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Institute of Molecular Medicine, Tumor Biology Center, D-79106 Freiburg, Germany
The growth of solid tumors and the formation of metastases are dependent on neoangiogenesis. One of the most important factors in inducing the formation of new blood vessels is the vascular endothelial growth factor (VEGF), which acts specifically on endothelial cells. VEGF is expressed and secreted by almost all solid tumors. The molecular mechanisms leading to enhanced production of this angiogenic mitogen are manyfold and have been elucidated to some degree. Two VEGF receptors, fms-like tyrosine kinase 1 (FLT-1) and KDR, have been identified almost specifically on human endothelial cells. They are expressed preferentially in the proliferating endothelium of vessels lining and/or penetrating solid tumors, whereas they are almost undetectable by convenient methods in vessels of healthy tissue. However, the underlying mechanisms are not understood. We could show that media conditioned by various cancer cell lines grown under hypoxic conditions were able to up-regulate expression of FLT-1 mRNA and protein but not of KDR mRNA. Furthermore, up-regulation of a shorter mRNA species was observed that most probably codes for the soluble variant of FLT-1. These effects were completely inhibited by VEGF-neutralizing extracellular VEGF receptor domains. The effect could be mimicked by adding recombinant VEGF instead of conditioned cancer cell medium to the endothelial cell cultures. Both mutant VEGF, which activates only KDR, and placenta growth factor, which activates only FLT-1, were able to enhance FLT-1 expression. VEGF-stimulated FLT-1 mRNA expression was inhibited by actinomycin D. These data suggest that VEGF itself is the main factor secreted by tumor cells that is able to enhance the expression of its receptor FLT-1 and of a soluble variant of FLT-1 in endothelial cells.
2 To whom requests for reprints should be addressed, at Institute of Molecular Medicine, Tumor Biology Center, Breisacher Strasse 117, D-79106 Freiburg, Germany. Phone: 49-761-206-1700; Fax: 49-761-206-1705; E-mail: marme@sun1.tumorbio.unifreiburg.de.
Received 7/30/97. Accepted 9/26/97.
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