Vascular endothelial growth factor and signaling in the prostate: more than angiogenesis.
In cloning tyrosine kinase genes in dog prostate cells, a fragment of the vascular endothelial growth factor (VEGF) receptor 1 or Flt-1 was sequenced. To test for a functional protein, Flt-1 antibodies were used to probe immunoprecipitated tyrosine phosphorylated proteins. Western blotting revealed a major 170-180 kDa band and a few bands below 116 kDa in dog prostate and human prostatic carcinoma PC-3 cells, with higher levels in PC-3. Similar results were obtained with human placental membranes used as a source of Flt-1. That the major Flt-1 tyrosine phosphorylated protein was likely VEGF-R1 and part of VEGF signaling pathways was shown by enhanced level of only this protein when PC-3 cells were exposed to VEGF. Accordingly specific cell surface receptor complexes, displaced by VEGF but not EGF and compatible with Flt-1 in size, were revealed by chemical cross-linking after 125I-VEGF binding. Similarly to the prostatic neuroproduct, gastrin-releasing peptide/bombesin, VEGF directly triggered the tyrosine phosphorylation of focal adhesion kinase and stimulated PC-3 cell motility. The titration of prostate tissue sections with VEGF-A antibodies revealed a confined staining in chromogranin A and/or serotonin positive neuroendocrine (NE) cells, including in primary tumors and lymph node metastases. Given that NE differentiation is associated with advanced disease, that NE cells are a significant source of VEGF in prostatic tumors, and that VEGF directly act on prostate cancer cells in vitro, VEGF-A may be more than angiogenic in prostate cancer and hence favor progression by affecting tumor cells.
Chevalier
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S
Urologic Oncology Research Group, Department of Surgery, Urology Division, Research Institute, McGill University Health Center, 1650 Cedar Avenue, Quebec, H3G IA4, Montreal, Canada. simone.chevalier@mcgill.ca
Defoy
I
I
Lacoste
J
J
Hamel
L
L
Guy
L
L
Bégin
L R
LR
Aprikian
A G
AG
D000595:Amino Acid Sequence; D000818:Animals; D002277:Carcinoma / Q000473:pathology; D016895:Culture Media, Serum-Free; D004285:Dogs; D016228:Endothelial Growth Factors / Q000378:metabolism*; D004847:Epithelial Cells / Q000502:physiology; D005260:Female; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008198:Lymph Nodes / Q000473:pathology; D008222:Lymphokines / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic; D009490:Neurosecretory Systems / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D010920:Placenta / Q000737:chemistry; D011247:Pregnancy; D011467:Prostate / Q000166:cytology / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000473:pathology; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*; D042442:Vascular Endothelial Growth Factors
D016895:Culture Media, Serum-Free; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human