Vascular endothelial growth factor-mediated autocrine stimulation of prostate tumor cells coincides with progression to a malignant phenotype

Am J Pathol. 2001 Aug;159(2):651-9. doi: 10.1016/S0002-9440(10)61736-1.


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 (125)I-VEGF(165) 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Division
  • Cell Line
  • Cell Transformation, Neoplastic*
  • Chemotaxis
  • Endothelial Growth Factors / genetics
  • Endothelial Growth Factors / physiology*
  • Epithelial Cells / cytology
  • Epithelial Cells / pathology
  • Factor VIII / analysis
  • Lung Neoplasms / blood supply
  • Lung Neoplasms / pathology*
  • Lung Neoplasms / secondary
  • Lymphokines / genetics
  • Lymphokines / physiology*
  • Male
  • Prostate / cytology*
  • Prostate / pathology
  • Prostatic Neoplasms / blood supply*
  • Prostatic Neoplasms / pathology*
  • Prostatic Neoplasms / physiopathology
  • Rats
  • Receptor Protein-Tyrosine Kinases / physiology*
  • Receptors, Growth Factor / physiology*
  • Receptors, Vascular Endothelial Growth Factor
  • Transplantation, Isogeneic
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Vena Cava, Inferior


  • Endothelial Growth Factors
  • Lymphokines
  • Receptors, Growth Factor
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Factor VIII
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor