Tumor Cell Invasion Is Promoted by Interstitial Flow-Induced Matrix Priming by Stromal Fibroblasts.

Abstract

Interstitial flow emanates from tumors into the microenvironment where it promotes tumor cell invasion. Fibroblasts are key constituents of the tumor stroma which modulate the mechanical environment by matrix remodeling and contraction. Here we explore how interstitial fluid flow affects fibroblast-tumor cell interactions. Using a 3-D invasion assay and MDA-MB-435S cells co-cultured with dermal fibroblasts in a collagen matrix, we demonstrated a synergistic enhancement of tumor cell invasion by fibroblasts in the presence of interstitial flow. Interstitial flow also drove transforming growth factor (TGF)-β1 and collagenase-dependent fibroblast migration, consistent with previously described mechanisms where flow promotes invasion through autologous chemotaxis and increased motility. Concurrently, migrating fibroblasts enhanced tumor cell invasion by matrix priming via Rho-mediated contraction. We propose a model where interstitial flow promotes fibroblast migration through TGF-β1 and collagenase activity, positioning fibroblasts to locally reorganize collagen fibers via Rho-dependent contractility, enhancing tumor cell invasion via mechanotactic cues. This represents a novel mechanism where interstitial flow causes stromal remodeling that facilitates tumor invasion.