Transient interactions involving interstitial flow and cell migration or vascular sprouting
Recent studies have demonstrated that cells either on or in an extracellular matrix are capable of sensing interstitial flows and responding in ways that have physiological or pathological significance. Here we consider three examples relevant to cancer progression and metastasis. 1. Angiogenic sprouting: The build-up of interstitial pressure inside a tumor gives rise to fluid pressure gradients, particularly at the tumor margin, and transmural pressure differences across the walls of small arteries or veins. Our studies [Vickerman and Kamm, IB, 2012], demonstrated that endothelial sprouting into matrix is induced by basal to apical flow and inhibited by apical to basal flow. This process is shown to be a mechanotransduction response by the endothelial cells mediated by outside-in signaling via the integrin receptors. 2. Directional migration of tumor cells: Cells at the tumor margin, in the vicinity of the gradient in interstitial fluid pressure, experience a flow that has been measured to be in the range of 1-10 mm/s. Such flows have been shown in in vitro experiments to cause directional migration either in the downstream (due to a CCR7-CCL21 autocrine signaling pathway [Shields et al., 2007]) or upstream direction (due to force activated integrin-mediated signaling) [Polacheck et al., PNAS, 2011, 2014]. The competition between these two mechanisms may be an important factor in tumor metastasis. 3. Directional migration of macrophages: Preliminary data from our lab suggests that macrophages, implicated in tumor cell invasion among other key processes, also respond to interstitial flow [Li, unpublished]. Although our initial results suggest that the mechanisms may be similar to those in tumor cells, the manifestations differ. Contrary to tumor cells for which flow affects tumor cell migration direction but not speed, in macrophages it gives rise to both directional (upstream) migration and an increase in migration speed.
Support from the National Cancer Institute (R21CA140096, R33CA174550) is gratefully acknowledged.
Bio
Professor Kamm began his career at Northwestern University earning a degree in Mechaniacal Engineering. He subsequently earned both a Master’s and a PhD in Mechanical Enginering at MIT. Since 1978, he has been a professor of Mechanical Engineering at MIT. Professor Kamm was one of the founding members of the Biological Engineering department when it was created in 1998.