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Production of VEGF165 by Ewing's sarcoma cells induces vasculogenesis and the incorporation of CD34 + stem cells into the expanding tumor vasculature
Author(s) -
Lee Tim H.,
Bolontrade Marcela F.,
Worth Laura L.,
Guan Hui,
Ellis Lee M.,
Kleinerman Eugenie S.
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21916
Subject(s) - cd34 , vasculogenesis , cd31 , biology , bone marrow , stem cell , endothelial stem cell , pathology , neovascularization , cancer research , sarcoma , angiogenesis , haematopoiesis , progenitor cell , immunology , medicine , microbiology and biotechnology , in vitro , biochemistry
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.