The mechanisms leading to lymphatic metastasis remain poorly understood, despite the fact that many cancers spread through the lymphatics, and debate currently exists as to the primary mechanism of tumor invasion into the lymphatics: do tumors invade surrounding lymphatics or induce lymphangiogenesis? Recent studies have demonstrated that interstitial fluid flow contributes to lymphatic regeneration and organization, possibly by directed macrophage proteolysis. In addition, it is well established that tumors exhibit high interstitial fluid pressure, which leads to net outward radial convection from a tumor mass. Finally, tumors that have high expression levels of VEGF-C, a lymphatic growth factor, have higher incidence of lymphatic metastasis. Taken together, these concepts led us to hypothesize that interstitial fluid flow may facilitate lymphatic metastasis by these mechanisms in a synergistic way. To this end, we investigated the roles of the extracellular matrix and interstitial flow on tumor-lymphatic interactions by comparing chemotaxis and migration of lymphatic endothelial cells (LECs) towards tumor cells and vice-versa, and in fibrin matrices. We found that under static conditions without a matrix, LECs were chemoattracted to tumor cells, particularly those that overexpress VEGF-C. However, in the physiological context of an extracellular matrix, tumor cells were much more migratory than LECs (reflecting the fact that they are more proteolytically active), and that interstitial fluid flow synergized with VEGF-C to strongly enhance tumor cell migration towards LECs but not vice-versa.We further showed that this flow enhanced effect could be blocked with protease inhibitors. Thus, we conclude that the biophysical environment of the tumor and surrounding stroma strongly prefers tumor invasion into lymphatics as opposed to induction of lymphangiogenesis towards or into the tumor.
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