Abstract 4806: Angiogenesis is independently influenced by interstitial flow and concentration gradients of tumor secreted morphogens

Abstract

Abstract Angiogenesis facilitates growth and entry of tumors into the systemic circulation leading to metastasis. Morphogens, such as vascular endothelial growth factor (VEGF), secreted by the tumors are believed to guide nearby vasculature towards the tumor. The distribution of morphogens in tissues is affected by interstitial fluid flow, which also exerts forces in the tissue microenvironment. Numerous cells in the tumor microenvironment can sense and respond to force, yet our understanding of the independent effect of interstitial flow in tumor angiogenesis is limited. This is due, in part, to inadequate experimental models that cannot decouple spatial morphogen concentrations and interstitial flow. Notably, control of these parameters is not possible in animal models, and 2D cell systems lack the complexity of in vivo tissue. We addressed these limitations by designing a microfluidic platform of polydimethlsiloxane (PDMS) polymer consisting of three parallel microporous tissue compartments (< 0.1 mm3 total volume) that are media-fed with microfluidic lines. Endothelial colony forming cell-derived endothelial cells (ECFC-EC) and stromal fibroblasts in extracellular matrix proteins (e.g., fibrin and collagen) seeded in the central compartment formed interconnected microvascular networks with hollow lumens in 7-14 days. A mathematical model of mass and momentum transport in the microfluidic device was used to determine experimental conditions that either minimize the concentration gradients or the interstitial flow across the tissue chamber. The conditions were validated experimentally using various molecular size fluorescent dextrans. In the absence of a concentration gradient, microvessels demonstrated a striking bias for angiogenesis against the direction of the interstitial flow. Furthermore, the extent of migration against the flow increased with increasing interstitial flow. In separate experiments with minimal/no interstitial flow, angiogenisis is biased towards a positive concentration gradient of the morphogens such as VEGF. In conclusion, we have developed a novel microfluidic platform that can decouple the effects of concentration gradients and interstitial flow. Using this platform we show that angiogenesis is independently influenced by interstitial flow and concentration gradients of tumor secreted morphogens. Citation Format: Venktesh S. Shirure, Steven C. George. Angiogenesis is independently influenced by interstitial flow and concentration gradients of tumor secreted morphogens. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4806. doi:10.1158/1538-7445.AM2014-4806