Mechanotransduction of Interstitial Fluid Stresses by Tumor Cells within 3D Collagen Scaffolds

Abstract

Solid tumors are characterized by high interstitial fluid pressure, which serves as a barrier to drug delivery and an indicator for poor prognosis (Milosevic et al. Cancer Res. 2001). Elevated intratumoral fluid pressure drives fluid efflux from the tumor and high interstitial flow velocities at the tumor margin. Recently, we have demonstrated that interstitial flow (∼3 m/s) influences the direction of tumor cell migration through two competing mechanisms (Polacheck et al. PNAS 2011). At low cell density and active autocrine chemokine receptors, cells migrate in the direction of flow, while at high cell density or when autocrine chemokine receptors are blocked, cells migrate upstream, against the flow. Tumor cell migration in the direction of flow has been well characterized by the autologous chemotaxis model (Shields et al. Cancer Cell 2007), but the mechanism leading to upstream migration remains unclear. Here, we discuss the nature of fluid stresses imparted on cells embedded within a porous medium, and we introduce a microfluidic platform that we have developed to study the effect of these stresses on cell migration. We demonstrate that interstitial fluid stresses result in a transcellular gradient in matrix adhesion tension.We further show that these stresses result in a statistically significant accumulation of vinculin and actin on the upstream side of the cell, where matrix adhesion tension is maximized. Interstitial flow affects matrix remodeling and results in increased matrix degradation on the downstream side of the cell; however, we observe upstream vinculin and actin accumulation even when MMPs are blocked, further suggesting that the fluid stresses and not matrix remodeling are responsible for the observed vinculin and actin distribution.