Suppression of Tumor Lymphangiogenesis and Lymph Node Metastasis by Blocking Vascular Endothelial Growth Factor Receptor 3 Signaling

Abstract

Lymph node metastasis appears to be regulated by additional factors besides VEGF-C. Inhibition of VEGFR-3 signaling can suppress tumor lymphangiogenesis and metastasis to regional lymph nodes but not to lungs.

Immunodetection and quantification of vascular endothelial growth factor receptor‐3 in human malignant tumor tissues

“…Thus, blocking of VEGFR-3 signaling by receptor bodies suppressed tumor-induced lymphangiogenesis and regional lymph node metastasis in animal lung and breast cancer models. 38,39 A considerable body of literature suggests that VEGF-C and VEGF-D expression in human tumors correlates with metastasis to regional lymph nodes and poor prognosis (reviewed in reference 40). For example, in a study with gastric cancer samples, it could be demonstrated that VEGFR-3 expression is localized on endothelial cells of lymphatic vessels and that VEGF-C secreted from cancer cells may directly induce the proliferation of lymphatic vessels in the stroma of primary gastric cancer; similar mechanisms have been proposed in thyroid tissue from patients with auto-immune disease.…”

Targeting lymphangiogenesis to prevent tumour metastasis

“…For example, the highly metastatic human lung cancer cell line NCI-H460-LNM35 was transfected with an expression construct for a soluble version of VEGFR-3 (soluble VEGFR-3) that binds VEGF-C and thereby inhibits signalling by endogenous VEGFR-3 (He et al, 2002). The resulting tumour xenografts in mice contained fewer intratumoural lymphatic vessels and there were less metastases in draining lymph nodes than for control tumours that did not express soluble VEGFR-3.…”

“…Mice with control NCI-H460-LNM35 tumours (i.e. not expressing soluble VEGFR-3) were treated with recombinant adenovirus expressing soluble VEGFR-3 as an alternative inhibitory strategy -this also restricted lymph node metastasis (He et al, 2002). In another animal model, expression of a soluble VEGFR-3 in highly metastatic MT-450 mammary tumour cells suppressed metastasis formation both in the regional lymph nodes and the lungs of rats (Krishnan et al, 2003).…”

“…The approach for targeting the VEGF-C/VEGF-D/VEGFR-3 pathway that has been most extensively employed in animal models of cancer, but is yet to be tested in the clinic, is the use of soluble versions of VEGFR-3 that bind VEGF-C and VEGF-D, thereby inhibiting activation of endogenous VEGFR-3 (see previous section) (He et al, 2002;Krishnan et al, 2003;Lin et al, 2005). It is yet to be determined if a soluble VEGFR-3 construct binds VEGF-C and VEGF-D so that these growth factors are also unable to activate endogenous VEGFR-2 -if this were the case soluble VEGFR-3 would have the merit of preventing the contribution made by these growth factors to angiogenic signalling in cancer via VEGFR-2 as well as lymphangiogenic signalling via VEGFR-3.…”

Downregulation of VEGF-C expression in lung and colon cancer cells decelerates tumor growth and inhibits metastasis via multiple mechanisms

“…Initially, it was thought that VEGF-C synthesized in cancer cells promotes metastasis mainly through induction of lymphangionenesis in tumor tissues and sentinel lymph nodes that facilitated the spread of cancer cells via the lymphatic vessels (Mandriota et al, 2001;He et al, 2002;Hoshida et al, 2006). However, several recent studies reported that autocrine regulation of cancer cells migration via VEGF-C/VEGFRs is an important inducer of tumor cell proliferation, invasion and metastasis (Timoshenko et al, 2007;Kodama et al, 2008;Su et al, 2006Su et al, , 2008Chen et al, 2010).…”