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...

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Bibliographic Details
Published in:Cancer cell 2005-09, Vol.8 (3), p.241-254
Main Authors: Paszek, Matthew J., Zahir, Nastaran, Johnson, Kandice R., Lakins, Johnathon N., Rozenberg, Gabriela I., Gefen, Amit, Reinhart-King, Cynthia A., Margulies, Susan S., Dembo, Micah, Boettiger, David, Hammer, Daniel A., Weaver, Valerie M.
Format: Article
Language:English
Subjects:
3T3 Cells
Animals
Cell Line, Tumor
Cell Shape
Cytoskeleton - physiology
Homeostasis - physiology
Mice
Neoplasms - genetics
Neoplasms - pathology
Neoplasms - physiopathology
Phenotype
Stress, Mechanical
Stromal Cells - pathology
Stromal Cells - physiology
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Summary: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.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2005.08.010