Bone Marrow Cells Participate in Tumor Vasculogenesis in Ewing's Sarcoma.

KLEINERMAN, EUGENIE S., BOLONTRADE, MARCELA F..

Chicago, Illinois.

Conferencia; AACR Conferencia especial, “Nuevas líneas de investigación en angiogénesis”. American Association for Cancer Research (American Association for Cancer Research).; 2003

American Association for Cancer Research (AACR).

The Ewing’s family of tumors is of neuralcrest origin, vascular and hemorrhagic in nature.  Unfortunately, no improvement in metastasis-free survival has occurred in over 15 years.  Once relapse occurs, second remissions are rare.  Since changes in chemotherapy have not been successful in improving disease outcome, we investigated factors that contribute to the growth of this tumor in the hope of uncovering new targets for therapy. We have demonstrated that different Ewing’s sarcoma cell lines overexpress VEGF with a shift to the more soluble VEGF165 isoform.  This isoform has been shown to mobilize circulating endothelial precursor cells (EPCs) as well as hematopoetic stem cells.  We therefore investigated the role of BM-derived precursor cells in Ewing’s tumor angiogenesis.  Using a human Ewing’s sarcoma mouse model we demonstrated that BM cells contributed to the formation of the tumor vasculature.  BM cells stained with a fluorescent cell tracker migrated into the area of vessel development and co-localized with the tumor microvessels.  To further investigate the role of BM-derived cells, a BM transplant (BMT) model was developed.  Balb/c nude mice (H-2d) were used as recipients while F1 mice (H-2b/d) were used as BM donors.  Recipients were irradiated and reconstituted with H-2b/d-BM cells.  Mice were injected subcutaneously with TC-71 cells after BMT.  Immunohistochemistry demonstrated numerous H-2b+ tumor vessels.  Since only donor cells have this phenotype, H-2b+ cells detected at remote sites must be derived from donor BM cells.  Co-localization of CD-31 and H-2Kb on the tumor vessels indicated that they were derived from transplanted BM cells. We have also begun studies to investigate which cell population(s) in the BM is responsible for this process.  Using our transplant model we demonstrated that BM-SP cells differentiated into nonhematopoetic endothelial cells and contributed to tumor vascular formation.  In addition, SP cells were present in higher frequencies in the BM from Ewing’s sarcoma-bearing mice. In summary, these data suggest that BM cells contain EPCs that are attracted to the tumor area and contribute to vascular development of the Ewing’s tumor.  The identification of BM cells that can localize directly to the tumor area and participate in vasculogenesis opens the possibility of exploiting these cells for therapy against Ewing’s sarcoma.