Fluid shear stress influences invasiveness of HeLa cells through the induction of autophagy.

ABSTRACT

Extravasation of metastatic cells from the blood or lymphatic circulation and formation of secondary tumor at a distant site is a key step of cancer metastasis. In this study, we report the role of hemodynamic shear stresses in fostering the release of pro-extravasation factors through the mediation of autophagy in cervical cancer HeLa cells. HeLa cells were exposed to physiological shear stress through the microfluidic approach adapted in our previous study on the role of hemodynamic shear stresses in survival of HeLa cells. Herein, an optimum number of passes through a cylindrical microchannel was chosen such that the viability of cells was unaffected by shear. Shear-exposed cells were then probed for their invasive and migratory potential through in vitro migration and invasion assays. The dependence of cancer cells on mechanically-induced autophagy for extravasation was further assessed through protein expression studies. Our results suggest that shear stress upregulates autophagy, which fosters paxillin turnover thereby leading to enhanced focal adhesion disassembly and in turn enhanced cell migration. Concurrently, shear stress-induced secretion of pro-invasive factors like MMP-2 and IL-6 were found to be autophagy-dependent thereby hinting at autophagy as a potential therapeutic target in metastatic cancer. Proposed model for mechano-autophagic modulation of extravasation.