III. Angiogenesis: complexity of tumor vasculature and microenvironment.

Vascular system plays critical roles in tumor progression and metastasis. Tumor vessels generally sprout from preexisting vascular cells. In addition, pluripotent progenitor cells also participate in tumor neovascularization. The latter populations include endothelial progenitor cells, hematopoietic stem cells and mesenchymal stem cells that are stimulated and attracted into the lesion. Recent studies on tumor microenvironment have disclosed that BM (bone marrow)-derived progenitor cells contain unique subpopulations that do not become fully-differentiated vascular constituents; instead, they show the nature of immature myeloid or mesenchymal lineage, and they enhance tumor angiogenic milieu in close contact with tumor vessels. BM-derived cells also migrate into pre-metastatic niche and stimulate vascular beds of distant organ for attracting circulating tumor cells. Currently, several antiangiogenic molecules are under clinical trials and they are expected to improve overall prognosis. Humanized monoclonal antibody bevacizumab specifically targeting VEGF (vascular endothelial growth factor), and several tyrosine kinase inhibitors targeting VEGF receptors-mediated pathways are the most widely studied agents in several types of advanced cancers. It is obvious that VEGF contributes to tumor neovascularization as a mastermind molecule. On the other hand, the mechanism has also been elucidated how tumors evade VEGF targeting therapies. To establish safer and more effective antiangiogenic therapies, it is important to understand the cross-communication between tumors and hosts in proinflammatory milieu. In this review, we discuss features of tumor angiogenic vessels and their microenvironment. Recent topics on the contribution of BM-derived cells, complexities of VEGF-targeting approaches, and chemoattractants that activate tumor vascular beds are summarized.