Integrins and their extracellular matrix ligands in lymphangiogenesis and lymph node metastasis

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.

Figure 1

Lymphatic system structure. (a) The lymphatic system is separated into two distinct sets of tubules. Lymphatic vessels drain various areas of the body passing the material through a series of lymph nodes before returning the material to the venous circulation through the thoracic ducts. (b) Lymphatic capillaries drain interstitial fluid that accumulates during capillary exchange. The protein and cell-rich fluid termed lymph is then transported into vein-like valved collecting tubules. (c) Anchoring filaments couple lymphatic capillary endothelial cells to the surrounding matrix. Forces applied through these anchoring filaments enhance lymphatic permeability to promote tissue drainage.

Figure 2

Local paracrine signaling controls lymphangiogenesis and lymph node metastasis. (a) Release of growth factors such as VEGF-C and VEGF-D by tumor and stromal cells promotes lymphatic endothelial cell sprouting, invasion, and capillary tube formation. (b) VEGF-C stimulates lymphatic endothelial cells to produce the chemokine CCL21. Expression of the CCL21 receptor on leukocytes and some tumor cells stimulates chemotaxis toward the lymphatic vessel promoting lymphatic dissemination.

Figure 3

The integrin family of matrix receptors in lymphangiogenesis. (a) Integrin subunits divided by their binding partners (connecting lines) and ligand-binding preferences (shaded areas). (b) Structure of integrin adhesions. Integrins link the extracellular matrix to the intracellular actin cytoskeleton through structural adaptor proteins. Recruitment of signaling proteins activates pathways that regulate gene expression (e.g., MAP kinases) and cytoskeletal reorganization (Rho GTPases). (c) Expression of the integrin α9β1 and its EDA-fibronectin ligand are required for proper lymphatic valve development. While α6β1 and α9β1 are implicated in tumor angiogenesis, only α4β1 has been shown to be upregulated in lymphangiogenic vessels, to mediate LEC migration and tube formation in culture, and to be required for tumor-associated lymphangiogenesis.