Role of Topographic Cues on Cancer Cell Proliferation

Abstract

Metastasis from a primary epithelial tumor is one of the main causes of cancer related deaths. While the roles of biochemical cues on the metastatic cascade are well known, mounting evidences suggest that physical cues such as extracellular matrix (ECM) stiffness, dimensionality, and topography also direct cancer cell behavior. Although the role of stiffness on proliferative response of cancer cells has been well studied, little is known about the effect of topographic cues in guiding cancer cell proliferation. Here, we examined the effect of topographic cues on cancer cell proliferation by fabricating micron scale topographic features. We observed that the proliferation response of non-cancer breast epithelial cells (MCF-10A) but not of metastatic (MDA-MB-231) and non-metastatic (MCF-7) breast cancer cells; decreases on the microgratings (gratings widths of 2, 3 and 4 μm) across all the ECM proteins, namely, fibronectin, collagen and laminin. However, isotropic features such as micropillars (pillars diameters of 2, 3 and 4 μm) do not reduce the proliferation of MCF-10A, indicating that the anisotropic environmental cues are essential for this process. Interestingly, micrograting mediated proliferation reduction is prevented in presence of acto-myosin contraction inhibitory drugs, namely, Y-27632 and blebbistatin, thereby confirming the activation of Rho-ROCK-Myosin in this phenomenon. In conclusion, we observe the existence of Mechanically Induced Dormancy (MID) where topographical cues induces proliferation inhibitory response to the normal epithelial cells but the malignant cells could successfully overcome this inhibitory barrier and continue uncontrolled proliferation.