Molecular mechanisms of resistance to tumour anti-angiogenic strategies

Abstract

Tumour angiogenesis, described by Folkman in the early seventies, is an essential, complex, and dynamic process necessary for the growth of all solid tumours. Among the angiogenic factors secreted by the tumour cells, the Vascular Endothelial Growth Factor (VEGF) is one of the most important. Most types of human cancer cells express elevated levels of this proangiogenic factor and its receptors. New molecules, called anti-angiogenic, are developed to impair VEGF pathway and tumour vasculature. Despite important results, the clinical benefits of anti-VEGF therapy are relatively modest and usually measured in weeks or months. Why following anti-angiogenic therapy do some patients respond transiently and then why does tumour grow again and disease progress and which compensatory mechanisms could explain the anti-angiogenic treatment failure?

Figure 1

Molecular mechanisms involved in tumor anti-angiogenesis therapies resistance. (1) Following anti-VEGF therapies, redundant angiogenic factors are produced by tumour cells. Antiangiogenic treatments reduce and normalize tumour vasculature but increase intratumour hypoxia (2). Hypoxia induces SDF-1α which recruits BMDCs such as CD11b+Gr1+, redundant angiogenic factors (1), and activates HGF/c-MET pathway (5). BMDCs are activated by factors secreted by stroma cells (SDF-1∝, G-CSF, and IL-6). Inhibition of VEGF induces endothelial cells apoptosis and pericytes attachment to endothelial cells is loosed (5). New vessels could be recruited to tumour site by vessel cooption (6). Finally mechanisms involved in tumor anti-angiogenesis resistances lead to select more invasive and metastatic tumour cells (3).