Vascular Endothelial Growth Factor Receptor 3 Is Involved in Tumor Angiogenesis and Growth

Abstract

Vascular endothelial growth factor receptor 3 (VEGFR-3) binds VEGF-C and VEGF-D and is essential for the development of the lymphatic vasculature. Experimental tumors that overexpress VEGFR-3 ligands induce lymphatic vessel sprouting and enlargement and show enhanced metastasis to regional lymph nodes and beyond, whereas a soluble form of VEGFR-3 that blocks receptor signaling inhibits these changes and metastasis. Because VEGFR-3 is also essential for the early blood vessel development in embryos and is up-regulated in tumor angiogenesis, we wanted to determine if an antibody targeting the receptor that interferes with VEGFR-3 ligand binding can inhibit primary tumor growth. Our results show that antibody interference with VEGFR-3 function can inhibit the growth of several human tumor xenografts in immunocompromised mice. Immunohistochemical analysis showed that the blood vessel density of anti-VEGFR-3-treated tumors was significantly decreased and hypoxic and necrotic tumor tissue was increased when compared with tumors treated with control antibody, indicating that blocking of the VEGFR-3 pathway inhibits angiogenesis in these tumors. As expected, the anti-VEGFR-3-treated tumors also lacked lymphatic vessels. These results suggest that the VEGFR-3 pathway contributes to tumor angiogenesis and that effective inhibition of tumor progression may require the inhibition of multiple angiogenic targets. [Cancer Res 2007;67(2):593-9]

SAR131675, a Potent and Selective VEGFR-3–TK Inhibitor with Antilymphangiogenic, Antitumoral, and Antimetastatic Activities

“…ÃÃ , P < 0.01; ÃÃÃ , P < 0.001. (49). Three major mechanisms could explain the role of VEGFR-3 in primary tumor growth: an autocrine effect on tumor cells, pathologic angiogenesis, and TAMs.…”

Interaction of tumor cells and lymphatic vessels in cancer progression

“…25 However, upon reactivation of angiogenesis, VEGFR-3 expression may be upregulated, most prominently in angiogenic vessel sprouts. 26,27 VEGFR-3 may function differentially on blood and lymphatic endothelial cells. VEGF ligand-induced activation of VEGFR-3 is indispensable for the development of the lymphatic vascular system, but not for blood vascular development.…”

“…26 Inhibition of the VEGF-C and VEGF-D receptor VEGFR-3, either by blocking antibodies or by a soluble receptor acting as a ligand trap, has been shown to inhibit lymphangiogenesis, and to a moderate degree angiogenesis, and is also found to restrict lymph node metastasis without effects on mature vessels in surrounding tissues. 26,74,75,81 In addition to VEGF-C and VEGF-D, overexpression of VEGF-A may also lead to the activation of lymphangiogenesis. We have observed intratumoral lymphatic vessels and enlargement of peritumoral lymphatic vessels in VEGF-C-or VEGF-A-overexpressing squamous cell carcinomas.…”

VEGF‐D deficiency in mice does not affect embryonic or postnatal lymphangiogenesis but reduces lymphatic metastasis

“…Expression levels of VEGF-D and VEGF-C correlate with lymph node metastasis in several human cancers [15,16], and addition or overexpression of exogenous VEGF-C or VEGF-D induces lymphatic growth and tumor metastasis in preclinical cancer models [17][18][19][20][21][22][23][24][25]. Addition of exogenous VEGF-D or VEGF-C also induces the formation of functional, mature collecting lymphatic collecting lymphatic vessels in mice [6].…”

“…Similarly, adenoviral or transgenic overexpression of VEGF-D corrects defective lymphangiogenesis in airway inflammation in wild type mice [26] or in the skin of VEGF-C +/-lymphedema mice [14]. Vice versa, strategies to prevent VEGF-C/D mediated signaling block tumor (lymph)angiogenesis and metastasis in cancer, or lymphangiogenesis in corneal inflammation [5,21,23,27,28]. …”