© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 3, 208-213,
February 7, 2001
© 2001 Oxford University Press
REPORT |
Angiogenic Potential of Prostate Carcinoma Cells Overexpressing bcl-2
Affiliations of authors: A. Fernandez, T. Udagawa, C. Schwesinger, W.-D. Beecken, E. Achilles-Gerte, Department of Surgery, Division of Surgical Research, Children's Hospital, Boston, MA; T. J. McDonnell, Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston; R. J. D'Amato, Department of Surgery, Division of Surgical Research, Children's Hospital, Boston, and Department of Ophthalmology, Harvard Medical School, Boston.
Correspondence to: Robert J. D'Amato, M.D., Ph.D., Department of Surgery, Division of Surgical Research, Children's Hospital, 300 Longwood Ave., Boston, MA 02115 (e-mail: Robert.damato{at}tch.harvard.edu).
Background: Tumors commonly outgrow their blood supply, thereby creating hypoxic conditions, which induce apoptosis and increase expression of angiogenic growth factors. The bcl-2 oncogene inhibits apoptosis induced by a variety of stimuli, including hypoxia. On the basis of bcl-2's role in regulating apoptosis in response to hypoxia, we hypothesized that this oncogene might affect other responses to hypoxia, such as the expression of angiogenic growth factors. Methods: Three prostate carcinoma cell lines, PC3, LNCaP, and DU-145, were stably transfected with a bcl-2 complementary DNA (cDNA), and transfectants were analyzed in vitro for the expression of angiogenic factors after exposure to either normoxic (19% O2) or hypoxic (1% O2) conditions. The in vivo angiogenic potential of the transfected cells was determined by analyzing vessel density in xenografts derived from them and by measuring the ability of these xenografts to induce neovascularization when implanted in mouse corneal micropockets. Statistical tests were two-sided. Results: When exposed to hypoxic conditions, prostate carcinoma cells overexpressing bcl-2 expressed statistically significantly higher levels of vascular endothelial growth factor (VEGF), an angiogenic factor, than control-transfected cells (P = .001 for PC3, P = .04 for DU-145 after 48 hours). This effect of bcl-2 was independent of its antiapoptotic activity because increased expression of VEGF was detected in PC3 cells overexpressing bcl-2 even though PC3 cells are inherently resistant to hypoxia-induced apoptosis. In vivo, xenograft tumors derived from the bcl-2-overexpressing prostate carcinoma cell lines displayed increased angiogenic potential and grew more aggressively than tumors derived from the control cell lines (P = .03 for PC3). Treatment of bcl-2-overexpressing and control tumors with the antiangiogenic drug TNP-470 neutralized the aggressive angiogenesis in bcl-2-overexpressing tumors (P = .04 for PC3, P = .004 for DU-145) and the moderate angiogenesis in control tumors (P = .01 for PC3, P = .05 for DU-145), resulting in similar growth rates for both tumors. Conclusions: bcl-2 may play a dual role in tumorigenesis by suppressing apoptosis and by stimulating angiogenesis.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  T. Kaneko, Z. Zhang, M. G. Mantellini, E. Karl, B. Zeitlin, M. Verhaegen, M. S. Soengas, M. Lingen, R. M. Strieter, G. Nunez, et al. Bcl-2 Orchestrates a Cross-talk between Endothelial and Tumor Cells that Promotes Tumor Growth Cancer Res., October 15, 2007; 67(20): 9685 - 9693. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Giorgini, D. Trisciuoglio, C. Gabellini, M. Desideri, L. Castellini, C. Colarossi, U. Zangemeister-Wittke, G. Zupi, and D. Del Bufalo Modulation of bcl-xL in Tumor Cells Regulates Angiogenesis through CXCL8 Expression Mol. Cancer Res., August 1, 2007; 5(8): 761 - 771. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Y. T. Inoue, M. Neira, C. Nelson, M. Gleave, and R. Etzioni Cluster-based network model for time-course gene expression data Biostat., July 1, 2007; 8(3): 507 - 525. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Pasquali, V. Rossi, S. Staibano, G. De Rosa, P. Chieffi, D. Prezioso, V. Mirone, M. Mascolo, D. Tramontano, A. Bellastella, et al. The Endocrine-Gland-Derived Vascular Endothelial Growth Factor (EG-VEGF)/Prokineticin 1 and 2 and Receptor Expression in Human Prostate: Up-Regulation of EG-VEGF/Prokineticin 1 with Malignancy Endocrinology, September 1, 2006; 147(9): 4245 - 4251. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Zlobec, R. Steele, N. Nigam, and C. C. Compton A Predictive Model of Rectal Tumor Response to Preoperative Radiotherapy Using Classification and Regression Tree Methods Clin. Cancer Res., August 1, 2005; 11(15): 5440 - 5443. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-T. Chen, C.-J. Huang, M.-T. Wu, S.-F. Yang, Y.-C. Su, and C.-Y. Chai Hypoxia-inducible Factor-1{alpha} is Associated with Risk of Aggressive Behavior and Tumor Angiogenesis in Gastrointestinal Stromal Tumor Jpn. J. Clin. Oncol., April 1, 2005; 35(4): 207 - 213. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Xu, D. Yang, S. Wang, W. Tang, M. Liu, M. Davis, J. Chen, J. M. Rae, T. Lawrence, and M. E. Lippman (-)-Gossypol enhances response to radiation therapy and results in tumor regression of human prostate cancer Mol. Cancer Ther., February 1, 2005; 4(2): 197 - 205. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Folkman Angiogenesis and c-Jun J Natl Cancer Inst, May 5, 2004; 96(9): 644 - 644. [Full Text] [PDF]
|
|
|
|
 |
|
 D. Trisciuoglio, A. Iervolino, A. Candiloro, G. Fibbi, M. Fanciulli, U. Zangemeister-Wittke, G. Zupi, and D. Del Bufalo bcl-2 Induction of Urokinase Plasminogen Activator Receptor Expression in Human Cancer Cells through Sp1 Activation: INVOLVEMENT OF ERK1/ERK2 ACTIVITY J. Biol. Chem., February 20, 2004; 279(8): 6737 - 6745. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Tosato Interferon-{alpha} Is Implicated in the Transcriptional Regulation of Vascular Endothelial Growth Factor J Natl Cancer Inst, March 19, 2003; 95(6): 420 - 421. [Full Text] [PDF]
|
|
|
|
|
|
G. Tortora, R. Caputo, V. Damiano, R. Caputo, T. Troiani, B. M. Veneziani, S. De Placido, A. R. Bianco, U. Zangemeister-Wittke, and F. Ciardiello Combined Targeted Inhibition of bcl-2, bcl-XL, Epidermal Growth Factor Receptor, and Protein Kinase A Type I Causes Potent Antitumor, Apoptotic, and Antiangiogenic Activity Clin. Cancer Res., February 1, 2003; 9(2): 866 - 871. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Inoue, M. Chikazawa, S. Fukata, C. Yoshikawa, and T. Shuin Docetaxel Enhances the Therapeutic Effect of the Angiogenesis Inhibitor TNP-470 (AGM-1470) in Metastatic Human Transitional Cell Carcinoma Clin. Cancer Res., February 1, 2003; 9(2): 886 - 899. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. UDAGAWA, A. FERNANDEZ, E.-G. ACHILLES, J. FOLKMAN, and R. J. D'AMATO Persistence of microscopic human cancers in mice: alterations in the angiogenic balance accompanies loss of tumor dormancy FASEB J, September 1, 2002; 16(11): 1361 - 1370. [Abstract] [Full Text] [PDF]
|
|