Integrins in angiogenesis and lymphangiogenesis

Abstract

Blood vessels promote tumour growth, and both blood and lymphatic vessels facilitate tumour metastasis by serving as conduits for the transport of tumour cells to new sites. Angiogenesis and lymphangiogenesis are regulated by integrins, which are members of a family of cell surface receptors whose ligands are extracellular matrix proteins and immunoglobulin superfamily molecules. Select integrins promote endothelial cell migration and survival during angiogenesis and lymphangiogenesis, whereas other integrins promote pro-angiogenic macrophage trafficking to tumours. Several integrin-targeted therapeutic agents are currently in clinical trials for cancer therapy. Here, we review the evidence implicating integrins as a family of fundamental regulators of angiogenesis and lymphangiogenesis.

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Figure 1. Mechanisms regulating angiogenesis and lymphangiogenesis

(A) Tumor cells near pre-existing blood vessels secrete growth factors and chemokines such as VEGF-A, bFGF, and TNFα that stimulate quiescent vascular endothelium to enter the cell cycle. Tumors also secrete factors such as VEGF-C, VEGF-A or HGF that stimulate the growth of new lymphatic vessels in the peritumoral space. (B) These growth factors activate or upregulate expression of integrins such as α1β1, α2β1, α4β1, α5β1 and αvβ3 on blood vessels and α4β1, α9β1, α2β1 and α1β1 on lymphatic vessels. Tumor derived VEGF-C also promotes new lymphatic vessel growth in draining lymph nodes. (C) These integrins then promote endothelial cell migration and survival during invasion of tumor tissue, resulting in the creation of new vessels sprouts. The new blood vessels promote tumor growth by removing waste products and providing nutrients. These new blood and lymphatic vessels also provide an avenue for tumor metastasis. (D) Lymphangiogenesis promotes metastasis to lymph nodes and, sometimes, more distant tissues such as lung, while angiogenesis promotes metastasis to local and distant sites, such as lung.

Figure 2. Myeloid cells promote angiogenesis

Myeloid precursor cells adhere to angiogenic endothelium via activated α4β1 or β2 integrins. A variety of tumor or stromal derived factors, including stromal derived factor 1 (SDF-1), colony stimulating factors (CSF), and others mobilize myeloid cells and activate integrins, promoting extravasation into the tumor environment. In the presence of other cytokines and growth factors, these cells differentiate into macrophages, which support tumor growth by expressing VEGF, other pro-angiogenic factors and proteases.