Anti-angiogenesis in cancer therapy: Hercules and hydra

• Over-expression of VEGF by tumour cells generates leaky vessels with low pericyte coverage.
• Concomitantly, VEGF suppresses metastasis by inhibiting HGF-induced MET phosphorylation.
• As a consequence, anti-angiogenesis is associated with enhanced HGF-dependent metastasis.
• Therefore, combining anti-angiogenesis with inhibition of metastasis is a clear option.
• Alternatively, metronomic anti-angiogenesis could be applied following normoxic chemotherapy.

Solid tumours initiate angiogenesis to support their growth by producing growth factors such as VEGF. Depriving the tumour of the excessive vessels that support its growth became the target for developing anti-angiogenic agents that could provide, in combination with chemotherapy, improved anti-cancer treatment. Naturally most agents targeted VEGF and its signalling cascades. Almost 10 years have lapsed since the first anti-angiogenic drug approved by the FDA in 2004 (a humanized antibody inhibiting VEGF-A) and several other agents followed afterwards. There is sufficient accumulated experience to conclude that the clinical results of anti-angiogenic therapy are very modest resulting in moderate improvement in overall survival. Moreover, the clinical outcome is associated with the development of resistance to the anti-angiogenic agent and the increased risk of invasion and metastasis. The initial expectations are, as yet, unfilled, and the entire concept and strategy of the anti-angiogenic intervention in cancer requires re-evaluation. In the present Mini Review we discuss these issues emphasising the underlying molecular mechanisms.