As cancer progresses, a dynamic microenvironment develops that creates and responds to cellular and biophysical cues. Increased intratumoral pressure and corresponding increases in interstitial flow from the tumor bulk to the healthy stroma is an observational hallmark of progressing cancers. Until recently, the role of interstitial flow was thought to be mostly passive in the transport and dissemination of cancer cells to metastatic sites. With research spanning the past decade, we have seen that interstitial flow has a promigratory effect on cancer cell invasion in multiple cancer types. This invasion is one mechanism by which cancers can resist therapeutics and recur, but the role of interstitial flow in cancer therapy is limited to the understanding of transport of therapeutics. Here we outline the current understanding of the role of interstitial flow in cancer and the tumor microenvironment through cancer progression and therapy. We also discuss the current role of fluid flow in the treatment of cancer, including drug transport and therapeutic strategies. By stating the current understanding of interstitial flow in cancer progression, we can begin exploring its role in therapeutic failure and treatment resistance.

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.

The importance of the tumor microenvironment in cancer progression is indisputable, yet a key component of the microenvironment--biomechanical forces--remains poorly understood. Tumor growth and progression is paralleled by a host of physical changes in the tumor microenvironment, such as growth-induced solid stresses, increased matrix stiffness, high fluid pressure, and increased interstitial flow. These changes to the biomechanical microenvironment promote tumorigenesis and tumor cell invasion and induce stromal cells--such as fibroblasts, immune cells, and endothelial cells--to change behavior and support cancer progression. This review highlights what we currently know about the biomechanical forces generated in the tumor microenvironment, how they arise, and how these forces can dramatically influence cell behavior, drawing not only upon studies directly related to cancer and tumor cells, but also work in other fields that have shown the effects of these types of mechanical forces vis-à-vis cell behaviors relevant to the tumor microenvironment. By understanding how all of these biomechanical forces can affect tumor cells, stromal cells, and tumor-stromal crosstalk, as well as alter how tumor and stromal cells perceive other extracellular signals in the tumor microenvironment, we can develop new approaches for diagnosis, prognosis, and ultimately treatment of cancer.