Production of VEGF165 by Ewing's sarcoma cells induces vasculogenesis and the incorporation of CD34+ stem cells into the expanding tumor vasculature
✍ Scribed by Tim H. Lee; Marcela F. Bolontrade; Laura L. Worth; Hui Guan; Lee M. Ellis; Eugenie S. Kleinerman
- Book ID
- 102862420
- Publisher
- John Wiley and Sons
- Year
- 2006
- Tongue
- French
- Weight
- 659 KB
- Volume
- 119
- Category
- Article
- ISSN
- 0020-7136
No coin nor oath required. For personal study only.
✦ Synopsis
Abstract
The Ewing's sarcoma cell line TC71 overexpresses vascular endothelial growth factor isoform 165 (VEGF~165~), a potent proangiogenic molecule that induces endothelial cell proliferation, migration, and chemotaxis. CD34^+^ bone marrow stem cells can differentiate into endothelial and hematopoietic cells. We used a transplant model to determine whether CD34^+^ cells migrate from the bone marrow to Ewing's sarcoma tumors and participate in the neovascularization process that supports tumor growth. We also examined the role of VEGF~165~ in CD34^+^ cell migration. Human umbilical cord CD34^+^ cells were transplanted into sublethally irradiated severe combined immunodeficient mice. Seven days later, the mice were injected subcutaneously with TC71 tumor cells. Tumors were excised 2 weeks later and analyzed by immunohistochemistry. The tumor sections expressed both human VE‐cadherin and mouse CD31, indicating involvement of donor‐derived human cells in the tumor vessels. To determine the role of VEGF~165~ in the chemoattraction of CD34^+^ cells, we generated two VEGF~165~‐deficient TC71 clones, a stable anti‐sense VEGF~165~ cell line (Clone 17) and a VEGF~165~ siRNA‐inhibited clone (TC/siVEGF~7‐1~). The resulting VEGF~165~‐deficient tumor cells had normal growth rates in vitro, but had delayed growth when implanted into mice. Immunohistochemical analysis revealed decreased infiltration of CD34^+^ cells into both VEGF~165~‐deficient tumors. These data show that bone marrow stem cells contribute to the growing tumor vasculature in Ewing's sarcoma and that VEGF~165~ is critical for the migration of CD34^+^ cells from the bone marrow into the tumor. © 2006 Wiley‐Liss, Inc.