Tumor Vessel Development and Expansion in Ewing's Sarcoma: A Review of the Vasculogenesis Process and Clinical Trials with Vascular-Targeting Agents
Figure 1
The steps for BM cell participation in tumor vessel development and expansion. (a) BM cell recruitment to the tumor. One major chemoattractant for BM cell recruitment to the tumor is VEGF165. VEGF165 is secreted by tumor cells to form a concentration gradient in the circulation, which attracts BM cells. When VEGF165 is silenced by siRNA, the number of BM-derived pericytes/vSMCs within tumor vasculature is significantly reduced and tumor growth is inhibited. In the absence of VEGF165, SDF-1α can recruit BM-derived cells to the tumor and rescue tumor growth. (b) Adhesion and Extravasation. When BM cells reach the developing tumor vasculature, they must adhere to the endothelial cell wall and extravasate to the extraluminal side of the vessel. (c) Differentiation. Once a BM cell has extravasated to the extraluminal side of a blood vessel within the tumor, it must differentiate from an immature progenitor cell into a mature pericyte/vSMCs, endothelial cell, or nonvascular cell. DLL4-Notch signaling is critical for BM cell differentiation into periyctes/vSMCs in Ewing’s sarcoma. BM cells express DLL4 as well as Notch receptors. When DLL4 is inhibited by shRNA or by a DLL4-neutralizing antibody, the number of BM-derived pericytes/vSMCs within the tumor is significantly inhibited and tumor growth is reduced.
