Angiogenic Potential of Prostate Carcinoma Cells Overexpressing bcl-2
- 7 February 2001
- journal article
- Published by Oxford University Press (OUP) in JNCI Journal of the National Cancer Institute
- Vol. 93 (3), 208-213
- https://doi.org/10.1093/jnci/93.3.208
Abstract
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. 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% O(2)) or hypoxic (1% O(2)) 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. 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. bcl-2 may play a dual role in tumorigenesis by suppressing apoptosis and by stimulating angiogenesis.Keywords
This publication has 24 references indexed in Scilit:
- The Hallmarks of CancerCell, 2000
- Mechanisms of apoptosis avoidance in cancerCurrent Opinion in Oncology, 1999
- Oncogenes and cell proliferationCurrent Opinion in Genetics & Development, 1997
- Somatic Frameshift Mutations in the BAX Gene in Colon Cancers of the Microsatellite Mutator PhenotypeScience, 1997
- Patterns and Emerging Mechanisms of the Angiogenic Switch during TumorigenesisCell, 1996
- Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumoursNature, 1996
- P53, cell cycle control and apoptosis: Implications for cancerCancer and Metastasis Reviews, 1995
- p53-Dependent apoptosis suppresses tumor growth and progression in vivoCell, 1994
- Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocationCell, 1986
- The Histological Structure of Some Human Lung Cancers and the Possible Implications for RadiotherapyBritish Journal of Cancer, 1955