We previously demonstrated that bone marrow (BM) cells migrate to Ewing's
tumors and differentiate into endothelial cells within the
tumor vasculature. Recent evidence suggests that the roles of BM cells in
tumors are more diverse. We investigated whether non-endothelial cell types critical for
tumor vessel development are also derived from migrated BM cells. We utilized BM
transplantation with GFP(+) transgenic mice as BM donors and nude mice as recipients to track the fate of migrated BM cells. After engraftment, we injected recipient mice either subcutaneously or intramuscularly with
Ewing's sarcoma cells. We labeled functional
tumor vessels using intravascular perfusion staining with
tomato lectin. We assessed BM cell recruitment/differentiation within the tumor microenvironment using immunohistochemistry. Ewing's
tumors contained BM-derived cells that had differentiated into endothelial cells lining perfused
tumor vessels. A substantial fraction of recruited BM cells also resided in the vessel vicinity and expressed
desmin and
PDGFR-beta, indicating smooth muscle cell differentiation. In order to further characterize the role of stem/progenitor cells in
Ewing's sarcoma, we sorted Tie2(-) BM cells from Tie2-GFP transgenic mice and then injected them intravenously into
Ewing's tumor-bearing mice. Tie2(-) BM progenitors migrated to Ewing's
tumors and differentiated into Tie2(+) cells occupying a perivascular residence and expressing alpha-smooth muscle actin,
desmin and
PDGFR-beta, as well as
VEGFR-2. We did not observe differentiation of Tie2(-) cells into Tie2(+) perivascular cells in VEGF(165)-inhibited TC/siVEGF(7-1)
tumors. The differentiation of Tie2(-) BM cells into Tie2(+) cells in parental but not VEGF(165)-inhibited
tumors indicates that the tumor microenvironment may influence the differentiation pathway.