Biomechanical Remodeling of the Microenvironment by Stromal Caveolin-1 Favors Tumor Invasion and Metastasis

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• 作者：Jacky  ; G. Goetz¹ ; ⁷ ; ⁸ ; ^{jgoetz@igbmc.fr"" rel=""nofollow} ; Susana Minguet¹ ; ⁷ ; Inmaculada Navarro-L&#xe9 ; rida¹ ; Juan  ; Jos&#xe9 ; Lazcano¹ ; Rafael Samaniego³ ; Enrique Calvo² ; Marta Tello⁴ ; Teresa Osteso-Ib&#xe1 ; ñ ; ez¹ ; Teijo Pellinen¹ ; Asier Echarri¹ ; Ana Cerezo¹ ; Andres  ; J.P. Klein-Szanto⁶ ; Ricardo Garcia⁴ ; Patricia  ; J. Keely⁵ ; Paloma S&#xe1 ; nchez-Mateos³ ; Edna Cukierman⁶ ; Miguel  ; A. Del  ; Pozo¹ ; ^{madelpozo@cnic.es"" rel=""nofollow}
• 刊名：Cell
• 出版年：2011
• 出版时间：8 July 2011
• 年：2011
• 卷：146
• 期：1
• 页码：148-163
• 全文大小：4859 K

文摘

Summary

Mechanotransduction is a key determinant of tissue homeostasis and tumor progression. It is driven by intercellular adhesions, cell contractility, and forces generated within the microenvironment and is dependent on extracellular matrix composition, organization, and compliance. We show that caveolin-1 (Cav1) favors cell elongation in three-dimensional cultures and promotes Rho- and force-dependent contraction, matrix alignment, and microenvironment stiffening through regulation of p190RhoGAP. In turn, microenvironment remodeling by Cav1 fibroblasts forces cell elongation. Cav1-deficient mice have disorganized stromal tissue architecture. Stroma associated with human carcinomas and melanoma metastases is enriched in Cav1-expressing carcinoma-associated fibroblasts (CAFs). Cav1 expression in breast CAFs correlates with low survival, and Cav1 depletion in CAFs decreases CAF contractility. Consistently, fibroblast expression of Cav1, through p190RhoGAP regulation, favors directional migration and invasiveness of carcinoma cells in vitro. In vivo, stromal Cav1 remodels peri- and intratumoral microenvironments to facilitate tumor invasion, correlating with increased metastatic potency. Thus, Cav1 modulates tissue responses through force-dependent architectural regulation of the microenvironment.

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