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1
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Limani R, Lež C, Krušlin B. Exploring the Relationship between E-Cadherin and β-Catenin Cell Adhesion Proteins and Periacinar Retraction Clefting in Prostatic Adenocarcinoma. Diagnostics (Basel) 2024; 14:511. [PMID: 38472982 DOI: 10.3390/diagnostics14050511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 02/17/2024] [Accepted: 02/22/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND Periacinar retraction clefts represent a histopathological criterion supporting the diagnosis of prostatic adenocarcinoma. The origin of these clefts in prostatic adenocarcinoma remains unclear. Exploring the established functions of E-cadherin and β-catenin as intercellular adhesion proteins, and aiming to elucidate the origin of periacinar retraction clefting, we conducted a correlation study between the immunohistochemical expression of E-cadherin and β-catenin and the presence of periacinar retraction clefts in prostatic adenocarcinoma. METHODS We examined 53 cases of morphologically diagnosed prostatic adenocarcinoma, assessing both the neoplastic and adjacent nonneoplastic prostatic tissues for the existence and degree of periacinar retraction clefts. Additionally, we analyzed the immunohistochemical expression of E-cadherin and β-catenin proteins in prostatic tissue and explored their correlation with periacinar retraction clefts, and Gleason score, Grade Group, preoperative serum prostate specific-antigen (sPSA) levels, surgical margin status, and Tumor, Node, Metastasis (TNM) stage in prostatic adenocarcinoma. RESULTS Our study confirms that periacinar retraction clefting is significantly more extensive in prostatic adenocarcinoma than in nonneoplastic prostatic tissue (p < 0.001). We report a decreased expression of E-cadherin and β-catenin immunostaining in prostatic adenocarcinoma and a negative correlation with Gleason score and Grade Group. Periacinar retraction clefting positively correlated with E-cadherin and β-catenin ((rho = 0.350; p = 0.010) and (rho = 0.340; p = 0.012)) immunostaining in prostatic adenocarcinoma. CONCLUSIONS Periacinar retraction clefts stand out as a dependable criterion in the diagnosis of prostatic adenocarcinoma. E-cadherin and β-catenin proteins are potential markers indicative of tumor progression and invasiveness in prostatic adenocarcinoma. Our discovery of a positive correlation between immunostaining of E-cadherin and β-catenin proteins and periacinar retraction clefts in prostatic adenocarcinoma aligns with the notion that periacinar retraction clefting is more characteristic of Gleason Grade3 pattern in prostatic adenocarcinomas, whereas the immunohistochemical expression of E-cadherin and β-catenin shows a decrease with increasing histopathological tumor grade.
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Affiliation(s)
- Rinë Limani
- Faculty of Medicine, University of Prishtina "Hasan Prishtina", 10000 Prishtina, Kosovo
- Institute of Anatomical Pathology, University Clinical Center of Kosovo, 10000 Prishtina, Kosovo
| | - Cvjetko Lež
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Department of Pathology, Zabok General Hospital, 49210 Zabok, Croatia
| | - Božo Krušlin
- "Ljudevit Jurak" Department of Pathology and Cytology, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
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2
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Wang Q, Guan YF, Hancock SE, Wahi K, van Geldermalsen M, Zhang BK, Pang A, Nagarajah R, Mak B, Freidman N, Horvath LG, Turner N, Holst J. Inhibition of guanosine monophosphate synthetase (
GMPS
) blocks glutamine metabolism and prostate cancer growth. J Pathol 2021; 254:135-146. [DOI: 10.1002/path.5665] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 03/15/2021] [Accepted: 03/23/2021] [Indexed: 01/01/2023]
Affiliation(s)
- Qian Wang
- Translational Cancer Metabolism Laboratory School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney Sydney Australia
| | - Yi Fang Guan
- Translational Cancer Metabolism Laboratory School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney Sydney Australia
| | - Sarah E Hancock
- Mitochondrial Bioenergetics Laboratory, Department of Pharmacology School of Medical Sciences, UNSW Sydney Sydney Australia
| | - Kanu Wahi
- Translational Cancer Metabolism Laboratory School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney Sydney Australia
| | - Michelle van Geldermalsen
- Origins of Cancer Program, Centenary Institute University of Sydney Camperdown Australia
- Sydney Medical School University of Sydney Sydney Australia
| | - Blake K Zhang
- Origins of Cancer Program, Centenary Institute University of Sydney Camperdown Australia
- Sydney Medical School University of Sydney Sydney Australia
| | - Angel Pang
- Translational Cancer Metabolism Laboratory School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney Sydney Australia
| | - Rajini Nagarajah
- Origins of Cancer Program, Centenary Institute University of Sydney Camperdown Australia
- Sydney Medical School University of Sydney Sydney Australia
| | - Blossom Mak
- Chris O'Brien Lifehouse Sydney Australia
- Garvan Institute of Medical Research Sydney Australia
- University of NSW Sydney Australia
- University of Sydney Sydney Australia
| | - Natasha Freidman
- Translational Cancer Metabolism Laboratory School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney Sydney Australia
- School of Medical Sciences, Faculty of Medicine and Health University of Sydney Sydney Australia
| | - Lisa G Horvath
- Chris O'Brien Lifehouse Sydney Australia
- Garvan Institute of Medical Research Sydney Australia
- University of NSW Sydney Australia
- University of Sydney Sydney Australia
| | - Nigel Turner
- Mitochondrial Bioenergetics Laboratory, Department of Pharmacology School of Medical Sciences, UNSW Sydney Sydney Australia
| | - Jeff Holst
- Translational Cancer Metabolism Laboratory School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney Sydney Australia
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3
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Jamal MH, Nunes ACF, Vaziri ND, Ramchandran R, Bacallao RL, Nauli AM, Nauli SM. Rapamycin treatment correlates changes in primary cilia expression with cell cycle regulation in epithelial cells. Biochem Pharmacol 2020; 178:114056. [PMID: 32470549 DOI: 10.1016/j.bcp.2020.114056] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Accepted: 05/22/2020] [Indexed: 02/07/2023]
Abstract
Primary cilia are sensory organelles that regulate cell cycle and signaling pathways. In addition to its association with cancer, dysfunction of primary cilia is responsible for the pathogenesis of polycystic kidney disease (PKD) and other ciliopathies. Because the association between cilia formation or length and cell cycle or division is poorly understood, we here evaluated their correlation in this study. Using Spectral Karyotyping (SKY) technique, we showed that PKD and the cancer/tumorigenic epithelial cells PC3, DU145, and NL20-TA were associated with abnormal ploidy. We also showed that PKD and the cancer epithelia were highly proliferative. Importantly, the cancer epithelial cells had a reduction in the presence and/or length of primary cilia relative to the normal kidney (NK) cells. We then used rapamycin to restore the expression and length of primary cilia in these cells. Our subsequent analyses indicated that both the presence and length of primary cilia were inversely correlated with cell proliferation. Collectively, our data suggest that restoring the presence and/or length of primary cilia may serve as a novel approach to inhibit cancer cell proliferation.
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Affiliation(s)
- Maha H Jamal
- Department of Biomedical and Pharmaceutical Sciences, Harry and Diane Rinker Health Science Campus, Chapman University, Irvine, CA, USA; Department of Pharmacology, School of Medicine, King Abdulaziz University, Jeddah, KSA, Saudi Arabia
| | - Ane C F Nunes
- Division of Nephrology and Hypertension, Department of Physiology and Biophysics Division of Nephrology and Hypertension, University of California, Irvine, USA
| | - Nosratola D Vaziri
- Division of Nephrology and Hypertension, Department of Physiology and Biophysics Division of Nephrology and Hypertension, University of California, Irvine, USA
| | - Ramani Ramchandran
- Department of Pediatrics, Developmental Vascular Biology Program, Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Robert L Bacallao
- Division of Nephrology, Department of Cellular and Integrative Physiology Indiana University School of Medicine, Indianapolis, IN, USA
| | - Andromeda M Nauli
- Department of Pharmaceutical Sciences, College of Pharmacy, Marshall B. Ketchum University, Fullerton, CA, USA
| | - Surya M Nauli
- Department of Biomedical and Pharmaceutical Sciences, Harry and Diane Rinker Health Science Campus, Chapman University, Irvine, CA, USA; Department of Medicine, University of California Irvine, Irvine, CA, USA.
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4
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Zhang AY, Chiam K, Haupt Y, Fox S, Birch S, Tilley W, Butler LM, Knudsen K, Comstock C, Rasiah K, Grogan J, Mahon KL, Bianco-Miotto T, Ricciardelli C, Böhm M, Henshall S, Delprado W, Stricker P, Horvath LG, Kench JG. An analysis of a multiple biomarker panel to better predict prostate cancer metastasis after radical prostatectomy. Int J Cancer 2018; 144:1151-1159. [PMID: 30288742 DOI: 10.1002/ijc.31906] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 08/22/2018] [Indexed: 12/23/2022]
Abstract
A plethora of individual candidate biomarkers for predicting biochemical relapse in localized prostate cancer (PCa) have been proposed. Combined biomarkers may improve prognostication, and ensuring validation against more clinically relevant endpoints are required. The Australian PCa Research Centre NSW has contributed to numerous studies of molecular biomarkers associated with biochemical relapse. In the current study, these biomarkers were re-analyzed for biochemical relapse, metastatic relapse and PCa death with extended follow-up. Biomarkers of significance were then used to develop a combined prognostic model for clinical outcomes and validated in a large independent cohort. The discovery cohort (n = 324) was based on 12 biomarkers with a median follow-up of 16 years. Seven biomarkers were significantly associated with biochemical relapse. Three biomarkers were associated with metastases: AZGP1, Ki67 and PML. Only AZGP1 was associated with PCa death. In their individual and combinational forms, AZGP1 and Ki67 as a dual BM signature was the most robust predictor of metastatic relapse (AUC 0.762). The AZPG1 and Ki67 signature was validated in an independent cohort of 347 PCa patients. The dual BM signature of AZGP1 and Ki67 predicted metastasis in the univariable (HR 7.2, 95% CI, 1.6-32; p = 0.01) and multivariable analysis (HR 5.4, 95% CI, 1.2-25; p = 0.03). The dual biomarker signature marginally improved risk prediction compared to AZGP1 alone (AUC 0.758 versus 0.738, p < 0.001). Our findings indicate that biochemical relapse is not an adequate surrogate for metastasis or PCa death. The dual biomarker signature of AZGP1 and Ki67 offers a small benefit in predicting metastasis over AZGP1 alone.
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Affiliation(s)
- Alison Y Zhang
- Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,Chris O'Brien Lifehouse, Camperdown, NSW, Australia.,University of Sydney, Camperdown, NSW, Australia
| | - Karen Chiam
- Cancer Research Division, Cancer Council New South Wales, Woolloomooloo, NSW, Australia
| | - Ygal Haupt
- Peter MacCallum Cancer Centre, Parkville, VIC, Australia
| | - Stephen Fox
- Peter MacCallum Cancer Centre, Parkville, VIC, Australia.,University of Melbourne, Parkville, VIC, Australia
| | - Simone Birch
- Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Wayne Tilley
- Freemason's Foundation Centre for Men's Health, University of Adelaide, Adelaide, SA, Australia.,South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Lisa M Butler
- Freemason's Foundation Centre for Men's Health, University of Adelaide, Adelaide, SA, Australia.,South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Karen Knudsen
- Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, US
| | - Clay Comstock
- Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, US
| | | | - Judith Grogan
- Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Kate L Mahon
- Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,Chris O'Brien Lifehouse, Camperdown, NSW, Australia.,Royal Prince Alfred Hospital, Camperdown, NSW, Australia
| | - Tina Bianco-Miotto
- School of Agriculture, Food and Wine, University of Adelaide, Adelaide, SA, Australia
| | - Carmela Ricciardelli
- Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia
| | - Maret Böhm
- Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Susan Henshall
- Union for International Cancer Control, Geneva, Switzerland
| | - Warick Delprado
- Douglass Hanly Moir Pathology, Macquarie Park, NSW, Australia
| | - Phillip Stricker
- Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,Department of Urology, St Vincent's Clinic, Darlinghurst, NSW, Australia
| | - Lisa G Horvath
- Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,Chris O'Brien Lifehouse, Camperdown, NSW, Australia.,University of Sydney, Camperdown, NSW, Australia.,Royal Prince Alfred Hospital, Camperdown, NSW, Australia
| | - James G Kench
- Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,University of Sydney, Camperdown, NSW, Australia.,Royal Prince Alfred Hospital, Camperdown, NSW, Australia
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5
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Calcium and Nuclear Signaling in Prostate Cancer. Int J Mol Sci 2018; 19:ijms19041237. [PMID: 29671777 PMCID: PMC5979488 DOI: 10.3390/ijms19041237] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 04/15/2018] [Accepted: 04/17/2018] [Indexed: 02/06/2023] Open
Abstract
Recently, there have been a number of developments in the fields of calcium and nuclear signaling that point to new avenues for a more effective diagnosis and treatment of prostate cancer. An example is the discovery of new classes of molecules involved in calcium-regulated nuclear import and nuclear calcium signaling, from the G protein-coupled receptor (GPCR) and myosin families. This review surveys the new state of the calcium and nuclear signaling fields with the aim of identifying the unifying themes that hold out promise in the context of the problems presented by prostate cancer. Genomic perturbations, kinase cascades, developmental pathways, and channels and transporters are covered, with an emphasis on nuclear transport and functions. Special attention is paid to the molecular mechanisms behind prostate cancer progression to the malignant forms and the unfavorable response to anti-androgen treatment. The survey leads to some new hypotheses that connect heretofore disparate results and may present a translational interest.
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6
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Acetylated histone variant H2A.Z is involved in the activation of neo-enhancers in prostate cancer. Nat Commun 2017; 8:1346. [PMID: 29116202 PMCID: PMC5676741 DOI: 10.1038/s41467-017-01393-8] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2016] [Accepted: 09/14/2017] [Indexed: 11/10/2022] Open
Abstract
Acetylation of the histone variant H2A.Z (H2A.Zac) occurs at active promoters and is associated with oncogene activation in prostate cancer, but its role in enhancer function is still poorly understood. Here we show that H2A.Zac containing nucleosomes are commonly redistributed to neo-enhancers in cancer resulting in a concomitant gain of chromatin accessibility and ectopic gene expression. Notably incorporation of acetylated H2A.Z nucleosomes is a pre-requisite for activation of Androgen receptor (AR) associated enhancers. H2A.Zac nucleosome occupancy is rapidly remodeled to flank the AR sites to initiate the formation of nucleosome-free regions and the production of AR-enhancer RNAs upon androgen treatment. Remarkably higher levels of global H2A.Zac correlate with poorer prognosis. Altogether these data demonstrate the novel contribution of H2A.Zac in activation of newly formed enhancers in prostate cancer. Acetylation of the histone variant H2A.Z at gene promoters is associated with oncogene activation; however, it is unclear if such modification has a role in regulating the function of enhancers. Here the authors show that acetylated H2A.Z is redistributed at cancer neo-enhancers and regulates the activity of specific enhancers of cancer-related genes.
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7
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Gao F, Alwhaibi A, Sabbineni H, Verma A, Eldahshan W, Somanath PR. Suppression of Akt1-β-catenin pathway in advanced prostate cancer promotes TGFβ1-mediated epithelial to mesenchymal transition and metastasis. Cancer Lett 2017; 402:177-189. [PMID: 28602980 DOI: 10.1016/j.canlet.2017.05.028] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 05/24/2017] [Accepted: 05/25/2017] [Indexed: 11/25/2022]
Abstract
Akt1 is essential for the oncogenic transformation and tumor growth in various cancers. However, the precise role of Akt1 in advanced cancers is conflicting. Using a neuroendocrine TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model, we first show that the genetic ablation or pharmacological inhibition of Akt1 in mice blunts oncogenic transformation and prostate cancer (PCa) growth. Intriguingly, triciribine (TCBN)-mediated Akt inhibition in 25-week old, tumor-bearing TRAMP mice and Akt1 gene silencing in aggressive PCa cells enhanced epithelial to mesenchymal transition (EMT) and promoted metastasis to the lungs. Mechanistically, Akt1 suppression leads to increased expression of EMT markers such as Snail1 and N-cadherin and decreased expression of epithelial marker E-cadherin in TRAMP prostate, and in PC3 and DU145 cells. Next, we identified that Akt1 knockdown in PCa cells results in increased production of TGFβ1 and its receptor TGFβ RII, associated with a decreased expression of β-catenin. Furthermore, treatment of PCa cells with ICG001 that blocks nuclear translocation of β-catenin promoted EMT and N-cadherin expression. Together, our study demonstrates a novel role of the Akt1-β-catenin-TGFβ1 pathway in advanced PCa.
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Affiliation(s)
- Fei Gao
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA; Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Abdulrahman Alwhaibi
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
| | - Harika Sabbineni
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
| | - Arti Verma
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
| | - Wael Eldahshan
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
| | - Payaningal R Somanath
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA; Department of Medicine, Vascular Biology Center and Cancer Center, Augusta University, Augusta, GA 30912, USA.
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8
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Nakata D, Koyama R, Nakayama K, Kitazawa S, Watanabe T, Hara T. Glycogen synthase kinase-3 inhibitors suppress the AR-V7-mediated transcription and selectively inhibit cell growth in AR-V7-positive prostate cancer cells. Prostate 2017; 77:955-961. [PMID: 28397338 DOI: 10.1002/pros.23351] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 03/14/2017] [Indexed: 11/05/2022]
Abstract
BACKGROUND Recent evidence suggests that androgen receptor (AR) splice variants, including AR-V7, play a pivotal role in resistance to androgen blockade in prostate cancer treatment. The development of new therapeutic agents that can suppress the transcriptional activities of AR splice variants has been anticipated as the next generation treatment of castration-resistant prostate cancer. METHODS High-throughput screening of AR-V7 signaling inhibitors was performed using an AR-V7 reporter system. The effects of a glycogen synthase kinase-3 (GSK3) inhibitor, LY-2090314, on endogenous AR-V7 signaling were evaluated in an AR-V7-positive cell line, JDCaP-hr, by quantitative reverse transcription polymerase chain reaction. The relationship between AR-V7 signaling and β-catenin signaling was assessed using RNA interference. The effect of LY-2090314 on cell growth in various prostate cancer cell lines was also evaluated. RESULTS We identified GSK3 inhibitors as transcriptional suppressors of AR-V7 using a high-throughput screen with an AR-V7 reporter system. LY-2090314 suppressed the reporter activity and endogenous AR-V7 activity in JDCaP-hr cells. Because silencing of β-catenin partly rescued the suppression, it was evident that the suppression was mediated, at least partially, via the activation of β-catenin signaling. AR-V7 signaling and β-catenin signaling reciprocally regulate each other in JDCaP-hr cells, and therefore, GSK3 inhibition can repress AR-V7 transcriptional activity by accumulating intracellular β-catenin. Notably, LY-2090314 selectively inhibited the growth of AR-V7-positive prostate cancer cells in vitro. CONCLUSIONS Our findings demonstrate the potential of GSK3 inhibitors in treating advanced prostate cancer driven by AR splice variants. In vivo evaluation of AR splice variant-positive prostate cancer models will help illustrate the overall significance of GSK3 inhibitors in treating prostate cancer.
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Affiliation(s)
- Daisuke Nakata
- Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan
| | - Ryokichi Koyama
- Biomolecular Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan
| | - Kazuhide Nakayama
- Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan
| | - Satoshi Kitazawa
- Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan
| | - Tatsuya Watanabe
- Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan
| | - Takahito Hara
- Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan
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9
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Chen J, Zhao J, Chen X, Ding C, Lee K, Jia Z, Zhang Y, Zhou Y, Wei C, He J, Xia Z, Peng J. Hyper activation of β-catenin signalling induced by IKKε inhibition thwarts colorectal cancer cell proliferation. Cell Prolif 2017; 50. [PMID: 28523736 DOI: 10.1111/cpr.12350] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 03/30/2017] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVE Aberrant activation of Wnt/β-catenin signalling contributes significantly to the development of human colorectal cancers and β-catenin is the key signalling molecule transducing canonical Wnt/β-catenin signalling. Therefore, β-catenin is a promising therapeutic target for cancer treatment. This study demonstrates that the oncogenic IKKε kinase phosphorylates β-catenin to restrain its hyper activation, therefore promoting colorectal cancer (CRC) cell proliferation. MATERIALS AND METHODS IKKε and β-catenin expression levels in human colorectal cancer tissues and cell lines were analysed by immunohistochemical staining and Western blotting. The regulation of IKKε on Wnt/β-catenin signalling pathway was studied by reporter assay and real-time PCR analysis in the context of IKKε stably knocking down. Co-immunoprecipitation was conducted to monitor the interaction between IKKε and β-catenin. Kinase assay was performed to measure β-catenin post-translational modifications induced by IKKε. RESULTS Oncogenic IKKε kinase is required for the proliferation of colorectal cancer cells. Mechanistically, inhibition of IKKε results in β-catenin hyper activation and thwarts CRC cell proliferation. Furthermore, IKKε phosphorylates β-catenin and inhibits the activation of β-catenin signalling. CONCLUSION Our study suggests that IKKε is a potential target to combat CRC induced by aberrant Wnt/β-catenin signalling.
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Affiliation(s)
- Jie Chen
- Division of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.,Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA
| | - Jun Zhao
- Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA
| | - Xuan Chen
- Division of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Chengming Ding
- Division of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Katie Lee
- Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA
| | - Zeming Jia
- Division of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Yaoting Zhang
- Division of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Yuzheng Zhou
- State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, Hunan, 410008, China
| | - Chaoying Wei
- State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, Hunan, 410008, China
| | - Jiantai He
- Division of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Zanxian Xia
- State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, Hunan, 410008, China
| | - Jian Peng
- Division of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
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10
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Brown K, Yang P, Salvador D, Kulikauskas R, Ruohola-Baker H, Robitaille AM, Chien AJ, Moon RT, Sherwood V. WNT/β-catenin signaling regulates mitochondrial activity to alter the oncogenic potential of melanoma in a PTEN-dependent manner. Oncogene 2017; 36:3119-3136. [PMID: 28092677 PMCID: PMC5467017 DOI: 10.1038/onc.2016.450] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 09/23/2016] [Accepted: 10/12/2016] [Indexed: 12/23/2022]
Abstract
Aberrant regulation of WNT/β-catenin signaling has a crucial role in the onset and progression of cancers, where the effects are not always predictable depending on tumor context. In melanoma, for example, models of the disease predict differing effects of the WNT/β-catenin pathway on metastatic progression. Understanding the processes that underpin the highly context-dependent nature of WNT/β-catenin signaling in tumors is essential to achieve maximal therapeutic benefit from WNT inhibitory compounds. In this study, we have found that expression of the tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), alters the invasive potential of melanoma cells in response to WNT/β-catenin signaling, correlating with differing metabolic profiles. This alters the bioenergetic potential and mitochondrial activity of melanoma cells, triggered through regulation of pro-survival autophagy. Thus, WNT/β-catenin signaling is a regulator of catabolic processes in cancer cells, which varies depending on the metabolic requirements of tumors.
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Affiliation(s)
- K Brown
- School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, UK
| | - P Yang
- Department of Pharmacology, Howard Hughes Medical Institute, Institute for Stem Cell and Regenerative Medicine, Seattle, WA, USA
| | - D Salvador
- Division of Cancer Research, Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
| | - R Kulikauskas
- Department of Pharmacology, Howard Hughes Medical Institute, Institute for Stem Cell and Regenerative Medicine, Seattle, WA, USA
| | - H Ruohola-Baker
- Department of Biochemistry, University of Washington, Seattle, WA, USA
| | - A M Robitaille
- Department of Pharmacology, Howard Hughes Medical Institute, Institute for Stem Cell and Regenerative Medicine, Seattle, WA, USA
| | - A J Chien
- Department of Pharmacology, Howard Hughes Medical Institute, Institute for Stem Cell and Regenerative Medicine, Seattle, WA, USA.,Division of Dermatology, University of Washington, Seattle, WA, USA
| | - R T Moon
- Department of Pharmacology, Howard Hughes Medical Institute, Institute for Stem Cell and Regenerative Medicine, Seattle, WA, USA
| | - V Sherwood
- School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, UK.,Division of Cancer Research, Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
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11
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Ma F, Ye H, He HH, Gerrin SJ, Chen S, Tanenbaum BA, Cai C, Sowalsky AG, He L, Wang H, Balk SP, Yuan X. SOX9 drives WNT pathway activation in prostate cancer. J Clin Invest 2016; 126:1745-58. [PMID: 27043282 DOI: 10.1172/jci78815] [Citation(s) in RCA: 136] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Accepted: 02/09/2016] [Indexed: 12/12/2022] Open
Abstract
The transcription factor SOX9 is critical for prostate development, and dysregulation of SOX9 is implicated in prostate cancer (PCa). However, the SOX9-dependent genes and pathways involved in both normal and neoplastic prostate epithelium are largely unknown. Here, we performed SOX9 ChIP sequencing analysis and transcriptome profiling of PCa cells and determined that SOX9 positively regulates multiple WNT pathway genes, including those encoding WNT receptors (frizzled [FZD] and lipoprotein receptor-related protein [LRP] family members) and the downstream β-catenin effector TCF4. Analyses of PCa xenografts and clinical samples both revealed an association between the expression of SOX9 and WNT pathway components in PCa. Finally, treatment of SOX9-expressing PCa cells with a WNT synthesis inhibitor (LGK974) reduced WNT pathway signaling in vitro and tumor growth in murine xenograft models. Together, our data indicate that SOX9 expression drives PCa by reactivating the WNT/β-catenin signaling that mediates ductal morphogenesis in fetal prostate and define a subgroup of patients who would benefit from WNT-targeted therapy.
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12
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Bauman TM, Vezina CM, Ricke EA, Halberg RB, Huang W, Peterson RE, Ricke WA. Expression and colocalization of β-catenin and lymphoid enhancing factor-1 in prostate cancer progression. Hum Pathol 2016; 51:124-33. [PMID: 27067790 DOI: 10.1016/j.humpath.2015.12.024] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2015] [Revised: 12/18/2015] [Accepted: 12/23/2015] [Indexed: 11/16/2022]
Abstract
The purpose of this study was to objectively investigate β-catenin and LEF1 abundance, subcellular localization, and colocalization across benign and staged prostate cancer (PCa) specimens. A tissue microarray containing tumor-adjacent histologically benign prostate tissue (BPT; n = 48 patients), high-grade prostatic intraepithelial neoplasia (HGPIN; n = 25), localized PCa (n = 42), aggressive PCa (n = 31), and metastases (n = 22) was stained using multiplexed immunohistochemistry with antibodies toward E-cadherin, β-catenin, and LEF1. Multispectral imaging was used for quantitation, and protein expression and colocalization was evaluated across PCa progression. Stromal nuclear β-catenin abundance was greater in HGPIN and PCa compared with BPT (P < .05 for both), and epithelial nuclear β-catenin abundance was lower in metastatic PCa than in BPT (P < .05 for both). Epithelial and stromal nuclear LEF1 abundance was greater in HGPIN compared with BPT, whereas epithelial nuclear LEF1 was also greater in metastases. The proportion of epithelial and stromal nuclear double-positive β-catenin(+)/LEF1(+) cells was greater in HGPIN compared with BPT. In addition, the proportion of epithelial β-catenin(+)/LEF1(+) cells was greater in localized PCa and metastases compared with BPT. A significant amount of stromal cells were positive for LEF1 but not β-catenin. β-Catenin and LEF1 abundance were negatively correlated in the epithelium (P < .0001) but not the stroma (P > .05). We conclude that β-catenin and LEF1 colocalization is increased in HGPIN and metastasis relative to BPT, suggesting a role for β-catenin/LEF1-mediated transcription in both malignant transformation and metastasis of PCa. Furthermore, our results suggest that LEF1 abundance alone is not a reliable readout for β-catenin activity in prostate tissues.
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Affiliation(s)
- Tyler M Bauman
- Division of Urologic Surgery, Washington University School of Medicine, St Louis, MO 53705
| | - Chad M Vezina
- Department of Comparative Biosciences, University of Wisconsin School of Veterinary Medicine, Madison, WI 53705; University of Wisconsin O'Brien Urology Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705
| | - Emily A Ricke
- Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705
| | - Richard B Halberg
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705
| | - Wei Huang
- University of Wisconsin O'Brien Urology Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705
| | - Richard E Peterson
- Division of Pharmaceutical Sciences, University of Wisconsin School of Pharmacy, Madison, WI 53705
| | - William A Ricke
- University of Wisconsin O'Brien Urology Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705; Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705.
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13
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Ghahhari NM, Babashah S. Interplay between microRNAs and WNT/β-catenin signalling pathway regulates epithelial-mesenchymal transition in cancer. Eur J Cancer 2015; 51:1638-49. [PMID: 26025765 DOI: 10.1016/j.ejca.2015.04.021] [Citation(s) in RCA: 193] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Revised: 04/29/2015] [Accepted: 04/30/2015] [Indexed: 12/16/2022]
Abstract
The WNT/β-catenin signalling implies its significance in maintaining an epithelial cell phenotype, proper cell-cell junctions, and tissue homeostasis. Dysregulation of the members of this pathway involves in the development of cancer and an epithelial-mesenchymal transition (EMT) required for metastasis. Loss of E-cadherin is the major contributor to an EMT process and is largely influenced by the WNT/β-catenin signalling. An E-cadherin/β-catenin complex maintains epithelial integrity and disturbance of this complex and WNT/β-catenin pathway will ultimately lead to the nuclear translocation of β-catenin and transcription of EMT-promoting genes. WNT/β-catenin signalling is controlled by microRNAs (miRNAs), several of which are either up- or downregulated during EMT. The strong association between the expression of the WNT signalling components with miRNAs in the initiation and achievement of an EMT phenotype is suggestive of introducing these miRNAs as therapeutic targets against metastatic tumours. Therefore, this review aims to describe these putative miRNAs in altering the WNT/β-catenin signalling in EMT, and whether targeting them is a useful therapeutic option for human invasive tumours.
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Affiliation(s)
| | - Sadegh Babashah
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
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14
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Le DH. A novel method for identifying disease associated protein complexes based on functional similarity protein complex networks. Algorithms Mol Biol 2015; 10:14. [PMID: 25969691 PMCID: PMC4427953 DOI: 10.1186/s13015-015-0044-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 04/01/2015] [Indexed: 12/21/2022] Open
Abstract
Background Protein complexes formed by non-covalent interaction among proteins play important roles in cellular functions. Computational and purification methods have been used to identify many protein complexes and their cellular functions. However, their roles in terms of causing disease have not been well discovered yet. There exist only a few studies for the identification of disease-associated protein complexes. However, they mostly utilize complicated heterogeneous networks which are constructed based on an out-of-date database of phenotype similarity network collected from literature. In addition, they only apply for diseases for which tissue-specific data exist. Methods In this study, we propose a method to identify novel disease-protein complex associations. First, we introduce a framework to construct functional similarity protein complex networks where two protein complexes are functionally connected by either shared protein elements, shared annotating GO terms or based on protein interactions between elements in each protein complex. Second, we propose a simple but effective neighborhood-based algorithm, which yields a local similarity measure, to rank disease candidate protein complexes. Results Comparing the predictive performance of our proposed algorithm with that of two state-of-the-art network propagation algorithms including one we used in our previous study, we found that it performed statistically significantly better than that of these two algorithms for all the constructed functional similarity protein complex networks. In addition, it ran about 32 times faster than these two algorithms. Moreover, our proposed method always achieved high performance in terms of AUC values irrespective of the ways to construct the functional similarity protein complex networks and the used algorithms. The performance of our method was also higher than that reported in some existing methods which were based on complicated heterogeneous networks. Finally, we also tested our method with prostate cancer and selected the top 100 highly ranked candidate protein complexes. Interestingly, 69 of them were evidenced since at least one of their protein elements are known to be associated with prostate cancer. Conclusions Our proposed method, including the framework to construct functional similarity protein complex networks and the neighborhood-based algorithm on these networks, could be used for identification of novel disease-protein complex associations. Electronic supplementary material The online version of this article (doi:10.1186/s13015-015-0044-6) contains supplementary material, which is available to authorized users.
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15
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Atkinson JM, Rank KB, Zeng Y, Capen A, Yadav V, Manro JR, Engler TA, Chedid M. Activating the Wnt/β-Catenin Pathway for the Treatment of Melanoma--Application of LY2090314, a Novel Selective Inhibitor of Glycogen Synthase Kinase-3. PLoS One 2015; 10:e0125028. [PMID: 25915038 PMCID: PMC4411090 DOI: 10.1371/journal.pone.0125028] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Accepted: 03/19/2015] [Indexed: 12/12/2022] Open
Abstract
It has previously been observed that a loss of β-catenin expression occurs with melanoma progression and that nuclear β-catenin levels are inversely proportional to cellular proliferation, suggesting that activation of the Wnt/β-catenin pathway may provide benefit for melanoma patients. In order to further probe this concept we tested LY2090314, a potent and selective small-molecule inhibitor with activity against GSK3α and GSK3β isoforms. In a panel of melanoma cell lines, nM concentrations of LY2090314 stimulated TCF/LEF TOPFlash reporter activity, stabilized β-catenin and elevated the expression of Axin2, a Wnt responsive gene and marker of pathway activation. Cytotoxicity assays revealed that melanoma cell lines are very sensitive to LY2090314 in vitro (IC50 ~10 nM after 72hr of treatment) in contrast to other solid tumor cell lines (IC50 >10 uM) as evidenced by caspase activation and PARP cleavage. Cell lines harboring mutant B-RAF or N-RAS were equally sensitive to LY2090314 as were those with acquired resistance to the BRAF inhibitor Vemurafenib. shRNA studies demonstrated that β-catenin stabilization is required for apoptosis following treatment with the GSK3 inhibitor since the sensitivity of melanoma cell lines to LY290314 could be overcome by β-catenin knockdown. We further demonstrate that in vivo, LY2090314 elevates Axin2 gene expression after a single dose and produces tumor growth delay in A375 melanoma xenografts with repeat dosing. The activity of LY2090314 in preclinical models suggests that the role of Wnt activators for the treatment of melanoma should be further explored.
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Affiliation(s)
- Jennifer M. Atkinson
- Oncology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, United States of America
| | - Kenneth B. Rank
- Oncology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, United States of America
| | - Yi Zeng
- Oncology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, United States of America
| | - Andrew Capen
- Oncology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, United States of America
| | - Vipin Yadav
- Oncology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, United States of America
| | - Jason R. Manro
- Statistics Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, United States of America
| | - Thomas A. Engler
- Discovery Chemistry Research and Technologies, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, United States of America
| | - Marcio Chedid
- Oncology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, United States of America
- * E-mail:
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16
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Ganguly SS, Li X, Miranti CK. The host microenvironment influences prostate cancer invasion, systemic spread, bone colonization, and osteoblastic metastasis. Front Oncol 2014; 4:364. [PMID: 25566502 PMCID: PMC4266028 DOI: 10.3389/fonc.2014.00364] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 11/29/2014] [Indexed: 12/28/2022] Open
Abstract
Prostate cancer (PCa) is the second leading cause of cancer death in men worldwide. Most PCa deaths are due to osteoblastic bone metastases. What triggers PCa metastasis to the bone and what causes osteoblastic lesions remain unanswered. A major contributor to PCa metastasis is the host microenvironment. Here, we address how the primary tumor microenvironment influences PCa metastasis via integrins, extracellular proteases, and transient epithelia-mesenchymal transition (EMT) to promote PCa progression, invasion, and metastasis. We discuss how the bone-microenvironment influences metastasis; where chemotactic cytokines favor bone homing, adhesion molecules promote colonization, and bone-derived signals induce osteoblastic lesions. Animal models that fully recapitulate human PCa progression from primary tumor to bone metastasis are needed to understand the PCa pathophysiology that leads to bone metastasis. Better delineation of the specific processes involved in PCa bone metastasize is needed to prevent or treat metastatic PCa. Therapeutic regimens that focus on the tumor microenvironment could add to the PCa pharmacopeia.
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Affiliation(s)
- Sourik S Ganguly
- Program for Skeletal Disease and Tumor Metastasis, Laboratory of Tumor Microenvironment and Metastasis, Center for Cancer and Cell Biology, Van Andel Research Institute , Grand Rapids, MI , USA ; Program for Skeletal Disease and Tumor Metastasis, Laboratory of Integrin Signaling and Tumorigenesis, Center for Cancer and Cell Biology, Van Andel Research Institute , Grand Rapids, MI , USA
| | - Xiaohong Li
- Program for Skeletal Disease and Tumor Metastasis, Laboratory of Tumor Microenvironment and Metastasis, Center for Cancer and Cell Biology, Van Andel Research Institute , Grand Rapids, MI , USA
| | - Cindy K Miranti
- Program for Skeletal Disease and Tumor Metastasis, Laboratory of Integrin Signaling and Tumorigenesis, Center for Cancer and Cell Biology, Van Andel Research Institute , Grand Rapids, MI , USA
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17
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Cordonnier T, Bishop JL, Shiota M, Nip KM, Thaper D, Vahid S, Heroux D, Gleave M, Zoubeidi A. Hsp27 regulates EGF/β-catenin mediated epithelial to mesenchymal transition in prostate cancer. Int J Cancer 2014; 136:E496-507. [DOI: 10.1002/ijc.29122] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Accepted: 07/28/2014] [Indexed: 12/31/2022]
Affiliation(s)
- Thomas Cordonnier
- Department of Urologic Sciences; The Vancouver Prostate Centre; University of British Columbia; Vancouver British Columbia Canada
| | - Jennifer L. Bishop
- Department of Urologic Sciences; The Vancouver Prostate Centre; University of British Columbia; Vancouver British Columbia Canada
| | - Masaki Shiota
- Department of Urologic Sciences; The Vancouver Prostate Centre; University of British Columbia; Vancouver British Columbia Canada
| | - Ka Mun Nip
- Department of Urologic Sciences; The Vancouver Prostate Centre; University of British Columbia; Vancouver British Columbia Canada
| | - Daksh Thaper
- Department of Urologic Sciences; The Vancouver Prostate Centre; University of British Columbia; Vancouver British Columbia Canada
| | - Sepideh Vahid
- Department of Urologic Sciences; The Vancouver Prostate Centre; University of British Columbia; Vancouver British Columbia Canada
| | - Devon Heroux
- Department of Urologic Sciences; The Vancouver Prostate Centre; University of British Columbia; Vancouver British Columbia Canada
| | - Martin Gleave
- Department of Urologic Sciences; The Vancouver Prostate Centre; University of British Columbia; Vancouver British Columbia Canada
| | - Amina Zoubeidi
- Department of Urologic Sciences; The Vancouver Prostate Centre; University of British Columbia; Vancouver British Columbia Canada
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18
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Abstract
WNT signaling was discovered in tumor models and has been recognized as a regulator of cancer development and progression for over 3 decades. Recent work has highlighted a critical role for WNT signaling in the metabolic homeostasis of mammals, where its misregulation has been heavily implicated in diabetes. While the majority of WNT metabolism research has focused on nontransformed tissues, the role of WNT in cancer metabolism remains underinvestigated. Cancer is also a metabolic disease where oncogenic signaling pathways regulate energy production and macromolecular synthesis to fuel rapidly proliferating tumors. This review highlights the emerging evidence for WNT signaling in the reprogramming of cancer cell metabolism and examines the role of these signaling pathways as mediators of tumor bioenergetics.
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19
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Lean FZX, Kontos S, Palmieri C. Expression of β-catenin and mesenchymal markers in canine prostatic hyperplasia and carcinoma. J Comp Pathol 2014; 150:373-81. [PMID: 24529514 DOI: 10.1016/j.jcpa.2013.12.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2013] [Revised: 10/22/2013] [Accepted: 12/17/2013] [Indexed: 01/18/2023]
Abstract
β-catenin is a nuclear signalling molecule that is associated with human prostatic neoplasia and the epithelial-mesenchymal transition (EMT) process. The present study evaluates immunohistochemically the expression of β-catenin and the mesenchymal markers vimentin, desmin, calponin and smooth muscle actin (SMA) in four normal canine prostates and prostate samples from 15 dogs with benign prostatic hyperplasia (BPH) and six with prostatic carcinoma (PC). β-catenin was located on the membrane of normal epithelial cells, while the same marker had both cytoplasmic and membrane expression in hyperplastic cells and a nuclear redistribution in PC. Vimentin-positive luminal cells were observed in two of the 15 cases of BPH and in all PC samples, suggesting the conversion of neoplastic epithelial cells to a mesenchymal type. SMA was consistently negative in PC, but there was mild desmin and calponin immunoreactivity in these lesions. As in men, β-catenin is involved in canine prostatic carcinogenesis, thus further validating the use of this animal model to study human prostatic disease.
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Affiliation(s)
- F Z X Lean
- School of Veterinary Science, University of Queensland, Gatton Campus, Gatton 4343, Queensland, Australia
| | - S Kontos
- Hellenic Veterinary Laboratories S.A., 20th Km Leoforos Lavriou, 19002 Paiania Attikis, Greece
| | - C Palmieri
- School of Veterinary Science, University of Queensland, Gatton Campus, Gatton 4343, Queensland, Australia.
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20
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Rodrigues MMP, Rema A, Gartner MF, Laufer-Amorim R. Role of adhesion molecules and proliferation hyperplasic, pre neoplastic and neoplastic lesions in canine prostate. Pak J Biol Sci 2013; 16:1324-1329. [PMID: 24511741 DOI: 10.3923/pjbs.2013.1324.1329] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
E-cadherin and beta-catenin are component of adherens junctions in epithelial cells. Loss of these proteins have been associated with progression of prostatic diseases. We performed immunohistochemistry for E-cadherin, beta-catenin and Ki-67 on canine prostatic lesions. We analyzed the expression of these antibodies in benign prostatic hyperplasia (BPH, n = 22), in pre neoplastic lesions Prostatic Intra-epithelial Neoplasia (PIN), n = 3 and Prostatic Inflammatory Atrophy (PIA), n = 7 and prostate carcinoma (PC, n = 10). In this study, a membranous expression of E-cadherin and beta-catenin and nuclear expression of Ki-67 antigen were demonstrated. The proliferative index was statistically different between carcinomas and BPH and carcinomas and pre-neoplastic lesions. Like in men, the reduction of E-cadherin and increase of Ki-67 expression in neoplastic lesions in dog prostate may be related to the carcinogenic process in this gland.
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Affiliation(s)
| | - A Rema
- Institute of Biomedical Sciences of Abel Salazar, University of Porto, Portugal
| | - M F Gartner
- Institute of Biomedical Sciences of Abel Salazar, University of Porto, Portugal
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21
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Hassounah NB, Nagle R, Saboda K, Roe DJ, Dalkin BL, McDermott KM. Primary cilia are lost in preinvasive and invasive prostate cancer. PLoS One 2013; 8:e68521. [PMID: 23844214 PMCID: PMC3699526 DOI: 10.1371/journal.pone.0068521] [Citation(s) in RCA: 114] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 05/30/2013] [Indexed: 12/11/2022] Open
Abstract
Prostate cancer is the second most commonly diagnosed cancer in men worldwide. Little is known about the role of primary cilia in preinvasive and invasive prostate cancer. However, reduced cilia expression has been observed in human cancers including pancreatic cancer, renal cell carcinoma, breast cancer, cholangiocarcinoma, and melanoma. The aim of this study was to characterize primary cilia expression in preinvasive and invasive human prostate cancer, and to investigate the correlation between primary cilia and the Wnt signaling pathway. Human prostate tissues representative of stages of prostate cancer formation (normal prostate, prostatic intraepithelial neoplasia (PIN), and invasive prostate cancer (including perineural invasion)) were stained for ciliary proteins. The frequency of primary cilia was determined. A decrease in the percentage of ciliated cells in PIN, invasive cancer and perineural invasion lesions was observed when compared to normal. Cilia lengths were also measured to indirectly test functionality. Cilia were shorter in PIN, cancer, and perineural invasion lesions, suggesting dysfunction. Primary cilia have been shown to suppress the Wnt pathway. Increased Wnt signaling has been implicated in prostate cancer. Therefore, we investigated a correlation between loss of primary cilia and increased Wnt signaling in normal prostate and in preinvasive and invasive prostate cancer. To investigate Wnt signaling in our cohort, serial tissue sections were stained for β-catenin as a measure of Wnt signaling. Nuclear β-catenin was analyzed and Wnt signaling was found to be higher in un-ciliated cells in the normal prostate, PIN, a subset of invasive cancers, and perineural invasion. Our results suggest that cilia normally function to suppress the Wnt signaling pathway in epithelial cells and that cilia loss may play a role in increased Wnt signaling in some prostate cancers. These results suggest that cilia are dysfunctional in human prostate cancer, and increase Wnt signaling occurs in a subset of cancers.
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Affiliation(s)
- Nadia B. Hassounah
- The University of Arizona Cancer Center, University of Arizona, Tucson, Arizona, United States of America
| | - Ray Nagle
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona, United States of America
| | - Kathylynn Saboda
- The University of Arizona Cancer Center, University of Arizona, Tucson, Arizona, United States of America
| | - Denise J. Roe
- The University of Arizona Cancer Center, University of Arizona, Tucson, Arizona, United States of America
| | - Bruce L. Dalkin
- Department of Urology, University of Washington, Seattle, Washington, United States of America
| | - Kimberly M. McDermott
- The University of Arizona Cancer Center, University of Arizona, Tucson, Arizona, United States of America
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona, United States of America
- Bio5 Institute, University of Arizona, Tucson, Arizona, United States of America
- *
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22
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Pereira FV, Arruda DC, Figueiredo CR, Massaoka MH, Matsuo AL, Bueno V, Rodrigues EG. FTY720 induces apoptosis in B16F10-NEX2 murine melanoma cells, limits metastatic development in vivo, and modulates the immune system. Clinics (Sao Paulo) 2013; 68:1018-27. [PMID: 23917669 PMCID: PMC3715017 DOI: 10.6061/clinics/2013(07)21] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Accepted: 03/14/2013] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVE Available chemotherapy presents poor control over the development of metastatic melanoma. FTY720 is a compound already approved by the Food and Drug Administration for the treatment of patients with multiple sclerosis. It has also been observed that FTY720 inhibits tumor growth in vivo (experimental models) and in vitro (animal and human tumor cells). The aim of this study was to evaluate the effects of FTY720 on a metastatic melanoma model and in tumor cell lines. METHODS We analyzed FTY720 efficacy in vivo in a syngeneic murine metastatic melanoma model, in which we injected tumor cells intravenously into C57BL/6 mice and then treated the mice orally with the compound for 7 days. We also treated mice and human tumor cell lines with FTY720 in vitro, and cell viability and death pathways were analyzed. RESULTS FTY720 treatment limited metastatic melanoma growth in vivo and promoted a dose-dependent decrease in the viability of murine and human tumor cells in vitro. Melanoma cells treated with FTY720 exhibited characteristics of programmed cell death, reactive oxygen species generation, and increased β-catenin expression. In addition, FTY720 treatment resulted in an immunomodulatory effect in vivo by decreasing the percentage of Foxp3+ cells, without interfering with CD8+ T cells or lymphocyte-producing interferon-gamma. CONCLUSION Further studies are needed using FTY720 as a monotherapy or in combined therapy, as different types of cancer cells would require a variety of signaling pathways to be extinguished.
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Affiliation(s)
- Felipe V Pereira
- Laboratório de Imunobiologia do Câncer, Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina (EPM-UNIFESP), Universidade Federal de São Paulo, São Paulo/SP, Brazil
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23
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Abstract
Since the initial discovery of the oncogenic activity of WNT1 in mouse mammary glands, our appreciation for the complex roles for WNT signalling pathways in cancer has increased dramatically. WNTs and their downstream effectors regulate various processes that are important for cancer progression, including tumour initiation, tumour growth, cell senescence, cell death, differentiation and metastasis. Although WNT signalling pathways have been difficult to target, improved drug-discovery platforms and new technologies have facilitated the discovery of agents that can alter WNT signalling in preclinical models, thus setting the stage for clinical trials in humans.
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Affiliation(s)
- Jamie N Anastas
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA
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24
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Zimmerman ZF, Moon RT, Chien AJ. Targeting Wnt pathways in disease. Cold Spring Harb Perspect Biol 2012; 4:cshperspect.a008086. [PMID: 23001988 DOI: 10.1101/cshperspect.a008086] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Wnt-mediated signal transduction pathways have long been recognized for their roles in regulating embryonic development, and have more recently been linked to cancer, neurologic diseases, inflammatory diseases, and disorders of endocrine function and bone metabolism in adults. Although therapies targeting Wnt signaling are attractive in theory, in practice it has been difficult to obtain specific therapeutics because many components of Wnt signaling pathways are also involved in other cellular processes, thereby reducing the specificity of candidate therapeutics. New technologies, and advances in understanding the mechanisms of Wnt signaling, have improved our understanding of the nuances of Wnt signaling and are leading to promising new strategies to target Wnt signaling pathways.
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Affiliation(s)
- Zachary F Zimmerman
- Department of Medicine, Division of Oncology, University of Washington, Seattle, 98195, USA
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25
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Abstract
The Wnts are secreted cysteine-rich glycoproteins that have important roles in the developing embryo as well as in tissue homeostasis in adults. Dysregulation of Wnt signalling can lead to several types of cancer, including prostate cancer. A hallmark of the signalling pathway is the stabilization of the transcriptional co-activator β-catenin, which not only regulates expression of many genes implicated in cancer but is also an essential component of cadherin cell adhesion complexes. β-catenin regulates gene expression by binding members of the T-cell-specific transcription factor/lymphoid enhancer-binding factor 1 (TCF/LEF-1) family of transcription factors. In addition, β-catenin associates with the androgen receptor, a key regulator of prostate growth that drives prostate cancer progression. Wnt/β-catenin signalling can be controlled by secreted Wnt antagonists, many of which are downregulated in cancer. Activation of the Wnt/β-catenin pathway has effects on prostate cell proliferation, differentiation and the epithelial-mesenchymal transition, which is thought to regulate the invasive behaviour of tumour cells. However, whether targeting Wnt/β-catenin signalling is a good therapeutic option for prostate cancer remains unclear.
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26
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Pathways involved in Drosophila and human cancer development: the Notch, Hedgehog, Wingless, Runt, and Trithorax pathway. Ann Hematol 2012; 91:645-669. [PMID: 22418742 DOI: 10.1007/s00277-012-1435-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2011] [Accepted: 02/19/2012] [Indexed: 12/15/2022]
Abstract
Animal models are established tools to study basic questions of biology in a systematic way. They have greatly facilitated our understanding of the mechanisms by which nature forms and maintains organisms. Much of the knowledge on molecular changes underlying the development of organisms originates from research in the fruit fly model Drosophila melanogaster. Vertebrate models including the mouse and zebrafish model, but also other animal models coming from different corners of the animal kingdom have shown that much of the basic machinery of development is essentially identical, not just in all vertebrates but in all major phyla of invertebrates too. Moreover, key elements of this machinery have been demonstrated to be involved in recurrent molecular abnormalities detected in tumor-tissue from patients, indicating their implication in the genesis of human cancer. Thus, research in this field has become a common topic for both biologists and hemato-oncologists. In this review, we summarize current knowledge on some of these key elements and molecular pathways such as Notch, Hedgehog, Wingless, Runt, and Trithorax that have been originally described and studied in animal models and which seem to play a major role in the pathophysiology and targeted management of human cancer.
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Jacob F, Ukegjini K, Nixdorf S, Ford CE, Olivier J, Caduff R, Scurry JP, Guertler R, Hornung D, Mueller R, Fink DA, Hacker NF, Heinzelmann-Schwarz VA. Loss of secreted frizzled-related protein 4 correlates with an aggressive phenotype and predicts poor outcome in ovarian cancer patients. PLoS One 2012; 7:e31885. [PMID: 22363760 PMCID: PMC3283709 DOI: 10.1371/journal.pone.0031885] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2011] [Accepted: 01/14/2012] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Activation of the Wnt signaling pathway is implicated in aberrant cellular proliferation in various cancers. In 40% of endometrioid ovarian cancers, constitutive activation of the pathway is due to oncogenic mutations in β-catenin or other inactivating mutations in key negative regulators. Secreted frizzled-related protein 4 (SFRP4) has been proposed to have inhibitory activity through binding and sequestering Wnt ligands. METHODOLOGY/PRINCIPAL FINDINGS We performed RT-qPCR and Western-blotting in primary cultures and ovarian cell lines for SFRP4 and its key downstream regulators activated β-catenin, β-catenin and GSK3β. SFRP4 was then examined by immunohistochemistry in a cohort of 721 patients and due to its proposed secretory function, in plasma, presenting the first ELISA for SFRP4. SFRP4 was most highly expressed in tubal epithelium and decreased with malignant transformation, both on RNA and on protein level, where it was even more profound in the membrane fraction (p<0.0001). SFRP4 was expressed on the protein level in all histotypes of ovarian cancer but was decreased from borderline tumors to cancers and with loss of cellular differentiation. Loss of membrane expression was an independent predictor of poor survival in ovarian cancer patients (p = 0.02 unadjusted; p = 0.089 adjusted), which increased the risk of a patient to die from this disease by the factor 1.8. CONCLUSIONS/SIGNIFICANCE Our results support a role for SFRP4 as a tumor suppressor gene in ovarian cancers via inhibition of the Wnt signaling pathway. This has not only predictive implications but could also facilitate a therapeutic role using epigenetic targets.
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Affiliation(s)
- Francis Jacob
- Translational Research Group, University Hospital Zurich, Zurich, Switzerland
- Gynaecological Cancer Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Kristjan Ukegjini
- Translational Research Group, University Hospital Zurich, Zurich, Switzerland
| | - Sheri Nixdorf
- Gynaecological Cancer Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Caroline E. Ford
- Wnt signaling and Metastasis Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Jake Olivier
- Biostatistics Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Rosmarie Caduff
- Institute of Clinical Pathology, University Hospital Zurich, Zurich, Switzerland
| | - James P. Scurry
- Hunter Area Pathology Services, John Hunter Hospital, University of Newcastle, Callaghan, Australia
| | - Rea Guertler
- Gynaecological Cancer Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Daniela Hornung
- Department of Obstetrics and Gynecology, University of Schleswig-Holstein, Lubeck, Germany
| | - Renato Mueller
- Department of Gynecology and Obstetrics, Spital Limmattal, Zurich, Switzerland
| | - Daniel A. Fink
- Department of Gynecology, University Hospital Zurich, Zurich, Switzerland
| | - Neville F. Hacker
- Gynaecological Cancer Centre, Royal Hospital for Women, Sydney, Australia
| | - Viola A. Heinzelmann-Schwarz
- Translational Research Group, University Hospital Zurich, Zurich, Switzerland
- Gynaecological Cancer Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
- Gynaecological Cancer Centre, Royal Hospital for Women, Sydney, Australia
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Yip PY, Kench JG, Rasiah KK, Benito RP, Lee CS, Stricker PD, Henshall SM, Sutherland RL, Horvath LG. Low AZGP1 expression predicts for recurrence in margin-positive, localized prostate cancer. Prostate 2011; 71:1638-45. [PMID: 21432866 DOI: 10.1002/pros.21381] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2010] [Accepted: 02/17/2011] [Indexed: 11/06/2022]
Abstract
BACKGROUND Men with positive margins after radical prostatectomy (RP) for localized prostate cancer (PC) have a 40-50% biochemical relapse rate at 5 years. Adjuvant radiotherapy improves biochemical progression-free and overall survival in men with positive margins, but is associated with increased toxicity. There is an urgent need to identify new prognostic markers to define the group of patients who would benefit from multimodality therapy. METHODS Nuclear β-catenin, membranous secreted frizzled-related protein 4 (sFRP4), zinc-alpha 2-glycoprotein (AZGP1), and macrophage inhibitory cytokine-1 (MIC-1) have previously been identified as molecular markers of outcome in localized PC. From these published studies, we identified a subset of patients with positive margins. The aim of this study was to assess the association between these four molecular markers and outcome in men with margin-positive, localized PC. RESULTS We identified 186 men with positive margins from 330 men with localized PC; 53% had preoperative PSA >10 ng/ml, 72% extraprostatic extension (EPE), 24% seminal vesicles involvement (SVI), and 57% RP Gleason score ≥ 7. AZGP1 (P = 0.009), membranous sFRP4 (P = 0.03) and MIC-1 (P = 0.04) expression predicted for biochemical relapse on univariate analysis. Only absent/low AZGP1 expression (P = 0.01) was an independent predictor of recurrence in margin-positive, localized PC when modeled with preoperative PSA (P = 0.2), EPE (P = 0.2), SVI (P = 0.4), Gleason score ≥ 7 (P = 0.5) and adjuvant treatment (P = 0.4). Furthermore, there was an association between absent/low AZGP1 expression and clinical recurrence (P = 0.007). CONCLUSIONS AZGP1 is a potential molecular marker for biochemical relapse in men with margin-positive, localized PC. Routine assessment of this biomarker may lead to better selection of patients who will benefit from post-RP radiotherapy.
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Affiliation(s)
- Po Yee Yip
- Department of Medical Oncology, Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
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Hall CL, Zhang H, Baile S, Ljungman M, Kuhstoss S, Keller ET. p21CIP-1/WAF-1 induction is required to inhibit prostate cancer growth elicited by deficient expression of the Wnt inhibitor Dickkopf-1. Cancer Res 2010; 70:9916-26. [PMID: 21098705 PMCID: PMC3059079 DOI: 10.1158/0008-5472.can-10-0440] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Osteoblastic bone metastases are the most common metastases produced by human prostate cancers (PCa). Deregulated activity of Wnt growth factors resulting from overexpression of the Wnt inhibitor Dickkopf-1 (DKK-1) is known to contribute to formation of the osteoblastic component of PCa skeletal bone metastases. In this study, we report that DKK-1 knockdown in osteolytic human PCa cells unexpectedly delays the development of both soft tissue and osseous lesions. PCa cells deficient in DKK-1 expression did not increase canonical Wnt signaling in target osteoblast cell lines; however, DKK-1 knockdown PCa cells exhibited increased expression of the CDK inhibitor p21(CIP1/WAF1) and a 32% increase in G(1) arrest compared with control cells. Ablating p21(CIP1/WAF1) in PCa cells deficient in DKK-1 was sufficient to rescue tumor growth. Collectively, our findings demonstrate that DKK-1 overexpression supports tumor growth in part by restricting expression of p21(CIP1/WAF1) through a mechanism independent of canonical Wnt signaling.
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Affiliation(s)
| | | | | | - Mats Ljungman
- Departments of Urology and Radiation Oncology, The University of Michigan, Ann Arbor, MI 48109
| | | | - Evan T. Keller
- Correspondence to: RM 5304 CCGCB, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0940, U.S.A. Phone: (734)-615-0280. Fax: (734)-936-9220.
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Lucero OM, Dawson DW, Moon RT, Chien AJ. A re-evaluation of the "oncogenic" nature of Wnt/beta-catenin signaling in melanoma and other cancers. Curr Oncol Rep 2010; 12:314-8. [PMID: 20603725 PMCID: PMC2910886 DOI: 10.1007/s11912-010-0114-3] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
In cancer, Wnt/β-catenin signaling is ubiquitously referred to as an “oncogenic” pathway that promotes tumor progression. This review examines how the regulation and downstream effects of Wnt/β-catenin signaling in cancer varies depending on cellular context, with a focus on malignant melanoma. We emphasize that the cellular homeostasis of Wnt/β-catenin signaling may represent a more appropriate concept than the simplified view of the Wnt/β-catenin pathway as either oncogenic or tumor-suppressing. Ultimately, a more refined understanding of the contextual regulation of Wnt/β-catenin signaling will be essential for addressing if and how therapeutic targeting of this pathway could be leveraged for patient benefit.
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Affiliation(s)
- Olivia M Lucero
- Department of Medicine, Division of Dermatology, The University of Washington, Seattle, WA 98109, USA
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Shen MM, Abate-Shen C. Molecular genetics of prostate cancer: new prospects for old challenges. Genes Dev 2010; 24:1967-2000. [PMID: 20844012 DOI: 10.1101/gad.1965810] [Citation(s) in RCA: 715] [Impact Index Per Article: 47.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Despite much recent progress, prostate cancer continues to represent a major cause of cancer-related mortality and morbidity in men. Since early studies on the role of the androgen receptor that led to the advent of androgen deprivation therapy in the 1940s, there has long been intensive interest in the basic mechanisms underlying prostate cancer initiation and progression, as well as the potential to target these processes for therapeutic intervention. Here, we present an overview of major themes in prostate cancer research, focusing on current knowledge of principal events in cancer initiation and progression. We discuss recent advances, including new insights into the mechanisms of castration resistance, identification of stem cells and tumor-initiating cells, and development of mouse models for preclinical evaluation of novel therapuetics. Overall, we highlight the tremendous research progress made in recent years, and underscore the challenges that lie ahead.
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Affiliation(s)
- Michael M Shen
- Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA.
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Bianco-Miotto T, Chiam K, Buchanan G, Jindal S, Day TK, Thomas M, Pickering MA, O'Loughlin MA, Ryan NK, Raymond WA, Horvath LG, Kench JG, Stricker PD, Marshall VR, Sutherland RL, Henshall SM, Gerald WL, Scher HI, Risbridger GP, Clements JA, Butler LM, Tilley WD, Horsfall DJ, Ricciardelli C. Global Levels of Specific Histone Modifications and an Epigenetic Gene Signature Predict Prostate Cancer Progression and Development. Cancer Epidemiol Biomarkers Prev 2010; 19:2611-22. [DOI: 10.1158/1055-9965.epi-10-0555] [Citation(s) in RCA: 119] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Beildeck ME, Gelmann EP, Byers SW. Cross-regulation of signaling pathways: an example of nuclear hormone receptors and the canonical Wnt pathway. Exp Cell Res 2010; 316:1763-72. [PMID: 20138864 PMCID: PMC2878914 DOI: 10.1016/j.yexcr.2010.02.001] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2009] [Revised: 01/28/2010] [Accepted: 02/01/2010] [Indexed: 12/24/2022]
Abstract
Predicting the potential physiological outcome(s) of any given molecular pathway is complex because of cross-talk with other pathways. This is particularly evident in the case of the nuclear hormone receptor and canonical Wnt pathways, which regulate cell growth and proliferation, differentiation, apoptosis, and metastatic potential in numerous tissues. These pathways are known to intersect at many levels: in the intracellular space, at the membrane, in the cytoplasm, and within the nucleus. The outcomes of these interactions are important in the control of stem cell differentiation and maintenance, feedback loops, and regulating oncogenic potential. The aim of this review is to demonstrate the importance of considering pathway cross-talk when predicting functional outcomes of signaling, using nuclear hormone receptor/canonical Wnt pathway cross-talk as an example.
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Lu W, Tinsley HN, Keeton A, Qu Z, Piazza GA, Li Y. Suppression of Wnt/beta-catenin signaling inhibits prostate cancer cell proliferation. Eur J Pharmacol 2009; 602:8-14. [PMID: 19026633 PMCID: PMC2637082 DOI: 10.1016/j.ejphar.2008.10.053] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2008] [Revised: 09/25/2008] [Accepted: 10/29/2008] [Indexed: 11/22/2022]
Abstract
Although mounting evidence has demonstrated an important role of Wnt/beta-catenin signaling in the development and progression of cancer, the therapeutic potential of small molecules that target this pathway for prostate cancer remains largely unknown. We reported herein that the highly invasive androgen-independent PC-3 and DU145 human prostate cancer cells exhibited higher levels of Wnt/beta-catenin signaling than the androgen-dependent LNCaP prostate cancer cells and non-cancerous PZ-HPV-7 and PWR-1E prostate cells, and that exogenous Wnt3A treatment exaggerated the difference of the Wnt/beta-catenin signaling levels among these prostate cells. Furthermore, we demonstrated that the non-steroidal anti-inflammatory drug, sulindac sulfide, the cyclooxygenase-2 (COX-2) selective inhibitor, celecoxib, and the nitric oxide-donating aspirin derivative, NO-ASA, blocked Wnt/beta-catenin signaling in PC-3 and DU145 cells. These effects occurred at concentrations comparable to those required to inhibit cell proliferation, indicating that the inhibitory effect of these drugs on prostate cancer cell proliferation may involve the suppression of Wnt/beta-catenin signaling. Finally, we showed that a novel small molecule inhibitor of Wnt/beta-catenin signaling, PKF118- 310, inhibited Wnt/beta-catenin signaling and proliferation in prostate cancer cells within the same concentration range. Together, these results suggest that small molecules that inhibit Wnt/beta-catenin signaling have therapeutic potential for the prevention or treatment of prostate cancer.
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Affiliation(s)
- Wenyan Lu
- Departments of Biochemistry and Molecular Biology, Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205
| | - Heather N. Tinsley
- Departments of Biochemistry and Molecular Biology, Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205
- Department of Pharmacology and Toxicology, The University of Alabama at Birmingham, Birmingham, AL 35294
| | - Adam Keeton
- Departments of Biochemistry and Molecular Biology, Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205
| | - Zhican Qu
- Departments of Biochemistry and Molecular Biology, Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205
| | - Gary A. Piazza
- Departments of Biochemistry and Molecular Biology, Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205
- Department of Pharmacology and Toxicology, The University of Alabama at Birmingham, Birmingham, AL 35294
| | - Yonghe Li
- Departments of Biochemistry and Molecular Biology, Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205
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Fiorentino M, Zadra G, Palescandolo E, Fedele G, Bailey D, Fiore C, Nguyen PL, Migita T, Zamponi R, Di Vizio D, Priolo C, Sharma C, Xie W, Hemler ME, Mucci L, Giovannucci E, Finn S, Loda M. Overexpression of fatty acid synthase is associated with palmitoylation of Wnt1 and cytoplasmic stabilization of beta-catenin in prostate cancer. J Transl Med 2008; 88:1340-8. [PMID: 18838960 PMCID: PMC3223737 DOI: 10.1038/labinvest.2008.97] [Citation(s) in RCA: 110] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Fatty acid synthase (FASN), a key metabolic enzyme for liponeogenesis highly expressed in several human cancers, displays oncogenic properties such as resistance to apoptosis and induction of proliferation when overexpressed. To date, no mechanism has been identified to explain the oncogenicity of FASN in prostate cancer. We generated immortalized prostate epithelial cells (iPrECs) overexpressing FASN, and found that (14)C-acetate incorporation into palmitate synthesized de novo by FASN was significantly elevated in immunoprecipitated Wnt-1 when compared to isogenic cells not overexpressing FASN. Overexpression of FASN caused membranous and cytoplasmic beta-catenin protein accumulation and activation, whereas FASN knockdown by short-hairpin RNA resulted in a reduction in the extent of beta-catenin activation. Orthotopic transplantation of iPrECs overexpressing FASN in nude mice resulted in invasive tumors that overexpressed beta-catenin. A strong significant association between FASN and cytoplasmic (stabilized) beta-catenin immunostaining was found in 862 cases of human prostate cancer after computerized subtraction of the membranous beta-catenin signal (P<0.001, Spearman's rho=0.33). We propose that cytoplasmic stabilization of beta-catenin through palmitoylation of Wnt-1 and subsequent activation of the pathway is a potential mechanism of FASN oncogenicity in prostate cancer.
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Affiliation(s)
- Michelangelo Fiorentino
- Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, MA, USA
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Takeda K, Kinoshita I, Shimizu Y, Ohba Y, Itoh T, Matsuno Y, Shichinohe T, Dosaka-Akita H. Clinicopathological significance of expression of p-c-Jun, TCF4 and beta-Catenin in colorectal tumors. BMC Cancer 2008; 8:328. [PMID: 18992165 PMCID: PMC2585585 DOI: 10.1186/1471-2407-8-328] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2008] [Accepted: 11/08/2008] [Indexed: 12/03/2022] Open
Abstract
Background A recent study has shown that phosphorylated c-Jun (p-c-Jun) interacts with TCF4 to form a complex that cooperatively enhances their transcriptional activity in the presence of β-Catenin, and that their interaction is critical for mouse intestinal tumorigenesis. To determine the significance of these three proteins in human colorectal tumors, we analyzed their nuclear expression by immunohistochemistry. Methods we analyzed their nuclear expression by immunohistochemistry using paraffin-embedded specimens of 68 resected colorectal tumors, which consisted of 19 adenomas, 14 high-grade intraepithelial neoplasia (HGINs) and 35 adenocarcinomas. We also analyzed the expression of MMP7, which has functional AP-1 and TCF binding sites in its promoter. Results Expression of p-c-Jun, TCF4 and β-Catenin were significantly higher in adenomas than in the adjacent normal epithelia. Expression of p-c-Jun and β-Catenin in HGINs and adenocarcinomas were also significantly higher than in the adjacent normal epithelia. p-c-Jun expression, but not TCF4 and β-Catenin, was higher in adenomas and HGINs than in adenocarcinomas, in which p-c-Jun expression was negatively correlated with pT stage progression. Furthermore, significant correlations of expression were observed between p-c-Jun and TCF4 (r = 0.25, p = 0.04), TCF4 and β-Catenin (r = 0.30, p = 0.01), p-c-Jun and MMP7 (r = 0.26, p = 0.03), and TCF4 and MMP7 (r = 0.39, p = 0.0008), respectively. Conclusion These results suggest that nuclear expression of p-c-Jun, TCF4 and β-Catenin have important roles in human colorectal tumor development and that p-c-Jun may play a pivotal role in the earlier stages of tumor development.
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Affiliation(s)
- Kayoko Takeda
- Department of Medical Oncology, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan.
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Whitaker HC, Girling J, Warren AY, Leung H, Mills IG, Neal DE. Alterations in beta-catenin expression and localization in prostate cancer. Prostate 2008; 68:1196-205. [PMID: 18459111 DOI: 10.1002/pros.20780] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND Wnt signaling is thought to be important in prostate cancer, in part because proteins such as beta-catenin can also affect androgen receptor signaling. beta-Catenin forms a cell adhesion complex with E-cadherin raising the possibility that loss of expression or a change in beta-catenin distribution in the cell could also alter downstream signaling, decreased inter-cellular adhesion and the promotion of metastasis. A number of studies have reported the altered expression and/or localization of beta-catenin as a biomarker in prostate cancer. METHODS Tissue microarrays comprised of BPH and low, moderate and high-grade prostate cancer (n=77) were assessed for beta-catenin expression and distribution using immunohistochemistry. Staining was also performed on a tissue microarray containing tissue from patients before and after hormone manipulation. The effects of fixation and different antibodies was assessed on fixed LNCaP cell pellets and small prostate tissue microarrays. RESULTS We have observed increased beta-catenin expression in only high Gleason score (>7) prostate cancer. A nuclear re-distribution of beta-catenin has previously been reported. We noted nuclear beta-catenin in benign prostatic hyperplasia and a gradual loss in nuclear distribution with increasing Gleason grade. We found no evidence for an alteration in beta-catenin expression or re-distribution with hormone ablation. Altered fixation, antibodies and antibody concentration did affect the intensity and specificity of staining. CONCLUSIONS A loss of nuclear beta-catenin is the most consistent feature in prostate cancer rather than absolute levels of expression. We also suggest that variation in immunohistochemical protocols may explain variations in the reported literature.
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Affiliation(s)
- Hayley C Whitaker
- Uro-Oncology Research Group, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK.
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Koriyama C, Akiba S, Itoh T, Sueyoshi K, Minakami Y, Corvalan A, Yonezawa S, Eizuru Y. E-cadherin and beta-catenin expression in Epstein-Barr virus-associated gastric carcinoma and their prognostic significance. World J Gastroenterol 2007; 13:3925-31. [PMID: 17663505 PMCID: PMC4171163 DOI: 10.3748/wjg.v13.i29.3925] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the role of E-cadherin and beta-catenin in carcinogenesis and to assess their prognostic implication in Epstein-Barr virus-associated gastric carcinomas (EBV-GCs).
METHODS: We compared the frequency of E-cadherin and beta-catenin expression in 59 EBV-GCs and 120 non-EBV-GCs, and examined the association between patients' prognosis and the expressions of these proteins.
RESULTS: Neither the cellular-membranous nor the cytoplasmic E-cadherin expression showed any difference between EBV-GCs and non-EBV-GCs. On the other hand, loss of membranous expression of beta-catenin occurred more frequently in non-EBV-GCs than EBV-GCs [odds ratio = 0.41; 95% confidence interval (CI), 0.19-0.90]. Furthermore, the nuclear and/or cytoplosmic expression of beta-catenin was seen more frequently in EBV-GCs than non-EBV-GCs (odds ratio = 2.23; 95% CI, 0.97-5.09), and was observed in a larger proportion of carcinoma cells of EBV-GCs than non-EBV-GCs (P = 0.024). Survival analysis for non-EBV-GC revealed that lymph node metastasis was significantly associated with poor prognosis (P < 0.001). Among EBV-GCs, the depth of invasion (P = 0.005), lymph node metastasis (P = 0.004) and an intestinal type by Lauren classification (hazard ratio = 9.47; 95% CI, 2.67-33.6) were significantly associated with poor prognosis. On the other hand, nuclear and/or cytoplasmic expression of beta-catenin was associated with a better prognosis in patients with EBV-GC (hazard ratio = 0.32; 95% CI, 0.11-0.93).
CONCLUSION: We observed more frequent preservation of beta-catenin in cell membrane and accumulation in nuclei and/or cytoplasm in EBV-GCs than in non-EBV-GCs. Factors involved in the prognosis of EBV-GCs and non-EBV-GCs are different in the two conditions.
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Affiliation(s)
- Chihaya Koriyama
- Department of Epidemiology and Preventive Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
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Lawrence MG, Veveris-Lowe TL, Whitbread AK, Nicol DL, Clements JA. Epithelial-mesenchymal transition in prostate cancer and the potential role of kallikrein serine proteases. Cells Tissues Organs 2007; 185:111-5. [PMID: 17587816 DOI: 10.1159/000101311] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Prostate cancer is associated with significant mortality once the tumour has spread outside the gland. Epithelial-mesenchymal transition (EMT) has been proposed to facilitate this dissemination of tumour cells. In this article we summarize the evidence for EMT in prostate cancer, drawing on the expression of EMT-related markers and the functions of factors known to induce EMT in other systems. We also discuss our recent findings that two members of the tissue kallikrein family of serine proteases, prostate-specific antigen (PSA/KLK3) and kallikrein-related peptidase 4 (KLK4), lead to EMT-like changes in PC3 prostate cancer cells.
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Affiliation(s)
- Mitchell G Lawrence
- Hormone-Dependent Cancer Program, School of Life Sciences and Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
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Horvath LG, Lelliott JE, Kench JG, Lee CS, Williams ED, Saunders DN, Grygiel JJ, Sutherland RL, Henshall SM. Secreted frizzled-related protein 4 inhibits proliferation and metastatic potential in prostate cancer. Prostate 2007; 67:1081-90. [PMID: 17476687 DOI: 10.1002/pros.20607] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Secreted frizzled-related proteins (sFRP4) inhibits Wnt signaling and thus cellular proliferation in androgen-independent prostate cancer cells in vitro. However, increased expression of membranous sFRP4 is associated with a good prognosis in human localized androgen-dependent prostate cancer, suggesting a role for sFRP4 in early stage disease. Here, we investigated the phenotype of sFRP4 overexpression in an androgen-dependent prostate cancer model. METHODS An sFRP4-overexpressing androgen-dependent (LNCaP) prostate cancer model was established to assess changes in cellular proliferation, the expression, and subcellular localization of adhesion molecules and cellular invasiveness, and compared with the findings in sFRP4-overexpressing androgen-independent cells (PC3). RESULTS sFRP4 overexpression in both cell line models resulted in a morphologic change to a more epithelioid cell type with increased localization of beta-catenin and cadherins (E-cadherin in LNCaP, N-cadherin in PC3) to the cell membrane. Functionally, sFRP4 overexpression was associated with a decreased rate of proliferation (P = 0.0005), decreased anchorage-independent growth (P < 0.001), and decreased invasiveness in PC3 cells (P < 0.0001). Furthermore, increased membranous sFRP4 expression was associated with increased membranous beta-catenin expression (P = 0.02) in a cohort of 224 localized human androgen-dependent prostate cancers. CONCLUSIONS These data suggest that sFRP4 is an inhibitor of prostate cancer growth and invasion in vitro independent of androgen receptor (AR) signaling with correlative evidence in human androgen-dependent disease suggesting similar changes in the clinical setting. Consequently, potential therapeutic strategies to modulate Wnt signaling by sFRP4 will be relevant to both localized androgen-dependent prostate cancer and advanced metastatic disease.
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Affiliation(s)
- Lisa G Horvath
- Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, Australia
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41
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Mol AJM, Geldof AA, Meijer GA, van der Poel HG, van Moorselaar RJA. New experimental markers for early detection of high-risk prostate cancer: role of cell-cell adhesion and cell migration. J Cancer Res Clin Oncol 2007; 133:687-95. [PMID: 17520286 DOI: 10.1007/s00432-007-0235-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2007] [Accepted: 04/26/2007] [Indexed: 11/24/2022]
Abstract
Today's treatment and diagnosis of prostate cancer still exhibit major limitations. The search for new and additional prognostic markers is therefore still an actual field of interest. Potential markers involved in numerous biological processes in the tumor cell have been investigated intensively. For therapeutic interventions it is important to distinguish between harmless and aggressive disease in an early stage. Therefore the subject of this review is limited to markers associated with those functional processes, which discriminate early stage aggressive, metastatic cancer from harmless disease. Important processes in this respect are: altered cell adhesion and cellular migration. E-cadherin, N-cadherin, beta-catenin, integrins, focal adhesion kinase, connexins and matrix metalloproteinases all appear promising biological markers associated with the early stage metastatic process in prostate cancer. Here we discuss their potential to become valid biological markers based on literature data. Thus far, none of these markers proved to be a valid individual marker by itself due to prostate cancer heterogeneity and transient expression. Analyzing a combination of the potential markers discussed in this review is expected to be a better approach toward discriminating high- from low-risk tumors in an early stage of prostate cancer.
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Affiliation(s)
- A J M Mol
- Department of Urology, VU University Medical Center, PO Box 7057, 1007, MB, Amsterdam, The Netherlands.
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42
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van der Poel HG. Molecular markers in the diagnosis of prostate cancer. Crit Rev Oncol Hematol 2006; 61:104-39. [PMID: 16945550 DOI: 10.1016/j.critrevonc.2006.07.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2006] [Revised: 06/30/2006] [Accepted: 07/07/2006] [Indexed: 01/17/2023] Open
Abstract
The genetic alterations leading to prostate cancer are gradually being discovered. A wide variety of genes have been associated with prostate cancer development as well as tumor progression. Knowledge of gene polymorphisms associated with disease aid in the understanding of important pathways involved in this process and may result in the near future in clinical applications. Urinary molecular markers will soon be available to aid in the decision of repeat prostate biopsies. Recent findings suggest the importance of androgen signaling in disease development and progression. The further understanding of interaction of inflammation, diet, and genetic predisposition will improve risk stratification in the near future.
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Affiliation(s)
- H G van der Poel
- Department of Urology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
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Zheng YM, Li F, Dong CW, Wu XT. Expression of Axin protein correlates with genesis and metastasis of gastric carcinoma. Shijie Huaren Xiaohua Zazhi 2006; 14:763-766. [DOI: 10.11569/wcjd.v14.i8.763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relationship between Axin protein expression and genesis and metastasis of gastric carcinoma.
METHODS: A total of 46 patients with gastric carcinoma underwent surgical resection were included in this study. The expression of Axin protein was detected by immunohistochemical techniques (SABC) in paraffin-embedded samples prepared from gastric carcinoma tissues and normal stomach tissues far from the tumor. In addition, the positive rate of Axin expression was calculated and its corrrelation with the pathological characteristics of gastric carcinoma was analyzed.
RESULTS: In normal stomach tissues, Axin protein expression was strongly positive and intensified in basal cells. Axin was also expressed in tissues from gastric carcinoma and normal stomach mucosa far from the tumor with a positive rate of 62.0% and 91.3%, respectively. There was a significant difference between them (P < 0.01). Axin protein expression was significantly correlated with clinical TNM classification (TNM Ⅰ, Ⅱ vs Ⅲ, Ⅳ: 78.6% vs 56.3%, P = 0.035) and lymphatic metastasis (without vs with: 85.7% vs 53.1%, P = 0.034). The expression of Axin protein was not markedly correlated with the age and gender of patients, tumor size, biological features and serosa invasion (P > 0.05).
CONCLUSION: The expression of Axin protein is down-regulated in gastric carcinoma, which correlates with the genesis and metastasis of the disease.
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Joesting MS, Perrin S, Elenbaas B, Fawell SE, Rubin JS, Franco OE, Hayward SW, Cunha GR, Marker PC. Identification of SFRP1 as a candidate mediator of stromal-to-epithelial signaling in prostate cancer. Cancer Res 2006; 65:10423-30. [PMID: 16288033 DOI: 10.1158/0008-5472.can-05-0824] [Citation(s) in RCA: 118] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Genetic changes in epithelial cells initiate the development of prostatic adenocarcinomas. As nascent tumors grow and undergo progression, epithelial tumor cells are intimately associated with stromal cells. Stromal cells within the tumor microenvironment acquire new properties, including the capacity to promote phenotypic and genetic progression in adjacent epithelial cells. Affymetrix microarrays were used to identify 119 genes differentially expressed between normal-derived and carcinoma-derived prostatic stromal cells. These included 31 genes encoding extracellular proteins that may act as stromal-to-epithelial paracrine signals. Further investigation of one of these genes, secreted frizzled related protein 1 (SFRP1), revealed that its expression parallels prostatic growth with high expression during prostatic development, low expression in the adult prostate, and elevated expression in prostatic tumor stroma. In addition, as prostatic epithelial cells progressed to a tumorigenic state under the influence of tumor stroma, SFRP1 became overexpressed in the progressed epithelial cells. To further understand the roles of SFRP1 in the prostate, we tested the affects of increased SFRP1 levels on prostatic tissues and cells. Treatment of developing prostates with SFRP1 in culture led to increased organ growth. Treatment of a human prostatic epithelial cell line with SFRP1 led to increased proliferation, decreased apoptosis, and decreased signaling through the Wnt/beta-catenin pathway in vitro and increased proliferation in vivo. These data suggest that overexpression of SFRP1 by prostatic tumor stroma may account for the previously reported capacity of prostatic tumor stroma to provide a pro-proliferative paracrine signal to adjacent epithelial cells.
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Affiliation(s)
- Margaret S Joesting
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota 55455, USA
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Song LN, Gelmann EP. Interaction of beta-catenin and TIF2/GRIP1 in transcriptional activation by the androgen receptor. J Biol Chem 2005; 280:37853-67. [PMID: 16141201 DOI: 10.1074/jbc.m503850200] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
The multifunctional oncoprotein beta-catenin interacts with the activation function-2 domain of androgen receptor (AR) to stimulate androgen receptor transcriptional activity, increase sensitivity, and broaden specificity of ligand interactions. beta-Catenin interacts with androgen receptor in close proximity to the binding groove for P160 coactivators such as transcriptional intermediary factor-2 (TIF2)/glucocorticoid receptor interacting protein-1 (GRIP1). beta-Catenin can also bind directly to TIF2/GRIP1. Both N- and C-terminal regions of beta-catenin are needed for optimal interaction with TIF2/GRIP1. We show that distinct residues of beta-catenin are responsible for both binding and functional interactions with androgen receptor and with TCF4, thus allowing the introduction of missense mutations that selectively affect these interactions. beta-Catenin and TIF2/GRIP1 are each able to mediate binding between the other and androgen receptor in functional interactions that enhance ligand-dependent transcription. The data strongly imply that AR, beta-catenin, and TIF2/GRIP1 bind in a three-way interaction that mediates transcription. Lastly, we observed that a beta-catenin C-terminal peptide containing 229 amino acids can bind TIF2/GRIP1 and AR but has a profound dominant inhibitory effect on ligand-dependent transcription. We propose that beta-catenin may play an integral role in formation of the androgen-receptor transcriptional complex.
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Affiliation(s)
- Liang-Nian Song
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007-2197, USA
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Quinn DI, Henshall SM, Sutherland RL. Molecular markers of prostate cancer outcome. Eur J Cancer 2005; 41:858-87. [PMID: 15808955 DOI: 10.1016/j.ejca.2004.12.035] [Citation(s) in RCA: 140] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2004] [Accepted: 12/02/2004] [Indexed: 01/14/2023]
Abstract
Molecular markers have the potential to serve not only as prognostic factors but may be targets for new therapeutic strategies and predictors of response in a range of cancers. Prostate cancer development and progression is predicated on a series of genetic and epigenetic events within the prostate cell and its milieu. Within this review, we identify candidate molecules involved in diverse processes such as cell proliferation, death and apoptosis, signal transduction, androgen receptor (AR) signalling, cellular adhesion and angiogenesis that are linked to outcome in prostate cancer. Current markers with potential prognostic value include p53, Bcl-2, p16INK4A, p27Kip1, c-Myc, AR, E-cadherin and vascular endothelial growth factor. Evolving technology permits the identification of an increasing number of molecular markers with prognosis and predictive potential. We also review the use of gene microarray analysis in gene discovery as a means of identifying and cosegregating novel markers of prostate cancer outcome. By integrating selected markers into prospective clinical trials, there is potential for us to provide specific targeted therapy tailored for an increasing number of patients.
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Affiliation(s)
- David I Quinn
- Division of Oncology, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastalke Avenue, Suite 3453, Los Angeles, CA 90033, USA.
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Chua CW, Lee DTW, Ling MT, Zhou C, Man K, Ho J, Chan FL, Wang X, Wong YC. FTY720, a fungus metabolite, inhibitsin vivo growth of androgen-independent prostate cancer. Int J Cancer 2005; 117:1039-48. [PMID: 15986440 DOI: 10.1002/ijc.21243] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
FTY720, a derivative of fungus, has demonstrated dramatic anticancer effect in several malignancies recently. Our study evaluates the therapeutic potential of FTY720 in the treatment of androgen-independent prostate cancer using a human prostate cancer xenograft in nude mice. CWR22R, an androgen-independent human prostate tumor xenograft was inoculated into castrated nude mice and the animals were administrated with either normal saline or FTY720 (10 mg/kg) through intraperitoneal (i.p.) injection for 20 days. Body weight and tumor volume were recorded every 2 days, and serum prostate specific antigen (PSA) levels were also measured before and after the treatment. The effect of FTY720 on tumor cell proliferation was examined using antibodies against PCNA and Ki-67 by immunohistochemical staining, MTT assay and colony forming assay, whereas apoptotic effect of FTY720 was evaluated by TUNEL assay and immunostaining using antibodies against cleaved caspase 3 and Bcl-2. In addition, the potential inhibitory effect of FTY720 on prostate cancer angiogenesis and metastasis was investigated by immunostaining of CD31, VEGF, E-cadherin and beta-catenin. Our results showed that FTY720 treatment led to suppression of CWR22R tumor growth without causing any detectable side effects in nude mice. The FTY720-induced tumor suppression was correlated with decreased serum PSA level as well as reduced proliferation rate, suppression of angiogenic factors, and restoration of E-cadherin and beta-catenin expression. In addition, the FTY720-treated tumors showed increased apoptosis rate demonstrated by increased TUNEL- and cleaved caspase 3-positive cells, and decreased Bcl-2 expression. Our results suggest a potential novel agent in the suppression of androgen-independent prostate cancer.
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Affiliation(s)
- Chee-Wai Chua
- Department of Anatomy, Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
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