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Angiogenesis depends on the cooperation of growth factors and cell adhesion events. Although alphav integrins have been shown to play critical roles in angiogenesis, recent studies in alphav-null mice suggest that other adhesion receptors and their ligands also regulate this process. Evidence is now provided that the integrin alpha5beta1 and its ligand fibronectin are coordinately up-regulated on blood vessels in human tumor biopsies and play critical roles in angiogenesis, resulting in tumor growth in vivo. Angiogenesis induced by multiple growth factors in chick embryos was blocked by monoclonal antibodies to the cell-binding domain of fibronectin. Furthermore, application of fibronectin or a proteolytic fragment of fibronectin containing the central cell-binding domain to the chick chorioallantoic membrane enhanced angiogenesis in an integrin alpha5beta1-dependent manner. Importantly, antibody, peptide, and novel nonpeptide antagonists of integrin alpha5beta1 blocked angiogenesis induced by several growth factors but had little effect on angiogenesis induced by vascular endothelial growth factor (VEGF) in both chick embryo and murine models. In fact, these alpha5beta1 antagonists inhibited tumor angiogenesis, thereby causing regression of human tumors in animal models. Thus, fibronectin and integrin alpha5beta1, like integrin alphavbeta3, contribute to an angiogenesis pathway that is distinct from VEGF-mediated angiogenesis, yet important for the growth of tumors.

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Myeloid cells are recruited to damaged tissues where they can resolve infections and tumor growth or stimulate wound healing and tumor progression. Recruitment of these cells is regulated by integrins, a family of adhesion receptors that includes integrin CD11b. Here we report that, unexpectedly, integrin CD11b does not regulate myeloid cell recruitment to tumors but instead controls myeloid cell polarization and tumor growth. CD11b activation promotes pro-inflammatory macrophage polarization by stimulating expression of microRNA Let7a. In contrast, inhibition of CD11b prevents Let7a expression and induces cMyc expression, leading to immune suppressive macrophage polarization, vascular maturation, and accelerated tumor growth. Pharmacological activation of CD11b with a small molecule agonist, Leukadherin 1 (LA1), promotes pro-inflammatory macrophage polarization and suppresses tumor growth in animal models of murine and human cancer. These studies identify CD11b as negative regulator of immune suppression and a target for cancer immune therapy.

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.