Vascular endothelial growth factor-mediated autocrine stimulation of prostate tumor cells coincides with progression to a malignant phenotype.
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.
Soker
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Department of Urology, Children's Hospital, 300 Longwood Ave., Boston, MA 02115, USA. shay.soker@tch.harvard.edu
Kaefer
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Johnson
M
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Klagsbrun
M
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Atala
A
A
Freeman
M R
MR
D000818:Animals; D002455:Cell Division; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002633:Chemotaxis; D016228:Endothelial Growth Factors / Q000235:genetics / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology / Q000473:pathology; D005169:Factor VIII / Q000032:analysis; D008175:Lung Neoplasms / Q000098:blood supply / Q000473:pathology* / Q000556:secondary; D008222:Lymphokines / Q000235:genetics / Q000502:physiology*; D008297:Male; D011467:Prostate / Q000166:cytology* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000473:pathology* / Q000503:physiopathology; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000502:physiology*; D040262:Receptors, Vascular Endothelial Growth Factor; D014185:Transplantation, Isogeneic; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014682:Vena Cava, Inferior
D016228:Endothelial Growth Factors; D008222:Lymphokines; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D005169:Factor VIII; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor