Abstract
In the 1970s, the late Judah Folkman postulated that tumors grow proportionately to their blood supply and that tumor angiogenesis removed this limitation promoting growth and metastasis. Work over the past 40 years, varying from molecular examination to clinical trials, verified this hypothesis and identified a host of therapeutic targets to limit tumor angiogenesis, including the integrin family of extracellular matrix receptors. However, the propensity for some tumors to spread through lymphatics suggests that lymphangiogenesis plays a similarly important role. Lymphangiogenesis inhibitors reduce lymph node metastasis, the leading indicator of poor prognosis, whereas inducing lymphangiogenesis promotes lymph node metastasis even in cancers not prone to lymphatic dissemination. Recent works highlight a role for integrins in lymphangiogenesis and suggest that integrin inhibitors may serve as therapeutic targets to limit lymphangiogenesis and lymph node metastasis. This review discusses the current literature on integrin-matrix interactions in lymphatic vessel development and lymphangiogenesis and highlights our current knowledge on how specific integrins regulate tumor lymphangiogenesis.
Highlights
Introduction to the Lymphatic CirculationBlood vessels supply tissues with nutrients and oxygen, remove waste products, and provide a mechanism for leukocyte homing
In addition to vessel density, the location of the lymphatic vessels may be critical as intratumoral vessels have been reported as non-functional based on high intratumoral interstitial fluid pressures which collapse lymphatics [39]. These results suggest peritumoral lymphatics may serve as the primary site of lymphatic entry for metastatic cells
Overexpression of vascular endothelial cell growth factor (VEGF)-C or VEGF-D in mouse xenograft models enhances both lymphangiogenesis and lymph node metastasis [10, 51], and VEGF-C expression in human cancer correlates with enhanced lymphangiogenesis, lymph node metastasis, and poor prognosis (Figure 2(a))
Summary
Blood vessels supply tissues with nutrients and oxygen, remove waste products, and provide a mechanism for leukocyte homing. This accumulation of interstitial fluid is augmented due to enhanced permeability of the capillaries resulting in tissue edema [2]. The lymphatic system regulates the transfer of interstitial fluid and cells from the tissue back into the circulation [1]. Lymphatic capillaries are closed ended tubes that lack a normal subendothelial basement membrane and show no smooth muscle cell or pericyte coverage [9, 10]. The material collected by these lymphatic capillaries, termed lymph, is driven into the collecting lymphatic vessels by International Journal of Cell Biology interstitial pressure. Collecting vessels resemble venous vessels in that both have a subendothelial basement membrane, smooth muscle cells, and bileaflet valves which prevent fluid backflow (Figure 1(b)). Elevated interstitial pressure creates tension on LEC anchoring filaments enhancing LEC permeability and interstitial fluid uptake (Figure 1(c))
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