Abstract
Cancer cells are subjected to fluid shear stress during passage through the venous and lymphatic system. Caveolin-1 (Cav-1), a principal structural component of caveolar membrane domains, contributes to cancer development but its mechanobiological roles under low shear stress (LSS) conditions remain largely unknown. Here, we identified Cav-1 is mechanosensitive to LSS exposure, and its activation-induced PI3K/Akt/mTOR signaling promotes motility, invadopodia formation and metastasis of breast carcinoma MDA-MB-231 cells. Application of LSS (1.8 and 4.0 dynes/cm2) to MDA-MB-231 cells significantly increased the cell motility, invadopodia formation, MT1-MMP expression, ECM degradation, and also induced a sustained activation of Cav-1 and PI3K/Akt/mTOR signaling cascades. Methyl-β-cyclodextrin-caused caveolae destruction markedly decreased LSS-induced activation of both Cav-1 and PI3K/Akt/mTOR, leading to suppress MT1-MMP expression, inhibit invadopodia formation and ECM degradation, suggesting that caveolae integrity also involved in metastasis. Immunocytochemical assay showed that LSS induces the Cav-1 clustering in lipid rafts and co-localization of Cav-1 and MT1-MMP on invadopodia. Immunofluorescence confocal analysis demonstrated that Cav-1 activation were required for the acquisition of a polarized phenotype in MDA-MB-231 cells. Finally, Cav-1 knockdown significantly suppressed tumor colonization in the lungs and distant metastases in animal models. Our findings highlight the importance of Cav-1 in hematogenous metastasis, and provide new insights into the underlying mechanisms of mechanotransduction induced by LSS.
Highlights
Metastasis is the final stage in tumor progression and is thought to be responsible for up to 90% of deaths associated with solid tumors, which arises through a complex series of sequential steps [1]
The formation of cancer metastasis requires the successful completion of several sequential interrelated steps, cancer cells migrating in vivo through the physical barriers of the dense extracellular matrix (ECM) existing in the tumor microenvironment plays an important role in the final metastasis formation
Cav-1 could be activated by low shear stress (LSS) in an exposure time- dependent manner in MDA-MB-231 cells, and Cav-1 translocation to cell membranes were found under LSS conditions
Summary
Metastasis is the final stage in tumor progression and is thought to be responsible for up to 90% of deaths associated with solid tumors, which arises through a complex series of sequential steps [1]. Some cancer cells escape from the primary tumor, enter the bloodstream and become circulating tumor cells in peripheral blood. Some of these circulating tumor cells acquire the capability to extravasate and colonize secondary sites, spreading tumors to distant organs. Metastasis occurs primarily in the venous circulation. This relatively low shear stress (LSS) venous environment facilitates the arrest of tumor cells to the vessel wall, eventually leading to penetration of the vascular wall. Identifying the precise molecular mechanisms which mediate cancer cell migration is necessary for us to design specific treatment to prevent breast cancer metastasis
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