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Vascular endothelial growth factor and signaling in the prostate: more than angiogenesis
S Chevalier1, I Defoy, J Lacoste
1Urologic 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
Abstract:
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.
Insights
Vascular Endothelial Growth Factor (VEGF) directly impacts prostate cancer progression by stimulating tumor cell motility and phosphorylation. VEGF-A is found in neuroendocrine cells, suggesting a role beyond angiogenesis in advanced prostate cancer.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Signaling
Background:
- Tyrosine kinase genes are crucial in cellular processes.
- Vascular Endothelial Growth Factor (VEGF) receptor 1 (Flt-1) is implicated in various cellular functions.
- Neuroendocrine (NE) differentiation in prostate cancer is linked to advanced disease.
Purpose of the Study:
- To investigate the role of Flt-1 and VEGF signaling in prostate cancer.
- To determine if VEGF directly affects prostate cancer cell behavior.
- To explore the presence and function of VEGF in prostate neuroendocrine cells.
Main Methods:
- Sequencing of Flt-1 fragments in dog prostate cells.
- Immunoprecipitation and Western blotting to detect tyrosine phosphorylated proteins.
- Chemical cross-linking assays with 125I-VEGF binding.
- Immunohistochemical staining of prostate tissue sections with VEGF-A antibodies.
Main Results:
- A 170-180 kDa tyrosine phosphorylated protein, likely VEGF-R1, was detected in dog prostate and human PC-3 cells.
- VEGF exposure increased the phosphorylation of this protein in PC-3 cells.
- VEGF directly triggered tyrosine phosphorylation of focal adhesion kinase and stimulated PC-3 cell motility.
- VEGF-A staining was confined to chromogranin A and/or serotonin positive NE cells in prostate tumors and metastases.
Conclusions:
- VEGF-R1 is present and tyrosine phosphorylated in prostate cancer cells.
- VEGF signaling pathways are active in prostate cancer and influence cell motility.
- VEGF-A is produced by NE cells in prostate tumors and may promote cancer progression by directly affecting tumor cells, suggesting a role beyond angiogenesis.