Increased expression of VEGF 121 /VEGF 165–189 ratio results in a significant enhancement of human prostate tumor angiogenesis

• Published in: International journal of cancer 2007-05, Vol.120 (10), p.2096-2109
• Main Authors: Catena, Raul, Muniz‐Medina, Vanessa, Moralejo, Beatriz, Javierre, Biola, Best, Carolyn J.M., Emmert‐Buck, Michael R., Green, Jeffrey E., Baker, Carl C., Calvo, Alfonso
• Format: Article
• Language: English
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.22461

Vascular endothelial growth factor (VEGF) is a proangiogenic factor upregulated in many tumors. The alternative splicing of VEGF mRNA renders 3 major isoforms of 121, 165 and 189 amino‐acids in humans (1 less amino‐acid for each mouse VEGF isoform). We have designed isoform specific real time QRT‐PCR assays to quantitate VEGF transcripts in mouse and human normal and malignant prostates. In the human normal prostate, VEGF 165 was the predominant isoform (62.8% ± 5.2%), followed by VEGF 121 (22.5% ± 6.3%) and VEGF 189 ( p < 0.001) (14.6% ± 2.1%). Prostate tumors showed a significant increase in the percentage of VEGF 121 and decreases in VEGF 165 ( p < 0.01) and VEGF 189 ( p < 0.05). However, the amount of total VEGF mRNA was similar between normal and malignant prostates. VEGF 164 was the transcript with the highest expression in the mouse normal prostate. Unlike human prostate cancer, tumors from TRAMP mice demonstrated a significant increase in total VEGF mRNA levels and in each of the VEGF isoforms, without changes in the relative isoform ratios. Morpholino phosphorodiamide antisense oligonucleotide technology was used to increase the relative amount of VEGF 121 while proportionally decreasing VEGF 165 and VEGF 189 levels in human prostate cell lines, through the modification of alternative splicing, without changing transcription levels and total amount of VEGF. The increase in the VEGF 121 /VEGF 165–189 ratio in PC3 cells resulted in a dramatic increase in prostate tumor angiogenesis in vivo . Our results underscore the importance of VEGF 121 in human prostate carcinoma and demonstrate that the relative expression of the different VEGF isoforms has an impact on prostate carcinogenesis. © 2007 Wiley‐Liss, Inc.