Mechanisms of Lymphangiogenesis: Targets for Blocking the Metastatic Spread of Cancer

Bradley   K.   McColl; Stephen   J.   Loughran; Natalia      Davydova; Steven   A.   Stacker; Marc   G.   Achen

doi:10.2174/156800905774932833

Abstract

The lymphatic vasculature is an important route of metastatic spread in cancer and recent studies have demonstrated that lymphangiogenesis (the growth of lymphatic vessels) associated with tumors promotes metastasis via the lymphatics. Therefore, the molecular mechanisms that drive lymphangiogenesis are attractive targets for development of novel therapeutics designed to restrict cancer metastasis. Such therapeutics would be of high priority as metastasis is the most lethal aspect of tumor biology. Research over the past seven years has identified protein growth factors and cell surface receptors that signal for lymphangiogenesis during embryonic development, in adult tissues and in cancer. Proteases that process and thereby activate lymphangiogenic growth factors have also been defined. Lymphangiogenic growth factors, the enzymes that activate them and the cell surface receptors signalling for growth of lymphatic vessels are prime targets for antilymphangiogenic drugs designed to restrict cancer metastasis. Agents targeting some of these proteins have already shown promise for blocking tumor lymphangiogenesis and lymphatic metastasis in animal models. This article focuses on current and emerging targets for blocking these processes that have been defined in recent studies of the molecular mechanisms controlling lymphangiogenesis. Strategies to block the actions of these proteins in cancer are also explored.

Keywords: Growth factor, metastasis, receptor tyrosine kinase, PDGF-BB, VEGF-C, VEGF-D, VEGFR-3