Tumor skewing of CD34+ progenitor cell differentiation into endothelial cells

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Abstract
Tumor production of granulocyte-macrophage colony-stimulating factor (GM-CSF) results in the mobilization of CD34+ progenitor cells into the peripheral blood and tumor tissue. Using the Lewis lung carcinoma (LLC) model, in vitro studies showed that LLC cells could chemoattract CD34+ cells predominantly through tumor production of VEGF. Addition of LLC-conditioned medium to CD34+ cells that were cultured under conditions that support myeloid lineage cells skewed the differentiation of these precursor cells toward endothelial cells expressing CD31 and CD144. This differentiation of CD34+ cells toward endothelial cells was attributed predominantly to angiopoietin-1 in the tumor-conditioned medium. The CD34+ cells expressed the angiopoietin receptor Tie-2 and their differentiation into endothelial cells was blocked with neutralizing angiopoietin-1 antibodies. In vivo studies showed that infusion of lacZ+ CD34+ cells from the bone marrow of transgenic mice into wild-type mice bearing LLC tumors resulted in the accumulation of lacZ+ cells within the tumor mass, particularly at the tumor's periphery. That these infused CD34+ progenitor cells could develop into endothelial cells of the tumor vasculature was supported by their acquisition of the endothelial cell markers CD31 or CD144 within the tumor tissue. These studies demonstrate the capacity of tumor to attract CD34+ cells to the tumor site and to direct the differentiation of these CD34+ cells into endothelial cells that can become a component of the tumor vasculature.

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