Vascular endothelial growth factor-D: signaling mechanisms, biology, and clinical relevance

Abstract

Vascular endothelial growth factor-D (VEGF-D) is a secreted glycoprotein that promotes growth of blood vessels (angiogenesis) and lymphatic vessels (lymphangiogenesis), and can induce remodeling of large lymphatics. VEGF-D enhances solid tumor growth and metastatic spread in animal models of cancer, and in some human cancers VEGF-D correlates with metastatic spread, poor patient outcome, and, potentially, with resistance to anti-angiogenic drugs. Hence, VEGF-D signaling is a potential target for novel anti-cancer therapeutics designed to enhance anti-angiogenic approaches and to restrict metastasis. In the cardiovascular system, delivery of VEGF-D in animal models enhanced angiogenesis and tissue perfusion, findings which have led to a range of clinical trials testing this protein for therapeutic angiogenesis in cardiovascular diseases. Despite these experimental and clinical developments, our knowledge of the signaling mechanisms driven by VEGF-D is still evolving—here we explore the biology of VEGF-D, its signaling mechanisms, and the clinical relevance of this growth factor.

Keywords::

• VEGF
• angiogenesis
• lymphangiogenesis
• NSAID
• metastasis
• clinical trial

Declaration of interest: MGA and SAS are supported by a Program Grant and Research Fellowships from the National Health and Medical Research Council of Australia. MGA and SAS are consultants to Vegenics Ltd, a company developing anti-cancer therapeutics, and shareholders of the parent company Circadian Technologies Ltd. They are also shareholders of Ark Therapeutics Group Plc.