Inhibition of VEGFR-3 Activation with the Antagonistic Antibody More Potently Suppresses Lymph Node and Distant Metastases than Inactivation of VEGFR-2

Abstract

Lymph nodes are the first site of metastases for most types of cancer, and lymph node status is a key indicator of patient prognosis. Induction of tumor lymphangiogenesis by vascular endothelial growth factor-C (VEGF-C) has been shown to play an important role in promoting tumor metastases to lymph nodes. Here, we employed receptor-specific antagonist antibodies in an orthotopic spontaneous breast cancer metastasis model to provide direct evidence for the key role of VEGFR-3 activation in metastasis. Inhibition of VEGFR-3 activation more potently suppressed regional and distant metastases than inactivation of VEGFR-2, although VEGFR-2 blockade was more effective in inhibiting angiogenesis and tumor growth. Despite prominent proliferation, metastases were not vascularized in any of the control and treatment groups, indicating that the growth of metastases was not dependent on angiogenesis at the secondary site for the duration of the experiment. Systemic treatment with either VEGFR-2 or VEGFR-3 antagonistic antibodies suppressed tumor lymphangiogenesis, indicating that VEGFR-3 signaling affects the rate of tumor cell entry into lymphatic vessels through both lymphangiogenesis-dependent and independent mechanisms. Combination treatment with the anti-VEGFR-2 and anti-VEGFR-3 antibodies more potently decreased lymph node and lung metastases than each antibody alone. These results validate the concept of targeting the lymphatic dissemination and thereby very early steps of the metastatic process for metastasis control and suggest that a combination therapy with antiangiogenic agents may be a particularly promising approach for controlling metastases. (Cancer Res 2006; 66(5): 2650-7)

Interaction of tumor cells and lymphatic vessels in cancer progression

“…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.…”

“…This target has provided promise of efficacy, although not complete blockage of metastasis, in several pre-clinical models. 69,74,75,81,112 Thus, there is a need to identify additional mediators of pathological lymphangiogenesis.…”

5-Aminoisoquinolinone Reduces the Expression of Vascular Endothelial Growth Factor-C via the Nuclear Factor-kappa B Signaling Pathway in CT26 Cells

“…Inhibition of tumor secreted VEGF-C is known to be a therapeutic target as well as VEGF-C specific inhibition using small interfering RNA (SiRNA) vectors has been indicated to suppress lymphatic metastasis (Chen et al, 2005). There is a substantial evidence that tumor derived VEGF-C plays a crucial role in lymphangiogenesis (Skobe et al, 2001;Chen et al, 2005;Lin et al, 2005;Roberts et al, 2006;Sun et al, 2008;He et al, 2009). Hence, these results directly hint the important role of the VEGF-C/VEGFR-3 signal transduction pathway in tumor associated lymphangiogenesis together with lymphatic metastasis.…”

“…Moreover, studies using experimental animal models have demonstrated that inhibition of VEGF-C/VEGFR-3 signal transduction would reduce the spread and metastasis of tumor cells via lymphatic lumens (Chen et al, 2005;Lin et al, 2005;Roberts et al, 2006). Inhibition of tumor secreted VEGF-C is known to be a therapeutic target as well as VEGF-C specific inhibition using small interfering RNA (SiRNA) vectors has been indicated to suppress lymphatic metastasis (Chen et al, 2005).…”

Developmental and pathological lymphangiogenesis: from models to human disease

“…These eVects are suppressed by speciWc inhibition of the VEGFR-3 pathway-using either blocking VEGFR-3 antibody, VEGF-C/D trap (VEGFR-3 extracellular domain fused with immunoglobulin Fc portion) or VEGF-C targeting siRNA-that prevents cancer metastasis to lymph nodes and beyond (e.g. (He et al 2002;Karpanen et al 2001;Lin et al 2005;Roberts et al 2006), underlining the direct link between VEGF-C or VEGF-D expression and metastasis. Moreover, a large number of clinicopathological studies of human cancers have shown a direct correlation between expression of VEGF-C or VEGF-D by tumor cells and lymphatic invasion, lymph node and distant metastasis, and poor patient survival, but not necessarily with the density of tumor-associated lymphatic vessels Pepper et al 2003;Stacker et al 2002a;Tobler and Detmar 2006).…”