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 that modulate the mechanical environment by matrix remodeling and contraction. Here, we explore how interstitial fluid flow affects fibroblast-tumor cell interactions. Using a 3-dimensional invasion assay and MDA-MB-435S cells cocultured with dermal fibroblasts in a collagen matrix, we showed a synergistic enhancement of tumor cell invasion by fibroblasts in the presence of interstitial flow. Interstitial flow also drove transforming growth factor (TGF)-b1 and collagenase-dependent fibroblast migration, consistent with previously described mechanisms in which 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 in which interstitial flow promotes fibroblast migration through increased TGF-b1 activation and collagen degradation, positioning fibroblasts to locally reorganize collagen fibers via Rho-dependent contractility, in turn enhancing tumor cell invasion via mechanotactic cues. This represents a novel mechanism in which interstitial flow causes fibroblastmediated stromal remodeling that facilitates tumor invasion. Cancer Res; 71(3); 790-800. Ó2011 AACR.

Cell motility and drug gradients in the emergence of resistance to chemotherapy

“…In the culture chamber, we found that the fluid flow speed was less than 1 μm/s, over 100 times lower than in the side channels and comparable to physiologic level of interstitial flow, about 0.5 μm/s (Fig. 1C) (26).…”

Immunomodulatory Roles of Lymphatic Vessels in Cancer Progression

“…VEGF-C also induces TGFb secretion by LECs (J. Munson and M. Swartz, unpublished data), which can promote regulatory T-cell education and drives fibroblast-to-myofibroblast transformation and stromal stiffening. Finally, increased interstitial flow in the tumor stroma due to high pressure gradients at the tumor margin also promotes TGFb activation, myofibroblast transformation, and stromal stiffening (44), and promote fibroblast-led tumor-cell invasion (45). Drawings are courtesy of Katie Hubbell, University College London, UK.…”

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“…13,44 In this case, the leader cells, which can be activated stromal fibroblasts or cancer cells themselves, 15 initiate and promote collective invasion of follower cells in a cell-cell contact dependent manner. This strand-like collective invasion widens the microtracks to become macropatterns that further enables directed invasion of the following cell mass.…”

“…51 Moreover, despite the intriguing invasion behavior of cancer cells themselves, the role of fibroblasts in priming local ECM microenvironment for cancer invasion has been increasingly recognized. 44 It will be highly instructive to conduct co-culture of fibroblasts and invasive cells and quantitative assays such as those performed in this study to further understand the potential feedback mechanism between the two cell types.…”