Angiogenic potential of prostate carcinoma cells overexpressing bcl-2

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 -