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(American Journal of Pathology. 2001;159:651-659.)
© 2001 American Society for Investigative Pathology

Regular Articles

Vascular Endothelial Growth Factor-Mediated Autocrine Stimulation of Prostate Tumor Cells Coincides with Progression to a Malignant Phenotype

Shay Soker*, Martin Kaefer*, Michelle Johnson*, Michael Klagsbrun{dagger}, Anthony Atala* and Michael R. Freeman*

From the Department of Urology*
and the Laboratory for Surgical Research,{dagger}
Children’s Hospital; and the Departments of Surgery*
{dagger}
and Pathology,{dagger}
Harvard Medical School, Boston, Massachusetts

Vascular endothelial growth factor (VEGF), which is often produced at high levels by tumor cells, is a well-known mediator of tumor angiogenesis. VEGF receptor tyrosine kinases, KDR/Flk-1 and Flt-1, have been thought to be expressed exclusively by endothelial cells. In this study, we have used a prostate tumor progression series comprised of a differentiated rat prostate epithelial cell line, NbE-1, and its highly motile clonal derivative, FB2. Injection of NbE-1 cells into the inferior vena cava of syngeneic rats indicated that these cells are nontumorigenic. Using the same model, FB2 cells generated rapidly growing and well-vascularized tumors in the lungs. NbE-1 expressed marginal levels of VEGF, whereas high levels of VEGF protein were detected in FB2-conditioned medium and in FB2 tumors in vivo. Analysis of 125I-VEGF165 binding to NbE-1 and FB2 cells indicated that only motile FB2 cells expressed the VEGF receptor Flt-1. Consistent with this finding, physiological concentrations of VEGF induced chemotactic migration in FB2 but not in NbE-1 cells. This is the first documentation of a functional Flt-1 receptor in prostate tumor cells. Our results suggest two roles for VEGF in tumor progression: a paracrine role as an angiogenic factor and a previously undescribed role as an autocrine mediator of tumor cell motility.




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