Targeting lymphangiogenesis to prevent tumour metastasis

Abstract

Recent studies involving animal models of cancer and clinicopathological analyses of human tumours suggest that the growth of lymphatic vessels (lymphangiogenesis) in or nearby tumours is associated with the metastatic spread of cancer. The best validated molecular signalling system for tumour lymphangiogenesis involves the secreted proteins vascular endothelial growth factor-C (VEGF-C) and VEGF-D that induce growth of lymphatic vessels via activation of VEGF receptor-3 (VEGFR-3) localised on the surface of lymphatic endothelial cells. In this review, we discuss the evidence supporting a role for this signalling system in the spread of cancer and potential approaches for blocking this system to prevent tumour metastasis.

A driving force for change: interstitial flow as a morphoregulator

“…These high interstitial pressures are due in part to the lack of functional lymphatics within the tumor [47] and result in a net convective flow out from the tumor mass into the surrounding tissue as a result of the lower interstitial pressure found there. (The conclusion that tumors lack functional lymphatics is controversial, however; several reports have suggested that metastatic tumors can induce lymphatic growth into the tumor mass [48]. )…”

Lentivirus‐Mediated Small Interfering RNA Targeting VEGF‐C Inhibited Tumor Lymphangiogenesis and Growth in Breast Carcinoma

“…The spread of tumor cells to regional lymph nodes through the lymphatic system plays a central role in the dissemination of various human cancers such as breast cancer (Achen et al, 2006). Experimental tumor models and human clinicopathologic data indicate that lymphangiogenesis and lymph node metastasis are important prognostic indicators for the spread of cancer (Eccles et al, 2007;Miyahara et al, 2007).…”

Combination therapy with short interfering RNA vectors against VEGF-C and VEGF-A suppresses lymph node and lung metastasis in a mouse immunocompetent mammary cancer model

“…3,30 In many animal models of cancer, VEGF-C has been shown to enhance tumor lymphangiogenesis, the metastatic spread of tumor cells to lymph nodes and, in some cases, distant organ metastasis. 31 Downregulation of VEGF-C using siRNA has been shown to reduce lymph node and lung metastases in murine mammary cancer models. 11 In addition, VEGFR-3, the VEGF-C receptor, is predominantly expressed on lymphatic endothelial cells, 32 and VEGF-C-dependent activation of VEGFR-3 stimulates the growth of lymph endothelial cells and lymphatics.…”