Tumor exploits alternative strategies to achieve vascularization.

Neoangiogenesis is crucial for solid tumor growth and invasion, as the vasculature provides metabolic support and access to the circulation. Current antiangiogenic therapies have been designed on the assumption that endothelial cells forming the tumor vasculature exhibit genetic stability. Recent studies demonstrate that this is not the case. Tumor endothelial cells possess a distinct phenotype, differing from normal endothelial cells at both molecular and functional levels. This challenges the concept that tumor angiogenesis exclusively depends on normal endothelial cell recruitment from the surrounding vascular network. Indeed, recent data suggest alternative strategies for tumor vascularization. It has been reported that tumor vessels may derive from an intratumor embryonic-like vasculogenesis. This condition might be due to differentiation of normal stem and progenitor cells of hematopoietic origin or resident in tissues. Cancer stem cells may also participate in tumor vasculogenesis by virtue of their stem and progenitor cell properties. Finally, normal endothelial cells might be reprogrammed to a proangiogenic or dedifferentiated phenotype by genetic information transmitted from the tumor trough apoptotic bodies, or following mRNA and microRNA transfer by exosomes and microvesicles. In this review, we discuss the different aspects of intratumor angiogenesis and vasculogenesis, the known mechanisms involved, and the possible implications for the response to antiangiogenic therapy.