Bone marrow-derived stem cells contribute to vascular growth in Ewing´s sarcoma tumors

BOLONTRADE MARCELA F, WORTH LAURA L, ZHOU ZHICHAO, MARINI FRANK, ANDREEFF MICHAEL, KLEINERMAN EUGENIE S

UT MD Anderson Cancer Center, Houston, TX, USA

Jornada; MD Anderson Cancer Center Trainee Recignition Day; 2003

UT MD Anderson Cancer Center

Ewing´s sarcoma is a primitive neuroectodermal tumor that affects children and young adults usually between the ages of 5 and 30. Despite multiple attempts to improve the efficacy of chemotherapy for this disease, the 2-year metastases free survival rate for patients with Ewing´s sarcoma has not improved over the past 15 years. Understanding the biology and mechanisms involved in Ewing´s sarcoma tumor growth may identify new therapeutic approaches for this disease. The growth of a tumor depends on a good vascular supply. We have previously demonstrated that VEGF is overexpressed in three human Ewing´s sarcoma cell lines (TC71, SK, A4573). We have demonstrated that bone marrow (BM) cells chemotax to VEGF-matrigel plugs in vivo. Using a mismatched-MHC BM transplant nude mouse model, we also demonstrated that BM derived cells contribute to the formation of new vessels in TC71 Ewing´s sarcoma tumors. BM Side Population (SP) cells are a subpopulation of bone marrow cells with stem cell activity. Mice with TC71 Ewing´s sarcoma tumors had a higher percentage of SP cells in their bone marrow. Furthermore, mice transplanted with MHC-mismatched SP cells following lethal irradiation developed CD31 positive tumor vessels, derived in part from the donor SP cells. These data suggests a “cross-talk” between tumor and bone marrow, with VEGF as a chemoatractor for BM cells into the tumor site. We have also determined that the cytokine G-CSF is produced by TC71 Ewing´s sarcoma cells and that TC71 cells express G-CSF receptors. G-CSF may therefore exert both an autocrine stimulatory effect on the tumor and contribute to the growth of the tumor vascular network by increasing SP cells in the bone marrow. Taken together, our data suggest that BM derived cells contribute to the growth and development of Ewing´s sarcoma by participating in the expansion of the tumor vasculature. Genetically modified BM cells may therefore provide a unique way to deliver tumor-specific genes to Ewing´s tumors.