Abstract
We have shown that the microtopography (mT) underlying colon cancer changes as a tumor de-differentiates. We distinguish the well-differentiated mT based on the increasing number of "pits" and poorly differentiated mT on the basis of increasing number of "posts." We investigated Rho A as a mechanosensing protein using mT features derived from those observed in the ECM of colon cancer. We evaluated Rho A activity in less-tumorogenic (Caco-2 E) and more tumorigenic (SW620) colon cancer cell-lines on microfabricated pits and posts at 2.5 μm diameter and 200 nm depth/height. In Caco-2 E cells, we observed a decrease in Rho A activity as well as in the ratio of G/F actin on surfaces with either pits or posts but despite this low activity, knockdown of Rho A led to a significant decrease in confined motility suggesting that while Rho A activity is reduced on these surfaces it still plays an important role in controlling cellular response to barriers. In SW620 cells, we observed that Rho A activity was greatest in cells plated on a post microtopography which led to increased cell motility, and an increase in actin cytoskeletal turnover.
Highlights
Mechanical signals sent to cells through physical changes in the tumor microenvironment are becoming increasingly understood as important regulators of tumor cell behavior
In order to evaluate the changes that a cell undergoes when exposed to extracellular matrix (ECM) microtopography, less tumorogenic (Caco-2 E) and more tumorigenic (SW620) colon cancer cells were plated at subconfluent densities on PDMS scaffolds with varying microtopographies (Figure 1)
Caco-2 E cells are a less tumorigenic colon cancer cell-line derived from a tumor of unknown differentiation, which have a villous appearance and well-organized tight junctions on Transmission Electron Microscopy (TEM)
Summary
Mechanical signals sent to cells through physical changes in the tumor microenvironment are becoming increasingly understood as important regulators of tumor cell behavior. Rho has been shown to regulate traction forces [14,15], to be a critical regulator of intracellular responses to micromechanical properties of the ECM [16,17,18], to aid in cellular response to physical surroundings in a spatially oriented manner [19], and to be an important regulator of integrins in mechanical tasks of high complexity in threedimensional surroundings [20] These proteins have been linked with epithelial differentiation in response to flexible surroundings [21] as well as to stem cell commitment [22,23]
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