Evidence from a leukemia model for maintenance of vascular endothelium by bone-marrow-derived endothelial cells.

The maintenance of tissues of virtually all organs depends on a sufficient blood supply. During embryogenesis, primitive blood vessels are formed de novo by the aggregation of angioblasts, a process that is termed vasculogenesis. In postnatal life, the development of new blood vessels is restricted to the female reproductive tract (during the ovulatory cycle) and to sites of wound healing, and occurs through a process called angiogenesis, i.e. the sprouting of new vessels from the preexisting vasculature. However, neovascularization can also occur under pathological conditions, e.g. tumor cells can "switch on" angiogenesis. New blood vessels bring in nutrients and proteins, so the tumor mass can expand. In fact, neovascularization appears to be one of the crucial steps in the transition of a tumor from a small cluster of malignant cells to a visible macroscopic tumor capable of spreading to other organs via the vasculature throughout the body. The association of tumor growth with the development of a vascular network was recognized nearly a century ago. Using a leukemia model, chronic myelogenous leukemia (CML), we were able to provide evidence for the existence of a hemangioblastic progenitor cell in the bone marrow of adult humans. Using the pathognomonic BCR-ABL-fusion gene as a genetic marker present in virtually all bone marrow derived cells of patients with CML, we were able to show that endothelial cells belong to the malignant cell clone, since they also contain the BCR-ABL-fusion gene. Our data suggest that CML arises from a hemangioblastic progenitor cell, the progeny of which are malignant blood cells and genotypically clonal endothelial cells. Thus, we provide substantial evidence that indeed a hemangioblast exists in the bone marrow of human adults. In addition, our data imply that normal as well as genotypically malignant bone-marrow-derived endothelial cells can contribute to maintenance angiogenesis in the vascular endothelium, a condition that is consistent with postnatal vasculogenesis. These findings were recently confirmed by other groups and should help in elucidating the pathophysiology of malignant and nonmalignant disorders. The integration of bone-marrow-derived endothelial cells into the vascular endothelium has implications for the development of vascular targeting strategies (e.g., gene therapy) for vascular diseases, inflammatory disorders, and cancer. The characterization of the hemangioblast at a clonal level as well as the translation of these findings into a clinically applicable concept for the delivery of therapeutic genes to malignant tumors is currently in progress in our laboratory.