A potential autocrine role for vascular endothelial growth factor in prostate cancer.
Vascular endothelial growth factor (VEGF) is a peptide growth factor specific for the tyrosine kinase receptors VEGF receptor-1 and -2 (VEGFR-1 and R-2). Whereas VEGF has well-defined actions on the vasculature, including the stimulation of endothelial cell growth and motility and blood vessel permeability, the function of the VEGF/receptor pathway in other cell types is largely unknown. Recently, VEGFR-1 and R-2 expression has been reported in prostate tumor cells. In this study, we demonstrate that these receptors colocalize with VEGF in prostate tumor cells, prostatic intraepithelial neoplasia, and the basal cells of normal glands. Furthermore, in comparison with normal glands, the expression of VEGFR-1 and R-2 is increased in prostatic intraepithelial neoplasia and malignant cells in well and moderately differentiated prostate cancer but is decreased in poorly differentiated cancer. Culture of the prostate cancer cell line LNCaP in the presence of recombinant human VEGF165 resulted in a 50% increase in [(3)H]thymidine uptake by these cells and recruitment of quiescent cells into the cell cycle. This effect of recombinant human VEGF165 was abolished by neutralizing antisera to VEGFR-2. These data suggest that VEGF may not only mediate neovascularization associated with prostate cancer progression but may also directly stimulate prostate tumor cells via VEGFR-2-dependent autocrine and/or paracrine mechanisms.
Jackson
Michael W
MW
Department of Surgery, Flinders Cancer Centre, Flinders University of South Australia, Bedford Park, SA 5042, Australia.
Roberts
James S
JS
Heckford
Susan E
SE
Ricciardelli
Carmela
C
Stahl
Jurgen
J
Choong
Catherine
C
Horsfall
David J
DJ
Tilley
Wayne D
WD
D004273:DNA, Neoplasm / Q000096:biosynthesis; D016228:Endothelial Growth Factors / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008222:Lymphokines / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D009389:Neovascularization, Pathologic / Q000378:metabolism; D019048:Prostatic Intraepithelial Neoplasia / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000096:biosynthesis / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D011994:Recombinant Proteins / Q000494:pharmacology; D016196:S Phase / Q000502:physiology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D004273:DNA, Neoplasm; D016228:Endothelial Growth Factors; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1