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      Tensional homeostasis and the malignant phenotype.

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          Abstract

          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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          Author and article information

          Journal
          Cancer Cell
          Cancer cell
          Elsevier BV
          1535-6108
          1535-6108
          Sep 2005
          : 8
          : 3
          Affiliations
          [1 ] Department of Bioengineering, University of Pennsylvania, Philadelphia, 19104, USA.
          Article
          S1535-6108(05)00268-0
          10.1016/j.ccr.2005.08.010
          16169468
          7ff47442-984f-467e-a1b0-eb5706c6c4a5
          History

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