Bone marrow-derived cells contribute to tumor neovasculature and, when modified to express an angiogenesis inhibitor, can restrict tumor growth in mice

Inhibition of tumor-induced neovascularization appears to be an effective a nticancer approach, although long-term angiogenesis inhibition may be requi red. An alternative to chronic drug administration is a gene therapy-mediat ed approach in which long-term in vivo protein expression is established. W e have tested this approach by modifying murine bone marrow-derived cells w ith a gene encoding an angiogenesis inhibitor: a soluble, truncated form of the vascular endothelial growth factor receptor-2, fetal liver kinase-1 (F lk-1). Murine bone marrow cells were transduced with a retroviral vector en coding either truncated, soluble Flk-1 (tsFIk-1) together with green fluore scent protein (GFP) or GFP alone. Tumor growth in mice challenged 3 months after transplantation with tsFIk-1-expressing bone marrow cells was signifi cantly inhibited when compared with tumor growth in control-transplanted mi ce. Immunohistochemical analysis of tumors in each group demonstrated coloc alization of GFP expression in cells staining with endothelial cell markers , suggesting that the endothelial cells of the tumor-induced neovasculature were derived, at least in part, from bone marrow precursors. These results suggest that long-term expression of a functional angiogenesis inhibitor c an be generated through gene-modified, bone marrow-derived stem cells, and that this approach can have significant anticancer efficacy. Modifying thes e cells seems to have the added potential benefit of targeting transgene ex pression to the tumor neovasculature, because bone marrow-derived endotheli al cell precursors seem to be recruited in the process of tumor-induced ang iogenesis.