This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Levine, A. C. Articles by Kirschenbaum, A. Search for Related Content PubMed PubMed Citation Articles by Levine, A. C. Articles by Kirschenbaum, A.

Androgens Induce the Expression of Vascular Endothelial Growth Factor in Human Fetal Prostatic Fibroblasts¹

Department of Medicine, Division of Endocrinology (A.C.L., P.D.G., M.E., J.D.S.), Division of Neoplastic Diseases (J.F.H.), Derald H. Ruttenberg Cancer Center (S.A.A.), and Department of Urology (X.-H.L., A.K.), Mount Sinai School of Medicine, New York, New York 10029

Address all correspondence and requests for reprints to: Dr. Alice C. Levine, Box 1055, Department of Medicine, Mount Sinai Medical Center, 1 Gustave L. Levy Place, New York, New York 10029.

Androgens are known to directly stimulate prostate cancer cell growth. We have previously reported that LNCaP prostate cancer cells were dependent upon stromal coinoculation for growth in nude mice and that the stromal cells secreted a potent angiogenic factor, vascular endothelial growth factor (VEGF), which stimulated tumor angiogenesis. Immunohistochemical staining localized VEGF expression primarily to the stromal cells of human fetal and adult hyperplastic prostates, with both stromal and epithelial cell VEGF expression in prostate cancer. In the present studies, we test the hypothesis that androgens, in addition to their direct effects on prostate epithelial cells, have indirect effects on these cells via up-regulation of stromal VEGF production and angiogenesis. Primary cultures of human prostate fetal fibroblasts were treated with dihydrotestosterone (DHT), and the effects on VEGF messenger RNA (mRNA) expression were determined by Northern blotting. DHT (10 nM) increased VEGF mRNA levels maximally after 2 h. Nuclear run-on transcription assays demonstrated a 2-fold increase in the VEGF transcription rate 2 h after the addition of DHT. VEGF mRNA stability was unaffected by DHT addition. VEGF protein levels were determined by enzyme-linked immunosorbent assay and were increased 2-fold 4 h after DHT addition. These data indicate that androgens increase VEGF transcription and secretion of biologically active VEGF from human prostatic stroma. Androgens, therefore, may indirectly enhance prostate growth via up-regulation of VEGF from the surrounding stroma.

This article has been cited by other articles:

				G.-S. Hwang, S.-W. Wang, W.-M. Tseng, C.-H. Yu, and P. S. Wang Effect of hypoxia on the release of vascular endothelial growth factor and testosterone in mouse TM3 Leydig cells Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1763 - E1769. [Abstract] [Full Text] [PDF]

				K. Horii, Y. Suzuki, Y. Kondo, M. Akimoto, T. Nishimura, Y. Yamabe, M. Sakaue, T. Sano, T. Kitagawa, S. Himeno, et al. Androgen-Dependent Gene Expression of Prostate-Specific Antigen Is Enhanced Synergistically by Hypoxia in Human Prostate Cancer Cells Mol. Cancer Res., April 1, 2007; 5(4): 383 - 391. [Abstract] [Full Text] [PDF]

				A. Kirschenbaum, X.-H. Liu, S. Yao, G. Narla, S. L. Friedman, J. A. Martignetti, and A. C. Levine Sex steroids have differential effects on growth and gene expression in primary human prostatic epithelial cell cultures derived from the peripheral versus transition zones Carcinogenesis, February 1, 2006; 27(2): 216 - 224. [Abstract] [Full Text] [PDF]

				D. R. Gray, W. J. Huss, J. M. Yau, L. E. Durham, E. S. Werdin, W. K. Funkhouser Jr., and G. J. Smith Short-Term Human Prostate Primary Xenografts: An in Vivo Model of Human Prostate Cancer Vasculature and Angiogenesis Cancer Res., March 1, 2004; 64(5): 1712 - 1721. [Abstract] [Full Text] [PDF]

				H. Schwarzenbach, G. Chakrabarti, H. J. Paust, and A. K. Mukhopadhyay Gonadotropin-Mediated Regulation of the Murine VEGF Expression in MA-10 Leydig Cells J Androl, January 1, 2004; 25(1): 128 - 139. [Abstract] [Full Text] [PDF]

				N. J. Mabjeesh, M. T. Willard, C. E. Frederickson, H. Zhong, and J. W. Simons Androgens Stimulate Hypoxia-inducible Factor 1 Activation via Autocrine Loop of Tyrosine Kinase Receptor/Phosphatidylinositol 3'-Kinase/Protein Kinase B in Prostate Cancer Cells Clin. Cancer Res., July 1, 2003; 9(7): 2416 - 2425. [Abstract] [Full Text] [PDF]

				R. J. K. Anand, H.-J. Paust, K. Altenpohl, and A. K. Mukhopadhyay Regulation of Vascular Endothelial Growth Factor Production by Leydig Cells In Vitro: The Role of Protein Kinase A and Mitogen-Activated Protein Kinase Cascade Biol Reprod, May 1, 2003; 68(5): 1663 - 1673. [Abstract] [Full Text] [PDF]

				J. A. Tuxhorn, S. J. McAlhany, T. D. Dang, G. E. Ayala, and D. R. Rowley Stromal Cells Promote Angiogenesis and Growth of Human Prostate Tumors in a Differential Reactive Stroma (DRS) Xenograft Model Cancer Res., June 1, 2002; 62(11): 3298 - 3307. [Abstract] [Full Text] [PDF]

				M. W. Jackson, J. S. Roberts, S. E. Heckford, C. Ricciardelli, J. Stahl, D. J. Horsfall, and W. D. Tilley A Potential Autocrine Role for Vascular Endothelial Growth Factor in Prostate Cancer Cancer Res., February 1, 2002; 62(3): 854 - 859. [Abstract] [Full Text] [PDF]

				M. E. Taplin and S.-M. Ho The Endocrinology of Prostate Cancer J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3467 - 3477. [Full Text] [PDF]

				J. I. Izawa and C. P.N. Dinney The role of angiogenesis in prostate and other urologic cancers: a review Can. Med. Assoc. J., March 1, 2001; 164(5): 662 - 670. [Abstract] [Full Text] [PDF]

				W. J. Huss, C. F. Hanrahan, R. J. Barrios, J. W. Simons, and N. M. Greenberg Angiogenesis and Prostate Cancer: Identification of A Molecular Progression Switch Cancer Res., March 1, 2001; 61(6): 2736 - 2743. [Abstract] [Full Text]

				J. H. Pinthus, T. Waks, D. G. Schindler, A. Harmelin, J. W. Said, A. Belldegrun, J. Ramon, and Z. Eshhar WISH-PC2: A Unique Xenograft Model of Human Prostatic Small Cell Carcinoma Cancer Res., December 1, 2000; 60(23): 6563 - 6567. [Abstract] [Full Text]

				M. I. Koukourakis, A. Giatromanolaki, P. E. Thorpe, R. A. Brekken, E. Sivridis, S. Kakolyris, V. Georgoulias, K. C. Gatter, and A. L. Harris Vascular Endothelial Growth Factor/KDR Activated Microvessel Density versus CD31 Standard Microvessel Density in Non-Small Cell Lung Cancer Cancer Res., June 1, 2000; 60(11): 3088 - 3095. [Abstract] [Full Text] [PDF]

				S. M. Hyder, Z. Nawaz, C. Chiappetta, and G. M. Stancel Identification of Functional Estrogen Response Elements in the Gene Coding for the Potent Angiogenic Factor Vascular Endothelial Growth Factor Cancer Res., June 1, 2000; 60(12): 3183 - 3190. [Abstract] [Full Text]

				R. M. Adam, J. G. Borer, B. J. Williams, J. A. Eastham, K. R. Loughlin, and M. R. Freeman Amphiregulin Is Coordinately Expressed with Heparin-Binding Epidermal Growth Factor-Like Growth Factor in the Interstitial Smooth Muscle of the Human Prostate Endocrinology, December 1, 1999; 140(12): 5866 - 5875. [Abstract] [Full Text]