, cells interact with a three-dimensional (3D) microenvironment (Yamada and Cukierman, 2007
). The mechanical force of these interactions, by altering tissue tension, acts as a molecular switch that determines cell fate (Engler et al., 2009
). Tension generated in an extracellular microenvironment induces and cooperates with opposing forces applied by cells (mechanoreciprocity). In embryogenesis such tensile forces govern tissue organization (Krieg et al., 2008
), and mammary acinar architecture relies on matrix compliance and cell tension (Ronnov-Jessen and Bissell, 2008
Microenvironment-mediated tensile forces also contribute to disease. Matrix stiffness promotes breast cancer progression via mechanoreciprocal induction of Rho-dependent cell contractility (Levental et al., 2009
). The microenvironment is also important for tumor invasion and metastasis: tumor cells (TCs) migrate along tracks made of ECM collagen fibers (Friedl and Gilmour, 2009
), and while reticular collagen surrounding mammary glands restrains invasion, Rho-mediated alignment of dense collagen fibers perpendicular to the tumor boundary promotes it (Provenzano et al., 2008
). Activated fibroblasts facilitate tumor cell invasion through protease and force dependent generation of ECM tracks (Gaggioli et al., 2007
). Carcinoma-associated fibroblasts (CAFs) and mesenchymal stem cells, via paracrine cytokine signaling, promote tumor growth, invasion and metastasis (Karnoub et al., 2007
; Orimo et al., 2005
). Elucidation of tumor microenvironment remodeling mechanisms is thus an important area of research.
Caveolin-1 (Cav1), the major component of endocytic caveolae plasma membrane (PM) invaginations, has many functions outside caveolae (Parton and Simons, 2007
). Cav1 activates Rho by regulating its endogenous inhibitor p190RhoGAP (p190) and assists in focal adhesion (FA) stabilization required for directional cell migration (Goetz et al., 2008a
; Grande-Garcia et al., 2007
). The role of Cav1 in tumor progression remains unclear. In most primary tumors Cav1 levels decrease, allowing proliferation, anchorage-independence and angiogenesis, while metastasis correlates with Cav1 re-expression, promoting invasion, survival and multidrug resistance (Goetz et al., 2008b
). Most studies have focused on Cav1 expression in TCs, with little attention paid to a possible role in the tumor microenvironment. Since Cav1, via a mechanism involving Cav1 Tyr14 and p190, is essential for fibroblast function (Grande-Garcia et al., 2007
), we investigated the role of fibroblast-Cav1 in stroma assembly.
We show that Cav1 regulates Rho GTPase activity by modulating membrane partitioning of p190 and thereby its phosphorylation. Fibroblast expression of Cav1 in vitro and in vivo favors an organized 3D stromal architecture that promotes spindle morphology, facilitates TC invasion and increases p190-dependent metastatic potency. These findings correlate with increased numbers of Cav1-expressing CAFs in the stroma of human tumor samples. Cav1 silencing in human CAFs decreases their contractility, identifying a novel role for Cav1 in normal tissue homeostasis and pathological scenarios.