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.

Summary Tumor inflammation promotes angiogenesis, immunosuppression and tumor growth, but the mechanisms controlling inflammatory cell recruitment to tumors are not well understood. We found that a range of chemoattractants activating G-protein coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and Toll-like/IL-1 receptors (TLR/IL1Rs) unexpectedly initiate tumor inflammation by activating the PI3-kinase isoform p110γ in Gr1+CD11b+ myeloid cells. Whereas GPCRs activate p110γ in a Ras/p101 dependent manner, RTKs and TLR/IL1Rs directly activate p110γ in a Ras/p87-dependent manner. Once activated, p110γ promotes inside-out activation of a single integrin, α4β1, causing myeloid cell invasion into tumors. Pharmacological or genetic blockade of p110γ suppressed inflammation, growth and metastasis of implanted and spontaneous tumors, revealing an important therapeutic target in oncology.

Recent studies have shown that lymphangiogenesis or the growth of lymphatic vessels at the periphery of tumors promotes tumor metastasis to lymph nodes. We show here that the fibronectin-binding integrin α4β1 and its ligand fibronectin are novel functional markers of proliferative lymphatic endothelium. Tumors and lymphangiogenic growth factors, such as vascular endothelial growth factor-C (VEGF-C) and VEGF-A, induce lymphatic vessel expression of integrin α4β1. Integrin α4β1 then promotes growth factor and tumor-induced lymphangiogenesis, as genetic loss of integrin α4β1 expression in Tie2Cre+ α4 loxp/loxp mice or genetic loss of α4 signaling in α4Y991A knock-in mice blocks growth factor and tumor-induced lymphangiogenesis, as well as tumor metastasis to lymph nodes. In addition, antagonists of integrin α4β1 suppress lymphangiogenesis and tumor metastasis. Our studies show that integrin α4β1 and the signals it transduces regulate the adhesion, migration, invasion, and survival of proliferating lymphatic endothelial cells. As suppression of α4β1 expression, signal transduction, or function in tumor lymphatic endothelium not only inhibits tumor lymphangiogenesis but also prevents metastatic disease, these results show that integrin α4β1-mediated tumor lymphangiogenesis promotes metastasis and is a useful target for the suppression of metastatic disease.

Tumor-associated macrophages promote tumor growth by stimulating angiogenesis and suppressing anti-tumor immunity. Thus, therapeutics that inhibit macrophage recruitment to tumors may provide new avenues for cancer therapy. Here we show how the chemoattractants SDF-1α and IL-1β collaborate with myeloid cell integrin α4β1 to promote tumor inflammation and growth. We found that SDF-1α and IL-1β are highly expressed in the microenvironments of murine lung, pancreatic and breast tumors; surprisingly, SDF-1α was expressed only by tumor cells, while IL-1β was produced only by tumor-derived granulocytes and macrophages. In vivo, both factors directly recruited pro-angiogenic macrophages to tissues, while antagonists of both factors suppressed tumor inflammation, angiogenesis and growth. Signals induced by IL-1β and SDF-1α promoted the interaction of talin and paxillin with the cytoplasmic tails of integrin α4β1, thereby stimulating myeloid cell adhesion to endothelium in vitro and in vivo. While inhibiting integrin α4β1, SDF-1α or IL-1β was sufficient to block tumor inflammation and growth, the combined blockade of these molecules greatly accentuated these effects. Furthermore, antagonists of integrin α4β1 inhibited chemotherapy-induced tumor inflammation and synergized with chemotherapeutic agents to suppress tumor inflammation and growth. These results demonstrate that targeting myeloid cell recruitment mechanisms can be an effective approach to suppress tumor progression.