenced by non-malignant cells of the tumour microenvironment. Many of these cells are derived from the bone marrow, particularly the myeloid lineage, and are recruited by cancer cells to enhance their survival, growth, invasion and dissemination. This Review describes experimental data demonstrating the role of the microenvironment in metastasis, identifies areas for future research and suggests possible new therapeutic avenues.
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            Tensional homeostasis and the malignant phenotype.

            Tumors are stiffer than normal tissue, and tumors have altered integrins. Because integrins are mechanotransducers that regulate cell fate, we asked whether tissue stiffness could promote malignant behavior by modulating integrins. We found that tumors are rigid because they have a stiff stroma and elevated Rho-dependent cytoskeletal tension that drives focal adhesions, disrupts adherens junctions, perturbs tissue polarity, enhances growth, and hinders lumen formation. Matrix stiffness perturbs epithelial morphogenesis by clustering integrins to enhance ERK activation and increase ROCK-generated contractility and focal adhesions. Contractile, EGF-transformed epithelia with elevated ERK and Rho activity could be phenotypically reverted to tissues lacking focal adhesions if Rho-generated contractility or ERK activity was decreased. Thus, ERK and Rho constitute part of an integrated mechanoregulatory circuit linking matrix stiffness to cytoskeletal tension through integrins to regulate tissue phenotype.
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              Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression.

              Tumors are like new organs and are made of multiple cell types and components. The tumor competes with the normal microenvironment to overcome antitumorigenic pressures. Before that battle is won, the tumor may exist within the organ unnoticed by the host, referred to as 'occult cancer'. We review how normal tissue homeostasis and architecture inhibit progression of cancer and how changes in the microenvironment can shift the balance of these signals to the procancerous state. We also include a discussion of how this information is being tailored for clinical use.
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                Author and article information

                Journal
                Cell Adh Migr
                Cell Adh Migr
                CAM
                Cell Adhesion & Migration
                Landes Bioscience
                1933-6918
                1933-6926
                01 May 2012
                01 May 2012
                : 6
                : 3
                : 203-219
                Affiliations
                [1 ]Department of Physiology; Faculty of Pharmacy; University of Limoges; Limoges, France
                [2 ]Histology and Embryology Department; State University of Rio de Janeiro (UERJ); Rio de Janeiro, Brazil
                [3 ]Laboratory of Tissue Repair and Regeneration; Matrix Dynamics Group; Faculty of Dentistry; University of Toronto; Toronto, ON Canada
                [4 ]LVMH Research; Saint-Jean-de-Braye, France
                [5 ]Department of Pathology and Immunology; Faculty of Medicine; University of Geneva; Geneva, Switzerland
                Author notes
                [†]

                These authors contributed equally to this work.

                [* ]Correspondence to: Alexis Desmouliere, Email: alexis.desmouliere@ 123456unilim.fr
                Article
                2012CAM0066R 20377
                10.4161/cam.20377
                3427235
                22568985
                723e9e46-e16c-4e99-9a87-f256a5a16ae0
                Copyright © 2012 Landes Bioscience

                This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

                History
                Categories
                Review

                Cell biology
                fibrosis,extracellular matrix,wound healing,transforming growth factor-beta,mechanosensing

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