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Suppression of Prostate Carcinogenesis by Dietary Supplementation of Celecoxib in Transgenic Adenocarcinoma of the Mouse Prostate Model
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increasing serum prostate specific antigen. No consensus has developed concerning the efficacy of treating men with T3 margin positive disease with radiation therapy. Peter C. Albertsen, M.D.
URO-SCIENCE Molecular Determinants of Resistance to Antiandrogen Therapy C. D. CHEN, D. S. WELSBIE, C. TRAN, S. H. BAEK, R. CHEN, R. VESSELLA, M. G. ROSENFELD AND C. L. SAWYERS, Department of Medicine, University of California at Los Angeles, Los Angeles, California Nat Med, 10: 33–39, 2004 Using microarray-based profiling of isogenic prostate cancer xenograft models, we found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy. This increase in androgen receptor mRNA and protein was both necessary and sufficient to convert prostate cancer growth from a hormone-sensitive to a hormonerefractory stage, and was dependent on a functional ligand-binding domain. Androgen receptor antagonists showed agonistic activity in cells with increased androgen receptor levels; this antagonist-agonist conversion was associated with alterations in the recruitment of coactivators and corepressors to the promoters of androgen receptor target genes. Increased levels of androgen receptor confer resistance to antiandrogens by amplifying signal output from low levels of residual ligand, and by altering the normal response to antagonists. These findings provide insight toward the design of new antiandrogens. Editorial Comment: The mechanisms by which prostate cancer escapes androgen control have not been clearly defined. This study using microarray profiling identifies a potential mechanism for androgen independence.1 Timothy L. Ratliff, Ph.D. 1. Isaacs, J. T. and Isaacs, W. B.: Androgen receptor outwits prostate cancer drugs. Nat Med, 10: 26, 2004
Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand: A Novel Mechanism for Bacillus Calmette-Guerin-Induced Antitumor Activity A. T. LUDWIG, J. M. MOORE, Y. LUO, X. CHEN, N. A. SALTSGAVER, M. A. O’DONNELL Department of Urology, University of Iowa, Iowa City, Iowa
AND
T. S. GRIFFITH,
Cancer Res, 64: 3386 –3390, 2004 Mycobacterium bovis Bacillus Calmette-Guerin (BCG) use in the treatment of bladder cancer was first reported in 1976, but the mechanism of the induced antitumor activity has still not been fully explained. BCG is a potent immunostimulant, normally producing a Th1 cytokine response, including IFN. Recent studies have shown CpG oligodeoxynucleotide induce tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression via IFN production. Given that Mycobacterial DNA contains high amounts of CpG motifs, we hypothesized that BCG’s antitumor properties are akin to CpG oligodeoxynucleotide, where the cytokine response to BCG induces TRAIL up-regulation. Using ELISA, urine IFN-gamma, and TRAIL levels were initially undetectable in BCG therapy patients but were high after later induction treatments. More importantly, patients that responded to BCG therapy had significantly higher urine TRAIL levels, which killed bladder tumor cells in vitro versus nonresponders. Flow cytometry of fresh urine revealed TRAIL-expressing neutrophils. Given these data, we propose TRAIL plays a role in BCG-induced antitumor effects. Editorial Comment: Ludwig et al identified a novel and potentially important apoptosis inducing ligand (TRAIL) in the urine after BCG treatment. Neutrophils, a dominant early infiltrate after BCG treatment, were shown to express TRAIL and release it into the urine. Timothy L. Ratliff, Ph.D. Suppression of Prostate Carcinogenesis by Dietary Supplementation of Celecoxib in Transgenic Adenocarcinoma of the Mouse Prostate Model S. GUPTA, V. M. ADHAMI, M. SUBBARAYAN, G. T. MACLENNAN, J. S. LEWIN, U. O. HAFELI, P. FU AND H. MUKHTAR, Department of Urology, James and Eilleen Dicke Research Laboratory, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio Cancer Res, 64: 3334 –3343, 2004 Epidemiological studies and clinical observations suggest that nonsteroidal anti-inflammatory drugs and certain selective cyclooxygenase (COX)-2 inhibitors may reduce the relative risk of clinically evident prostate cancer. This prompted us to investigate the chemopreventive potential of celecoxib, a selective
2114
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COX-2 inhibitor, against prostate carcinogenesis in a transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Similar to prostate cancer in humans, prostate malignancies in TRAMP mice progress from precursor intraepithelial lesions, to invasive carcinoma that metastasizes to lymph nodes, liver, lungs, and occasionally to bone. The basal enzyme activity and protein expression of COX-2 is significantly higher (⬎4-fold) in the dorsolateral prostate of TRAMP mice up to 24 weeks of age compared with their nontransgenic littermates. Eight-week-old TRAMP mice were randomly divided and fed either control diet (AIN 76A) or a custom prepared AIN 76A diet containing 1500-ppm celecoxib ad libitum for 24 weeks, a dosage that would compare with the normal recommended dose for the treatment of human disease. Studies from two independent experiments, each consisting of 10 mice on test, showed that the cumulative incidence of prostate cancer development at 32 weeks of age in animals fed with AIN 76A diet was 100% (20 of 20) as observed by tumor palpation, whereas 65% (13 of 20), 35% (7 of 20), and 20% (4 of 20) of the animals exhibited distant site metastases to lymph nodes, lungs, and liver. Celecoxib supplementation to TRAMP mice from 8 –32 weeks of age exhibited significant reduction in tumor development (5 of 20) with no signs of metastasis. Celecoxib feeding resulted in a significant decrease in prostate (56%; P ⬍ 0.0003) and genitourinary weight (48%; P ⬍ 0.008). Sequential magnetic resonance imaging analysis of celecoxib-fed mice documented lower prostate volume compared with the AIN 76A-fed group. Histopathological examination of celecoxib-fed animals showed reduced proliferation, and down-modulation of COX-2 and prostaglandin E2 levels in the dorsolateral prostate and plasma, respectively. These results correlated with retention of antimetastasis markers, viz E-cadherin, and alpha- and beta-catenin, along with a significant decrease in vascular endothelial growth factor protein expression. Celecoxib supplementation also resulted in enhanced in vivo apoptosis in the prostate as monitored by several techniques including a recently perfected technique of 99mTc-labeled annexin V in live animals followed by phosphor imaging. One striking observation in an additional study was that celecoxib feeding to mice with established tumors (16 weeks of age) significantly improved their overall survival (P ⫽ 0.014), compared with AIN 76A-fed group. Our findings suggest that celecoxib may be useful in chemoprevention of prostate cancer. Sequence Variants of Toll-Like Receptor 4 are Associated With Prostate Cancer Risk: Results From the CAncer Prostate in Sweden Study S. L. ZHENG, K. AUGUSTSSON-BALTER, B. CHANG, M. HEDELIN, L. LI, H. O. ADAMI, J. BENSEN, G. LI, J. E. JOHNASSON, A. R. TURNER, T. S. ADAMS, D. A. MEYERS, W. B. ISAACS, J. XU AND H. GRONBERG, Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina Cancer Res, 64: 2918 –2922, 2004 Inflammation has been implicated as an etiological factor in several human cancers. Growing evidence suggests that chronic inflammation may also play a role in the etiology of prostate cancer. Considering that genetic susceptibility is a major risk factor for this disease, we hypothesize that sequence variants in genes that regulate inflammation may modify individual susceptibility to prostate cancer. The lipopolysaccharide receptor Toll-like receptor 4 (TLR4) is a central player in the signaling pathways of the innate immune response to infection by Gram-negative bacteria and is an important candidate inflammatory gene. We performed a systematic genetic analysis of TLR4 sequence variants by evaluating eight single-nucleotide polymorphisms that span the entire gene among 1383 newly diagnosed prostate cancer patients and 780 age- and residence-matched controls in Sweden. We found an association between a sequence variant (11381G/C) in the 3⬘-untranslated region of the TLR4 gene and prostate cancer risk. The frequency of the variant genotypes (CG or CC) was significantly higher in the patients (24.1%) than in the controls (19.7%; P ⫽ 0.02). The frequency of risk genotypes among patients diagnosed before the age of 65 years was even higher (26.3%). Compared with men who had the wild-type genotype of this single-nucleotide polymorphism (GG), those with GC or CC genotypes had a 26% increased risk for prostate cancer (odds ratio, 1.26; 95% confidence interval, 1.01–1.57) and 39% increased risk for early onset prostate cancer (before age 65 years; odds ratio, 1.39; 95% confidence interval, 1.02–1.91). The risk attributable to this variant for prostate cancer in Sweden was estimated to be 4.9%. Although the biological mechanism of the observed association remains to be elucidated, our finding supports a role for a bacteria-associated response pathway, possibly acting via inflammation, in the development of prostate cancer. Editorial Comment: The role of inflammation and its by-products in the development of prostate cancer is unclear but the area is under intense investigation. These 2 articles deal with separate aspects of this issue, with Gupta et al addressing the potential for inhibitors of cyclooxygenase activity to prevent prostate cancer and Zheng et al studying the role of inflammation inducing toll-like receptors in prostate cancer development. The studies reported by Gupta et al using the transgenic prostate cancer model TRAMP suggest that the cyclooxygenase inhibitor celecoxib may be useful in chemoprevention of prostate cancer. The study by Zheng et al suggests that mutations in TLR4 are associated with a higher risk of development of prostate cancer. Timothy L. Ratliff, Ph.D.
URO-SCIENCE
increasing serum prostate specific antigen. No consensus has developed concerning the efficacy of treating men with T3 margin positive disease with radiation therapy. Peter C. Albertsen, M.D.
URO-SCIENCE Molecular Determinants of Resistance to Antiandrogen Therapy C. D. CHEN, D. S. WELSBIE, C. TRAN, S. H. BAEK, R. CHEN, R. VESSELLA, M. G. ROSENFELD AND C. L. SAWYERS, Department of Medicine, University of California at Los Angeles, Los Angeles, California Nat Med, 10: 33–39, 2004 Using microarray-based profiling of isogenic prostate cancer xenograft models, we found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy. This increase in androgen receptor mRNA and protein was both necessary and sufficient to convert prostate cancer growth from a hormone-sensitive to a hormonerefractory stage, and was dependent on a functional ligand-binding domain. Androgen receptor antagonists showed agonistic activity in cells with increased androgen receptor levels; this antagonist-agonist conversion was associated with alterations in the recruitment of coactivators and corepressors to the promoters of androgen receptor target genes. Increased levels of androgen receptor confer resistance to antiandrogens by amplifying signal output from low levels of residual ligand, and by altering the normal response to antagonists. These findings provide insight toward the design of new antiandrogens. Editorial Comment: The mechanisms by which prostate cancer escapes androgen control have not been clearly defined. This study using microarray profiling identifies a potential mechanism for androgen independence.1 Timothy L. Ratliff, Ph.D. 1. Isaacs, J. T. and Isaacs, W. B.: Androgen receptor outwits prostate cancer drugs. Nat Med, 10: 26, 2004
Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand: A Novel Mechanism for Bacillus Calmette-Guerin-Induced Antitumor Activity A. T. LUDWIG, J. M. MOORE, Y. LUO, X. CHEN, N. A. SALTSGAVER, M. A. O’DONNELL Department of Urology, University of Iowa, Iowa City, Iowa
AND
T. S. GRIFFITH,
Cancer Res, 64: 3386 –3390, 2004 Mycobacterium bovis Bacillus Calmette-Guerin (BCG) use in the treatment of bladder cancer was first reported in 1976, but the mechanism of the induced antitumor activity has still not been fully explained. BCG is a potent immunostimulant, normally producing a Th1 cytokine response, including IFN. Recent studies have shown CpG oligodeoxynucleotide induce tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression via IFN production. Given that Mycobacterial DNA contains high amounts of CpG motifs, we hypothesized that BCG’s antitumor properties are akin to CpG oligodeoxynucleotide, where the cytokine response to BCG induces TRAIL up-regulation. Using ELISA, urine IFN-gamma, and TRAIL levels were initially undetectable in BCG therapy patients but were high after later induction treatments. More importantly, patients that responded to BCG therapy had significantly higher urine TRAIL levels, which killed bladder tumor cells in vitro versus nonresponders. Flow cytometry of fresh urine revealed TRAIL-expressing neutrophils. Given these data, we propose TRAIL plays a role in BCG-induced antitumor effects. Editorial Comment: Ludwig et al identified a novel and potentially important apoptosis inducing ligand (TRAIL) in the urine after BCG treatment. Neutrophils, a dominant early infiltrate after BCG treatment, were shown to express TRAIL and release it into the urine. Timothy L. Ratliff, Ph.D. Suppression of Prostate Carcinogenesis by Dietary Supplementation of Celecoxib in Transgenic Adenocarcinoma of the Mouse Prostate Model S. GUPTA, V. M. ADHAMI, M. SUBBARAYAN, G. T. MACLENNAN, J. S. LEWIN, U. O. HAFELI, P. FU AND H. MUKHTAR, Department of Urology, James and Eilleen Dicke Research Laboratory, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio Cancer Res, 64: 3334 –3343, 2004 Epidemiological studies and clinical observations suggest that nonsteroidal anti-inflammatory drugs and certain selective cyclooxygenase (COX)-2 inhibitors may reduce the relative risk of clinically evident prostate cancer. This prompted us to investigate the chemopreventive potential of celecoxib, a selective
2114
URO-SCIENCE
COX-2 inhibitor, against prostate carcinogenesis in a transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Similar to prostate cancer in humans, prostate malignancies in TRAMP mice progress from precursor intraepithelial lesions, to invasive carcinoma that metastasizes to lymph nodes, liver, lungs, and occasionally to bone. The basal enzyme activity and protein expression of COX-2 is significantly higher (⬎4-fold) in the dorsolateral prostate of TRAMP mice up to 24 weeks of age compared with their nontransgenic littermates. Eight-week-old TRAMP mice were randomly divided and fed either control diet (AIN 76A) or a custom prepared AIN 76A diet containing 1500-ppm celecoxib ad libitum for 24 weeks, a dosage that would compare with the normal recommended dose for the treatment of human disease. Studies from two independent experiments, each consisting of 10 mice on test, showed that the cumulative incidence of prostate cancer development at 32 weeks of age in animals fed with AIN 76A diet was 100% (20 of 20) as observed by tumor palpation, whereas 65% (13 of 20), 35% (7 of 20), and 20% (4 of 20) of the animals exhibited distant site metastases to lymph nodes, lungs, and liver. Celecoxib supplementation to TRAMP mice from 8 –32 weeks of age exhibited significant reduction in tumor development (5 of 20) with no signs of metastasis. Celecoxib feeding resulted in a significant decrease in prostate (56%; P ⬍ 0.0003) and genitourinary weight (48%; P ⬍ 0.008). Sequential magnetic resonance imaging analysis of celecoxib-fed mice documented lower prostate volume compared with the AIN 76A-fed group. Histopathological examination of celecoxib-fed animals showed reduced proliferation, and down-modulation of COX-2 and prostaglandin E2 levels in the dorsolateral prostate and plasma, respectively. These results correlated with retention of antimetastasis markers, viz E-cadherin, and alpha- and beta-catenin, along with a significant decrease in vascular endothelial growth factor protein expression. Celecoxib supplementation also resulted in enhanced in vivo apoptosis in the prostate as monitored by several techniques including a recently perfected technique of 99mTc-labeled annexin V in live animals followed by phosphor imaging. One striking observation in an additional study was that celecoxib feeding to mice with established tumors (16 weeks of age) significantly improved their overall survival (P ⫽ 0.014), compared with AIN 76A-fed group. Our findings suggest that celecoxib may be useful in chemoprevention of prostate cancer. Sequence Variants of Toll-Like Receptor 4 are Associated With Prostate Cancer Risk: Results From the CAncer Prostate in Sweden Study S. L. ZHENG, K. AUGUSTSSON-BALTER, B. CHANG, M. HEDELIN, L. LI, H. O. ADAMI, J. BENSEN, G. LI, J. E. JOHNASSON, A. R. TURNER, T. S. ADAMS, D. A. MEYERS, W. B. ISAACS, J. XU AND H. GRONBERG, Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina Cancer Res, 64: 2918 –2922, 2004 Inflammation has been implicated as an etiological factor in several human cancers. Growing evidence suggests that chronic inflammation may also play a role in the etiology of prostate cancer. Considering that genetic susceptibility is a major risk factor for this disease, we hypothesize that sequence variants in genes that regulate inflammation may modify individual susceptibility to prostate cancer. The lipopolysaccharide receptor Toll-like receptor 4 (TLR4) is a central player in the signaling pathways of the innate immune response to infection by Gram-negative bacteria and is an important candidate inflammatory gene. We performed a systematic genetic analysis of TLR4 sequence variants by evaluating eight single-nucleotide polymorphisms that span the entire gene among 1383 newly diagnosed prostate cancer patients and 780 age- and residence-matched controls in Sweden. We found an association between a sequence variant (11381G/C) in the 3⬘-untranslated region of the TLR4 gene and prostate cancer risk. The frequency of the variant genotypes (CG or CC) was significantly higher in the patients (24.1%) than in the controls (19.7%; P ⫽ 0.02). The frequency of risk genotypes among patients diagnosed before the age of 65 years was even higher (26.3%). Compared with men who had the wild-type genotype of this single-nucleotide polymorphism (GG), those with GC or CC genotypes had a 26% increased risk for prostate cancer (odds ratio, 1.26; 95% confidence interval, 1.01–1.57) and 39% increased risk for early onset prostate cancer (before age 65 years; odds ratio, 1.39; 95% confidence interval, 1.02–1.91). The risk attributable to this variant for prostate cancer in Sweden was estimated to be 4.9%. Although the biological mechanism of the observed association remains to be elucidated, our finding supports a role for a bacteria-associated response pathway, possibly acting via inflammation, in the development of prostate cancer. Editorial Comment: The role of inflammation and its by-products in the development of prostate cancer is unclear but the area is under intense investigation. These 2 articles deal with separate aspects of this issue, with Gupta et al addressing the potential for inhibitors of cyclooxygenase activity to prevent prostate cancer and Zheng et al studying the role of inflammation inducing toll-like receptors in prostate cancer development. The studies reported by Gupta et al using the transgenic prostate cancer model TRAMP suggest that the cyclooxygenase inhibitor celecoxib may be useful in chemoprevention of prostate cancer. The study by Zheng et al suggests that mutations in TLR4 are associated with a higher risk of development of prostate cancer. Timothy L. Ratliff, Ph.D.