Angiogenic potential of prostate carcinoma cells overexpressing bcl-2
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Angiogenic potential of prostate carcinoma cells overexpressing bcl-2. / Fernandez, A; Udagawa, T; Meyer-Schwesinger, Catherine; Beecken, W; Achilles-Gerte, E; McDonnell, T; D'Amato, R.
in: JNCI-J NATL CANCER I, Jahrgang 93, Nr. 3, 07.02.2001, S. 208-13.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Angiogenic potential of prostate carcinoma cells overexpressing bcl-2
AU - Fernandez, A
AU - Udagawa, T
AU - Meyer-Schwesinger, Catherine
AU - Beecken, W
AU - Achilles-Gerte, E
AU - McDonnell, T
AU - D'Amato, R
PY - 2001/2/7
Y1 - 2001/2/7
N2 - 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% 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.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.
AB - 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% 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.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.
KW - Angiogenesis Inducing Agents
KW - Angiogenesis Inhibitors
KW - Animals
KW - Antibiotics, Antineoplastic
KW - Antigens, CD31
KW - Apoptosis
KW - Blotting, Western
KW - Cell Hypoxia
KW - Cornea
KW - Cyclohexanes
KW - Endothelial Growth Factors
KW - Enzyme-Linked Immunosorbent Assay
KW - Eye Neoplasms
KW - Gene Expression Regulation, Neoplastic
KW - Humans
KW - Immunohistochemistry
KW - Lymphokines
KW - Male
KW - Mice
KW - Neovascularization, Pathologic
KW - Prostatic Neoplasms
KW - Proto-Oncogene Proteins c-bcl-2
KW - Sesquiterpenes
KW - Transcription Factors
KW - Transfection
KW - Transplantation, Heterologous
KW - Tumor Cells, Cultured
KW - Up-Regulation
KW - Vascular Endothelial Growth Factor A
KW - Vascular Endothelial Growth Factors
M3 - SCORING: Journal article
C2 - 11158189
VL - 93
SP - 208
EP - 213
JO - JNCI-J NATL CANCER I
JF - JNCI-J NATL CANCER I
SN - 0027-8874
IS - 3
ER -