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Kaltsas A, Giannakas T, Stavropoulos M, Kratiras Z, Chrisofos M. Oxidative Stress in Benign Prostatic Hyperplasia: Mechanisms, Clinical Relevance and Therapeutic Perspectives. Diseases 2025; 13:53. [PMID: 39997060 PMCID: PMC11854834 DOI: 10.3390/diseases13020053] [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: 01/14/2025] [Revised: 02/05/2025] [Accepted: 02/10/2025] [Indexed: 02/26/2025] Open
Abstract
BACKGROUND/OBJECTIVES Benign prostatic hyperplasia (BPH) is among the most common conditions affecting men as they age, resulting in lower urinary tract symptoms (LUTS) that can profoundly impact quality of life. While historically attributed primarily to androgenic imbalances, current evidence implicates additional factors-particularly oxidative stress (OS) and chronic inflammation-in BPH pathogenesis. This review aims to synthesize research on the interplay between OS, inflammation, and hormonal regulation in BPH, emphasizing their clinical relevance and potential therapeutic implications. METHODS A comprehensive review of peer-reviewed literature was conducted focusing on mechanistic studies, clinical trials, and observational reports. Searches included data on ROS generation, antioxidant capacity, inflammatory mediators, and their contribution to pathological prostatic overgrowth. Potential interventions targeting OS-such as antioxidant supplementation, anti-inflammatory drugs, vitamin D receptor agonists, and phytotherapeutics-were also evaluated for their efficacy and safety profiles. RESULTS Chronic inflammation and OS were consistently identified within hyperplastic prostate tissue. Excessive ROS production, diminished antioxidant defense, and sustained cytokine release create a proproliferative and antiapoptotic environment, accelerating disease progression. Metabolic comorbidities (e.g., obesity, insulin resistance) further exacerbate these imbalances. Standard therapies (α-blockers and 5-ARIs) effectively relieve symptoms but do not directly address the oxidative-inflammatory axis. Emerging evidence suggests that pharmacological and dietary approaches targeting OS and inflammation may reduce prostate volume expansion and alleviate LUTS. CONCLUSIONS Findings indicate that OS and inflammation are key contributors to BPH progression. Incorporating antioxidant and anti-inflammatory strategies alongside conventional treatments holds promise for improving clinical outcomes and patient quality of life. Future research should focus on validating OS-specific biomarkers and optimizing personalized therapy regimens.
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Affiliation(s)
| | | | | | | | - Michael Chrisofos
- Third Department of Urology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece; (A.K.); (T.G.); (M.S.); (Z.K.)
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Kim ES, Kim SY, Moon A. C-Reactive Protein Signaling Pathways in Tumor Progression. Biomol Ther (Seoul) 2023; 31:473-483. [PMID: 37562952 PMCID: PMC10468419 DOI: 10.4062/biomolther.2023.132] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 07/25/2023] [Accepted: 07/27/2023] [Indexed: 08/12/2023] Open
Abstract
Many cancers arise from sites of chronic inflammation, which creates an inflammatory microenvironment surrounding the tumor. Inflammatory substances secreted by cells in the inflammatory environment can induce the proliferation and survival of cancer cells, thereby promoting cancer metastasis and angiogenesis. Therefore, it is important to identify the role of inflammatory factors in cancer progression. This review summarizes the signaling pathways and roles of C-reactive protein (CRP) in various cancer types, including breast, liver, renal, and pancreatic cancer, and the tumor microenvironment. Mounting evidence suggests the role of CRP in breast cancer, particularly in triple-negative breast cancer (TNBC), which is typically associated with a worse prognosis. Increased CRP in the inflammatory environment contributes to enhanced invasiveness and tumor formation in TNBC cells. CRP promotes endothelial cell formation and angiogenesis and contributes to the initiation and progression of atherosclerosis. In pancreatic and kidney cancers, CRP contributes to tumor progression. In liver cancer, CRP regulates inflammatory responses and lipid metabolism. CRP modulates the activity of various signaling molecules in macrophages and monocytes present in the tumor microenvironment, contributing to tumor development, the immune response, and inflammation. In the present review, we overviewed the role of CRP signaling pathways and the association between inflammation and cancer in various types of cancer. Identifying the interactions between CRP signaling pathways and other inflammatory mediators in cancer progression is crucial for understanding the complex relationship between inflammation and cancer.
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Affiliation(s)
- Eun-Sook Kim
- Duksung Innovative Drug Center, College of Pharmacy, Duksung Women’s University, Seoul 01369, Republic of Korea
| | - Sun Young Kim
- Department of Chemistry, College of Science and Technology, Duksung Women’s University, Seoul 01369, Republic of Korea
| | - Aree Moon
- Duksung Innovative Drug Center, College of Pharmacy, Duksung Women’s University, Seoul 01369, Republic of Korea
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Sedeta E, Sung H, Laversanne M, Bray F, Jemal A. Recent Mortality Patterns and Time Trends for the Major Cancers in 47 Countries Worldwide. Cancer Epidemiol Biomarkers Prev 2023; 32:894-905. [PMID: 37195435 DOI: 10.1158/1055-9965.epi-22-1133] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 02/22/2023] [Accepted: 04/25/2023] [Indexed: 05/18/2023] Open
Abstract
BACKGROUND Most prior studies have reported cancer mortality trends across countries for specific cancer types. Herein, we examine recent patterns and trends in cancer mortality rates for the eight common forms of cancer in 47 countries across five continents (except Africa) based on the World Health Organization mortality database. METHODS Rates were age-standardized to the 1966 Segi-Doll world population, and trends in the age-standardized rates for the most recent 10 years of data were examined using Joinpoint regression. RESULTS Cancer-specific mortality rates vary substantially across countries, with rates of infection-related (cervix and stomach) and tobacco-related cancers (lung and esophagus) varying by 10-fold. Recent mortality rates for all major cancers decreased in most of the studied countries except lung cancer in females and liver cancer in males, where increasing rates were observed in most countries. Rates decreased or stabilized in all countries for lung cancer in men and stomach cancer in both sexes. CONCLUSIONS The findings reinforce the importance of implementing and strengthening resource-stratified and targeted cancer prevention and control programs in all parts of the world to further reduce or halt the rising cancer burden. IMPACT The results may inform cancer prevention and treatment strategies and in so doing, reduce the marked global cancer disparities observed today.
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Affiliation(s)
- Ephrem Sedeta
- Brookdale University Hospital Medical Center, Brooklyn, New York
| | - Hyuna Sung
- Surveillance & Health Equity Science, American Cancer Society, Atlanta, Georgia
| | - Mathieu Laversanne
- Cancer Surveillance Branch, International Agency for Research on Cancer, Lyon, France
| | - Freddie Bray
- Cancer Surveillance Branch, International Agency for Research on Cancer, Lyon, France
| | - Ahmedin Jemal
- Surveillance & Health Equity Science, American Cancer Society, Atlanta, Georgia
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Nepal SP, Nakasato T, Fukagai T, Ogawa Y, Nakagami Y, Shichijo T, Morita J, Maeda Y, Oshinomi K, Unoki T, Noguchi T, Inoue T, Kato R, Amano S, Mizunuma M, Kurokawa M, Tsunokawa Y, Yasuda S. Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios alone or combined with prostate-specific antigen for the diagnosis of prostate cancer and clinically significant prostate cancer. Asian J Urol 2023; 10:158-165. [PMID: 36942115 PMCID: PMC10023529 DOI: 10.1016/j.ajur.2022.02.007] [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: 12/06/2020] [Revised: 06/21/2021] [Accepted: 09/26/2021] [Indexed: 11/24/2022] Open
Abstract
Objective We evaluated whether the blood parameters before prostate biopsy can diagnose prostate cancer (PCa) and clinically significant PCa (Gleason score [GS] ≥7) in our hospital. Methods This study included patients with increased prostate-specific antigen (PSA) up to 20 ng/mL. The associations of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) alone or with PSA with PCa and clinically significant PCa were analyzed. Results We included 365 patients, of whom 52.9% (193) had PCa including 66.8% (129) with GS of ≥7. PSA density (PSAD) and PSA had better the area under the curve (AUC) of 0.722 and 0.585, respectively with p=0.001 for detecting PCa compared with other blood parameters. PSA combined with PLR (PsPLR) and PSA with NLR (PsNLR) had better AUC of 0.608 and 0.610, respectively with p<0.05, for diagnosing GS≥7 population, compared with PSA, free/total PSA, NLR, PLR, and PsNPLR (PSA combined with NLR and PLR). NLR and PLR did not predict PCa on multivariate analysis. For GS≥7 cancer detection, in the multivariate analysis, separate models with PSA and NLR (Model 1: PsNLR+baseline parameters) or PSA and PLR (Moder 2: PsPLR+baseline parameters) were made. Baseline parameters comprised age, digital rectal exam-positive lesions, PSA density, free/total PSA, and magnetic resonance imaging. Model 2 containing PsPLR was statistically significant (odds ratio: 2.862, 95% confidence interval: 1.174-6.975, p=0.021) in finding aggressive PCa. The predictive accuracy of Model 2 was increased (AUC: 0.734, p<0.001) than that when only baseline parameters were used (AUC: 0.693, p<0.001). Conclusion NLR or PLR, either alone or combined with PSA, did not detect PCa. However, the combined use of PSA with PLR could find the differences between clinically significant and insignificant PCa in our retrospective study limited by the small number of samples.
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Inflammation and Prostate Cancer: Pathological Analysis from Pros-IT CNR 2. Cancers (Basel) 2023; 15:cancers15030630. [PMID: 36765589 PMCID: PMC9913270 DOI: 10.3390/cancers15030630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 01/13/2023] [Accepted: 01/17/2023] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Extensive research effort has been devoted to investigating the link between inflammation and PCa. However, this relationship remains unclear and controversial. The aim of our multi-center study was to investigate this association by histologically evaluating the distribution of PI and PCA in prostate biopsy cores from patients of eight referral centers in Italy. RESULTS We evaluated 2220 cores from 197 patients; all the frustules were re-evaluated by dedicated pathologists retrospectively. Pathologists assigned IRANI scores and determined the positions of PIs; pathologists also re-evaluated the presence of PCa and relative ISUP grade. PCa was recorded in 749/2220 (33.7%). We divided this sample into a PCa PI group (634/749 cores [84.7%]) and a non-PCa + PI group (1157/1471 cores [78.7%]). We observed a statistically significant difference in the presence of inflammation among cores with cancer (p < 0.01). Moreover, periglandular inflammation was higher in the cores with neoplasia, while stromal inflammation was higher in cores without neoplasia (38.5% vs. 31.1% and 55.4% vs. 63.5% p < 0.01). CONCLUSIONS In our experience, there is evidence of an association between PI and PCa at a tissue level. Further studies are needed to confirm our findings and to identify patients who might benefit from target therapies to prevent PCa occurrence and/or progression.
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Johnson RP, Ratnacaram CK, Kumar L, Jose J. Combinatorial approaches of nanotherapeutics for inflammatory pathway targeted therapy of prostate cancer. Drug Resist Updat 2022; 64:100865. [PMID: 36099796 DOI: 10.1016/j.drup.2022.100865] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 08/27/2022] [Accepted: 08/30/2022] [Indexed: 12/24/2022]
Abstract
Prostate cancer (PC) is the most prevalent male urogenital cancer worldwide. PC patients presenting an advanced or metastatic cancer succumb to the disease, even after therapeutic interventions including radiotherapy, surgery, androgen deprivation therapy (ADT), and chemotherapy. One of the hallmarks of PC is evading immune surveillance and chronic inflammation, which is a major challenge towards designing effective therapeutic formulations against PC. Chronic inflammation in PC is often characterized by tumor microenvironment alterations, epithelial-mesenchymal transition and extracellular matrix modifications. The inflammatory events are modulated by reactive nitrogen and oxygen species, inflammatory cytokines and chemokines. Major signaling pathways in PC includes androgen receptor, PI3K and NF-κB pathways and targeting these inter-linked pathways poses a major therapeutic challenge. Notably, many conventional treatments are clinically unsuccessful, due to lack of targetability and poor bioavailability of the therapeutics, untoward toxicity and multidrug resistance. The past decade witnessed an advancement of nanotechnology as an excellent therapeutic paradigm for PC therapy. Modern nanovectorization strategies such as stimuli-responsive and active PC targeting carriers offer controlled release patterns and superior anti-cancer effects. The current review initially describes the classification, inflammatory triggers and major inflammatory pathways of PC, various PC treatment strategies and their limitations. Subsequently, recent advancement in combinatorial nanotherapeutic approaches, which target PC inflammatory pathways, and the mechanism of action are discussed. Besides, the current clinical status and prospects of PC homing nanovectorization, and major challenges to be addressed towards the advancement PC therapy are also addressed.
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Affiliation(s)
- Renjith P Johnson
- Polymer Nanobiomaterial Research Laboratory, Nanoscience and Microfluidics Division, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka 575018, India
| | - Chandrahas Koumar Ratnacaram
- Cell Signaling and Cancer Biology Division, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka 575018, India
| | - Lalit Kumar
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Udupi, Karnataka 576 104, India
| | - Jobin Jose
- NITTE Deemed-to-be University, NGSM Institute of Pharmaceutical Sciences, Department of Pharmaceutics, Mangalore 575018, India.
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Lin SY, Lin CL, Chang SS, Chang YH, Hsu WH, Lin CC, Kao CH. Risk of diabetes mellitus in patients with prostate cancer receiving injection therapy: A nationwide population-based propensity score-matched study. Int J Clin Pract 2021; 75:e14416. [PMID: 34047432 DOI: 10.1111/ijcp.14416] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 05/24/2021] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVES We aimed to investigate whether the risk of diabetes mellitus (DM) is heightened in patients with prostate cancer receiving injection therapy. METHODS Men diagnosed with prostate cancer between 2000 and 2012 were included in the case cohort, and men without prostate cancer were included as controls. Each patient with prostate cancer was matched with a control patient with the same index year, demographic variables and comorbidities, and comparisons were made using propensity score matching. The hazard ratio of DM was estimated using the Cox proportional hazards model. RESULTS This cohort study consisted of 1213 patients with prostate cancer and 1213 control patients. The risk of DM in patients with prostate cancer was 1.60 times (95% CI = 1.12, 2.27) that of patients without prostate cancer. Compared with the controls, the hazard ratios of DM for patients with prostate cancer not receiving oral hormone therapy, patients with prostate cancer receiving oral hormone therapy, and patients with prostate cancer not receiving injection hormone therapy were 1.65 (95% CI = 1.01, 2.70), 1.57 (95% CI = 1.07, 2.70), and 1.94 (95% CI = 1.34, 2.81), respectively. The risk of DM in patients who received injection hormone therapy was 0.45 times (95% CI = 0.25, 0.82) that of patients who did not receive injection hormone therapy. CONCLUSION Patients with prostate cancer had an increased risk of DM compared with patients without prostate cancer. Patients with prostate cancer who received injection therapy had a lower risk of DM compared with those who did not.
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Affiliation(s)
- Shih-Yi Lin
- Graduate Institute of Biomedical Sciences and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Division of Nephrology and Kidney Institute, China Medical University Hospital, Taichung, Taiwan
| | - Cheng-Li Lin
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
- College of Medicine, China Medical University, Taichung, Taiwan
| | - Shih-Sheng Chang
- Division of Cardiology, China Medical University Hospital, Taichung, Taiwan
| | - Yi-Huei Chang
- Division of Urology, China Medical University Hospital, Taichung, Taiwan
| | - Wu-Huei Hsu
- Graduate Institute of Biomedical Sciences and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Division of Pulmonary and Critical Care Medicine, China Medical University Hospital and China Medical University, Taichung, Taiwan
| | - Cheng-Chieh Lin
- Graduate Institute of Biomedical Sciences and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chia-Hung Kao
- Graduate Institute of Biomedical Sciences and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan
- Center of Augmented Intelligence in Healthcare, China Medical University Hospital, Taichung, Taiwan
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Kay JE, Mirabal S, Briley WE, Kimoto T, Poutahidis T, Ragan T, So PT, Wadduwage DN, Erdman SE, Engelward BP. Analysis of mutations in tumor and normal adjacent tissue via fluorescence detection. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2021; 62:108-123. [PMID: 33314311 PMCID: PMC7880898 DOI: 10.1002/em.22419] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 12/04/2020] [Accepted: 12/11/2020] [Indexed: 06/12/2023]
Abstract
Inflammation is a major risk factor for many types of cancer, including colorectal. There are two fundamentally different mechanisms by which inflammation can contribute to carcinogenesis. First, reactive oxygen and nitrogen species (RONS) can damage DNA to cause mutations that initiate cancer. Second, inflammatory cytokines and chemokines promote proliferation, migration, and invasion. Although it is known that inflammation-associated RONS can be mutagenic, the extent to which they induce mutations in intestinal stem cells has been little explored. Furthermore, it is now widely accepted that cancer is caused by successive rounds of clonal expansion with associated de novo mutations that further promote tumor development. As such, we aimed to understand the extent to which inflammation promotes clonal expansion in normal and tumor tissue. Using an engineered mouse model that is prone to cancer and within which mutant cells fluoresce, here we have explored the impact of inflammation on de novo mutagenesis and clonal expansion in normal and tumor tissue. While inflammation is strongly associated with susceptibility to cancer and a concomitant increase in the overall proportion of mutant cells in the tissue, we did not observe an increase in mutations in normal adjacent tissue. These results are consistent with opportunities for de novo mutations and clonal expansion during tumor growth, and they suggest protective mechanisms that suppress the risk of inflammation-induced accumulation of mutant cells in normal tissue.
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Affiliation(s)
- Jennifer E. Kay
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA
| | - Sheyla Mirabal
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA
| | | | - Takafumi Kimoto
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA
| | - Theofilos Poutahidis
- Laboratory of Pathology, Faculty of Veterinary Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Greece
| | | | - Peter T. So
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA
| | - Dushan N. Wadduwage
- The John Harvard Distinguished Science Fellows Program, Harvard University, Cambridge, MA
- Center for Advanced Imaging, Harvard University, Cambridge, MA, USA
| | - Susan E. Erdman
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA
| | - Bevin P. Engelward
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA
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Fu BC, Tabung FK, Pernar CH, Wang W, Gonzalez-Feliciano AG, Chowdhury-Paulino IM, Clinton SK, Folefac E, Song M, Kibel AS, Giovannucci EL, Mucci LA. Insulinemic and Inflammatory Dietary Patterns and Risk of Prostate Cancer. Eur Urol 2021; 79:405-412. [PMID: 33422354 DOI: 10.1016/j.eururo.2020.12.030] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 12/17/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hyperinsulinemia and inflammation are inter-related pathways that link diet with the risk of several chronic diseases. Evidence suggests that these pathways may also increase prostate cancer risk. OBJECTIVE To determine whether hyperinsulinemic diet and inflammatory diet are associated with prostate cancer incidence and mortality. DESIGN, SETTING, AND PARTICIPANTS We prospectively followed 41 209 men in the Health Professionals Follow-up Study (1986-2014). Scores for two validated dietary patterns were calculated from food frequency questionnaires at baseline and updated every 4 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Total, advanced, and lethal prostate cancer outcomes were assessed. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were determined for associations between two empirical hypothesis-oriented dietary patterns-empirical dietary index for hyperinsulinemia and empirical dietary inflammatory pattern-and prostate cancer risk estimated using Cox proportional hazard regression. RESULTS AND LIMITATIONS During 28 yr of follow-up, 5929 incident cases of total prostate cancer, including 1019 advanced and 667 fatal, were documented. In multivariable-adjusted models, there was a 7% higher risk of advanced prostate cancer (HR: 1.07; 95% CI: 1.01-1.15) and a 9% higher risk of fatal prostate cancer (HR: 1.09; 95% CI: 1.00-1.18) per standard deviation (SD) increase in the hyperinsulinemic diet. When stratified by age, the hyperinsulinemic diet was associated with only earlier-onset aggressive prostate cancer (men under 65 yr), with per SD HRs of 1.20 (95% CI: 1.06-1.35) for advanced, 1.22 (1.04-1.42) for fatal, and 1.20 (1.04-1.38) for lethal. The inflammatory diet was not associated with prostate cancer risk in the overall study population, but was associated with earlier-onset lethal prostate cancer (per SD increase HR: 1.16; 95% CI: 1.00-1.35). CONCLUSIONS Hyperinsulinemia and inflammation may be potential mechanisms linking dietary patterns with the risk of aggressive prostate cancer, particularly earlier-onset disease. PATIENT SUMMARY Avoiding inflammatory and hyperinsulinemic dietary patterns may be beneficial for the prevention of clinically relevant prostate cancer, especially among younger men.
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Affiliation(s)
- Benjamin C Fu
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| | - Fred K Tabung
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA; The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Claire H Pernar
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Weike Wang
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | | | | | - Steven K Clinton
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA; The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
| | - Edmund Folefac
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA; The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
| | - Mingyang Song
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Adam S Kibel
- Division of Urology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Edward L Giovannucci
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Lorelei A Mucci
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
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Wang Z, Zhou Y, Guan C, Ding Y, Tao S, Huang X, Chen L, Zhang F, Zhang R. The impact of previous cancer on overall survival of bladder cancer patients and the establishment of nomogram for overall survival prediction. Medicine (Baltimore) 2020; 99:e22191. [PMID: 32957347 PMCID: PMC7505356 DOI: 10.1097/md.0000000000022191] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
To investigate the role of previous cancer on overall survival in patients with bladder cancer (BCa) and to establish an effective prognostic tool for individualized overall survival prediction.A total of 78,660 patients diagnosed with BCa between 2000 and 2013 were selected from the Surveillance, Epidemiology, and End Results (SEER) database, among which 8915 patients had a history of other cancers. We compared the overall survival between patients with and without previous cancer after propensity score matching and we further established a nomogram for overall survival prediction.Univariate and multivariate Cox analyses were used to determine independent prognostic factors. The calibration curve and concordance index (C-index) were used to assess the accuracy of the nomogram. Cox proportional hazards models and Kaplan-Meier analysis were used to compare survival outcomes.BCa patients with previous cancer had worse overall survival compared with those without previous cancer (HR = 1.37; 95%CI = 1.32-1.42, P < .001). Cancers in lung prior to BCa had the most adverse impact on overall survival (HR = 2.35; 95%CI = 2.10-2.63; P < .001), and the minimal impact was located in prostate (HR = 1.16; 95%CI = 1.10-1.22; P < .001) for male and in gynecological (HR = 1.15; 95%CI = 1.02-1.30; P = .027) for female. The shorter interval time between 2 cancers and the higher stage of the previous cancer development, the higher risk of death. Age, race, sex, marital status, surgery, radiation, grade, stage, type of previous cancer as the independent prognostic factors were selected into the nomogram. The favorable calibration curve and C-index value (0.784, 95%CI = 0.782-0.786) indicated the nomogram could accurately predict the 1-, 3-, and 5-year overall survival rate of BCa patients.Previous cancer has a negative impact on the overall survival of BCa patients and requires more effective clinical management. The nomogram provides accurate survival prediction for BCa patients and might be helpful for clinical treatment selection and follow-up strategy adjustment.
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Affiliation(s)
- Zhengquan Wang
- Department of Urology Surgery, The People's Hospital of Xuancheng City, Xuanzhou, Xuancheng
| | - Yuan Zhou
- Department of Urology Surgery, The People's Hospital of Xuancheng City, Xuanzhou, Xuancheng
- Department of Urology Surgery, The Second Affiliated Hospital of Bengbu Medical College, Longzi, Bengbu, China
| | - Chao Guan
- Department of Urology Surgery, The Second Affiliated Hospital of Bengbu Medical College, Longzi, Bengbu, China
| | - Yinman Ding
- Department of Urology Surgery, The People's Hospital of Xuancheng City, Xuanzhou, Xuancheng
| | - Sha Tao
- Department of Urology Surgery, The People's Hospital of Xuancheng City, Xuanzhou, Xuancheng
| | - Xiaoqi Huang
- Department of Urology Surgery, The People's Hospital of Xuancheng City, Xuanzhou, Xuancheng
| | - Liang Chen
- Department of Urology Surgery, The People's Hospital of Xuancheng City, Xuanzhou, Xuancheng
| | - Fei Zhang
- Department of Urology Surgery, The People's Hospital of Xuancheng City, Xuanzhou, Xuancheng
| | - Rentao Zhang
- Department of Urology Surgery, The People's Hospital of Xuancheng City, Xuanzhou, Xuancheng
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Haddad A, Al-Sabbagh MQ, Al-Ani H, Siyam AM, Aborajooh E, Iwata T, Kimura S, Shariat SF, Abufaraj M. Inflammatory bowel disease and prostate cancer risk: A systematic review. Arab J Urol 2020; 18:207-212. [PMID: 33312730 PMCID: PMC7717159 DOI: 10.1080/2090598x.2020.1761674] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Objective: To evaluate the risk of prostate cancer (PCa) in patients with inflammatory bowel disease (IBD), focussing on ulcerative colitis (UC) and Crohn's disease (CD) separately. Methods: A systemic search was carried out using PubMed and Web of Science databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We retrieved a total of 349 articles. All the articles were in the English language and investigated the incidence of PCa in patients with IBD. Results: Nine studies met our inclusion criteria, with a total of 205 037 men. Two studies reported an increase in the risk of PCa in men with IBD in general. Five other studies reported an increased risk of PCa in men with UC or with CD specifically. On the other hand, two studies reported a decreased risk of PCa in patients with UC and patients with IBD treated with aminosalicylates. Conclusions: While men with UC appear to have higher risk of developing PCa, data on patients with CD are inconclusive. Therefore, patients with UC may benefit from earlier PCa screening. Our findings confirm a complex interplay between IBD and PCa, including factors such as genetic predisposition, systemic inflammation and treatment effects. The modulatory effect of treatment strategies for IBD on the development and progression of PCa might be of clinical significance. Abbreviations: CD: Crohn's disease; CRP: C- reactive protein; FOLH1: folate hydrolase 1; GIT: gastrointestinal tract; IBD: inflammatory bowel disease; IL-6: interleukin 6; NOS: Newcastle-Ottawa Scale; PCa: prostate cancer; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; PSMA: prostate-specific membrane antigen; UC: ulcerative colitis.
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Affiliation(s)
- Anoud Haddad
- Division of Urology, Department of Special Surgery, Jordan University Hospital, the University of Jordan, Amman, Jordan
| | - Mohammed Qussay Al-Sabbagh
- Division of Urology, Department of Special Surgery, Jordan University Hospital, the University of Jordan, Amman, Jordan
| | - Hashim Al-Ani
- Division of Urology, Department of Special Surgery, Jordan University Hospital, the University of Jordan, Amman, Jordan
| | - Abdel Muez Siyam
- Division of Urology, Department of Special Surgery, Jordan University Hospital, the University of Jordan, Amman, Jordan
| | - Emad Aborajooh
- Department of Surgery, Faculty of Medicine, Mutah University, Kerak, Jordan
| | - Takehiro Iwata
- Department of Urology, Medical University of Vienna, Vienna, Austria.,Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shoji Kimura
- Department of Urology, Medical University of Vienna, Vienna, Austria.,Department of Urology, Jikei University School of Medicine, Tokyo, Japan
| | - Shahrokh F Shariat
- Department of Urology, Medical University of Vienna, Vienna, Austria.,Department of Urology, Weill Cornell Medical College, New York, NY, USA.,Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.,Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria.,Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia
| | - Mohammad Abufaraj
- Division of Urology, Department of Special Surgery, Jordan University Hospital, the University of Jordan, Amman, Jordan.,Department of Urology, Medical University of Vienna, Vienna, Austria
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12
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Hempel Sullivan H, Heaphy CM, Kulac I, Cuka N, Lu J, Barber JR, De Marzo AM, Lotan TL, Joshu CE, Sfanos KS. High Extratumoral Mast Cell Counts Are Associated with a Higher Risk of Adverse Prostate Cancer Outcomes. Cancer Epidemiol Biomarkers Prev 2020; 29:668-675. [PMID: 31932412 DOI: 10.1158/1055-9965.epi-19-0962] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 10/16/2019] [Accepted: 12/20/2019] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Given our previous findings that low intratumoral and high extratumoral mast cell numbers are associated with higher risk of biochemical recurrence after radical prostatectomy, we now assessed this relationship with race and the development of metastases. METHODS We stained for mast cell tryptase via IHC and fluorescent immunolabeling in 885 men across multiple tissue microarray sets designed to assess biomarkers in association with race and prostate cancer outcomes (median follow-up, 7.0 years). RESULTS Intratumoral and extratumoral mast cell counts were significantly lower in tissues from African-American compared with European-American men, but not within strata of cancer grade. There was no association between mast cell counts and ERG positivity, PTEN loss, or TP53 missense mutation. Higher minimum extratumoral mast cells were associated with an increased risk of biochemical recurrence [comparing highest with lowest tertiles: HR, 1.61; 95% confidence interval (CI), 1.12-2.29; P trend = 0.01]; this pattern was similar among European-American and African-American men and by grade of disease. There was no significant association between minimum intratumoral mast cell count and biochemical recurrence, overall or within strata of race and grade. Finally, high minimum number of extratumoral mast cells was associated with prostate cancer metastases (comparing highest with lowest tertiles: HR, 2.12; 95% CI, 1.24-3.63; P trend = 0.01). CONCLUSIONS High extratumoral mast cell numbers are associated with biochemical recurrence and the development of metastases after radical prostatectomy. IMPACT Higher numbers of benign tissue mast cells are associated with a higher risk of adverse outcomes after radical prostatectomy, including metastatic prostate cancer.
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Affiliation(s)
- Heidi Hempel Sullivan
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Christopher M Heaphy
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
| | - Ibrahim Kulac
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Nathan Cuka
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jiayun Lu
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - John R Barber
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Angelo M De Marzo
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.,Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Tamara L Lotan
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
| | - Corinne E Joshu
- Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.,Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Karen S Sfanos
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. .,Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.,Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
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13
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Gholami M, Larijani B, Zahedi Z, Mahmoudian F, Bahrami S, Omran SP, Saadatian Z, Hasani-Ranjbar S, Taslimi R, Bastami M, Amoli MM. Inflammation related miRNAs as an important player between obesity and cancers. J Diabetes Metab Disord 2019; 18:675-692. [PMID: 31890692 PMCID: PMC6915181 DOI: 10.1007/s40200-019-00459-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 10/23/2019] [Indexed: 12/13/2022]
Abstract
The growing trend in addition to their burden, prevalence, and death has made obesity and cancer two of the most concerning diseases worldwide. Obesity is an important risk factor for common types of cancers where the risk of some cancers is directly related to the obesity. Various inflammatory mechanisms and increased level of pro-inflammatory cytokines have been investigated in many previous studies, which play key roles in the pathophysiology and development of both of these conditions. On the other hand, in the recent years, many studies have individually focused on the biomarker's role and therapeutic targeting of microRNAs (miRNAs) in different types of cancers and obesity including newly discovered small noncoding RNAs (sncRNAs) which regulate gene expression and RNA silencing. This study is a comprehensive review of the main inflammation related miRNAs in obesity/obesity related traits. For the first time, the main roles of miRNAs in obesity related cancers have been discussed in response to the question raised in the following hypothesis; do the main inflammatory miRNAs link obesity with obesity-related cancers regarding their role as biomarkers? Graphical abstractConceptual design of inflammatory miRNAs which provide link between obesity and cancers.
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Affiliation(s)
- Morteza Gholami
- Obesity and Eating Habits Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Zhila Zahedi
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Mahmoudian
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Samira Bahrami
- Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sima Parvizi Omran
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, 5th floor, Shariati Hospital, North Kargar Ave, Tehran, Iran
| | - Zahra Saadatian
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shirin Hasani-Ranjbar
- Obesity and Eating Habits Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Taslimi
- Department of Gastroenterology, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Milad Bastami
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahsa M. Amoli
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, 5th floor, Shariati Hospital, North Kargar Ave, Tehran, Iran
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14
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Chen H, Krishnamachari S, Guo J, Yao L, Murugan P, Weight CJ, Turesky RJ. Quantitation of Lipid Peroxidation Product DNA Adducts in Human Prostate by Tandem Mass Spectrometry: A Method That Mitigates Artifacts. Chem Res Toxicol 2019; 32:1850-1862. [PMID: 31361128 DOI: 10.1021/acs.chemrestox.9b00181] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Reactive oxygen species (ROS) and chronic inflammation contribute to DNA damage of many organs, including the prostate. ROS cause oxidative damage to biomolecules, such as lipids, proteins, and nucleic acids, resulting in the formation of toxic and mutagenic intermediates. Lipid peroxidation (LPO) products covalently adduct to DNA and can lead to mutations. The levels of LPO DNA adducts reported in humans range widely. However, a large proportion of the DNA adducts may be attributed to artifact formation during the steps of isolation and nuclease digestion of DNA. We established a method that mitigates artifacts for most LPO adducts during the processing of DNA. We have applied this methodology to measure LPO DNA adducts in the genome of prostate cancer patients, employing ultrahigh-performance liquid chromatography electrospray ionization ion trap multistage mass spectrometry. Our preliminary data show that DNA adducts of acrolein, 6-hydroxy-1,N2-propano-2'-deoxyguanosine (6-OH-PdG) and 8-hydroxy-1,N2-propano-2'-deoxyguanosine (8-OH-PdG) (4-20 adducts per 107 nucleotides) are more prominent than etheno (ε) adducts (<0.5 adducts per 108 nucleotides). This analytical methodology will be used to examine the correlation between oxidative stress, inflammation, and LPO adduct levels in patients with benign prostatic hyperplasia and prostate cancer.
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15
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The impact of obesity and insulin resistance on thyroid cancer: A systematic review. Maturitas 2019; 125:45-49. [DOI: 10.1016/j.maturitas.2019.03.022] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Revised: 03/23/2019] [Accepted: 03/27/2019] [Indexed: 02/07/2023]
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16
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Geller A, Yan J. The Role of Membrane Bound Complement Regulatory Proteins in Tumor Development and Cancer Immunotherapy. Front Immunol 2019; 10:1074. [PMID: 31164885 PMCID: PMC6536589 DOI: 10.3389/fimmu.2019.01074] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 04/26/2019] [Indexed: 12/17/2022] Open
Abstract
It has long been understood that the control and surveillance of tumors within the body involves an intricate dance between the adaptive and innate immune systems. At the center of the interplay between the adaptive and innate immune response sits the complement system—an evolutionarily ancient response that aids in the destruction of microorganisms and damaged cells, including cancer cells. Membrane-bound complement regulatory proteins (mCRPs), such as CD46, CD55, and CD59, are expressed throughout the body in order to prevent over-activation of the complement system. These mCRPs act as a double-edged sword however, as they can also over-regulate the complement system to the extent that it is no longer effective at eliminating cancerous cells. Recent studies are now indicating that mCRPs may function as a biomarker of a malignant transformation in numerous cancer types, and further, are being shown to interfere with anti-tumor treatments. This highlights the critical roles that therapeutic blockade of mCRPs can play in cancer treatment. Furthermore, with the complement system having the ability to both directly and indirectly control adaptive T-cell responses, the use of a combinatorial approach of complement-related therapy along with other T-cell activating therapies becomes a logical approach to treatment. This review will highlight the biomarker-related role that mCRP expression may have in the classification of tumor phenotype and predicted response to different anti-cancer treatments in the context of an emerging understanding that complement activation within the Tumor Microenvironment (TME) is actually harmful for tumor control. We will discuss what is known about complement activation and mCRPs relating to cancer and immunotherapy, and will examine the potential for combinatorial approaches of anti-mCRP therapy with other anti-tumor therapies, especially checkpoint inhibitors such as anti PD-1 and PD-L1 monoclonal antibodies (mAbs). Overall, mCRPs play an essential role in the immune response to tumors, and understanding their role in the immune response, particularly in modulating currently used cancer therapeutics may lead to better clinical outcomes in patients with diverse cancer types.
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Affiliation(s)
- Anne Geller
- Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, United States
| | - Jun Yan
- Immuno-Oncology Program, Department of Medicine, The James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, United States
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17
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Kelly SP, Lennon H, Sperrin M, Matthews C, Freedman ND, Albanes D, Leitzmann MF, Renehan AG, Cook MB. Body mass index trajectories across adulthood and smoking in relation to prostate cancer risks: the NIH-AARP Diet and Health Study. Int J Epidemiol 2019; 48:464-473. [PMID: 30376043 PMCID: PMC6469294 DOI: 10.1093/ije/dyy219] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/20/2018] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Previously we showed that adulthood body mass index (BMI) trajectories that result in obesity were associated with elevated risks of fatal prostate cancer (PCA). To further explore this relationship, we conducted a study within the NIH-AARP Diet and Health Study. METHODS Among 153 730 eligible men enrolled in the NIH-AARP cohort from 1995 to 1996 (median follow-up = 15.1 years), we identified 630 fatal PCA cases and 16 896 incident cases. BMI was assessed for ages 18, 35 and 50 and at study entry, enabling examination of latent class-identified BMI trajectories. Hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression. RESULTS BMI at study entry (mean age = 63, HR = 1.12; 95% CI = 1.01, 1.24, per 5-unit increase) and maximum BMI during adulthood (HR = 1.12; 95% CI = 1.02, 1.24, per 5-unit increase) shared modest associations with increased risk of fatal PCA. Smoking status likely modified the relationship between BMI trajectories and fatal PCA (Pinteraction = 0.035 via change-in-estimate variable section, P = 0.065 via full a priori model). Among never-smokers, BMI trajectory of normal weight to obesity was associated with increased risk of fatal disease (HR = 2.37; 95% CI = 1.38, 4.09), compared with the maintained normal weight trajectory, whereas there was no association among former or current-smokers. Total and non-aggressive PCA exhibited modest inverse associations with BMI at all ages, whereas no association was observed for aggressive PCA. CONCLUSIONS Increased BMI was positively associated with fatal PCA, especially among never-smokers. Future studies that examine PCA survival will provide additional insight as to whether these associations are the result of biology or confounding.
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Affiliation(s)
- Scott P Kelly
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Hannah Lennon
- Division of Cancer Sciences, School Faculty of Biology, Medicine and Health
| | - Matthew Sperrin
- Farr Institute, MRC Health eResearch Centre, University of Manchester, Manchester, UK
| | - Charles Matthews
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Neal D Freedman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Michael F Leitzmann
- Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany
| | - Andrew G Renehan
- Division of Cancer Sciences, School Faculty of Biology, Medicine and Health
- Farr Institute, MRC Health eResearch Centre, University of Manchester, Manchester, UK
| | - Michael B Cook
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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18
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Burns JA, Weiner AB, Catalona WJ, Li EV, Schaeffer EM, Hanauer SB, Strong S, Burns J, Hussain MHA, Kundu SD. Inflammatory Bowel Disease and the Risk of Prostate Cancer. Eur Urol 2018; 75:846-852. [PMID: 30528221 DOI: 10.1016/j.eururo.2018.11.039] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 11/19/2018] [Indexed: 02/09/2023]
Abstract
BACKGROUND There are limited data examining the risk of prostate cancer (PCa) in patients with inflammatory bowel disease (IBD). OBJECTIVE To compare the incidence of PCa between men with and those without IBD. DESIGN, SETTING, AND PARTICIPANTS This was a retrospective, matched-cohort study involving a single academic medical center and conducted from 1996 to 2017. Male patients with IBD (cases=1033) were randomly matched 1:9 by age and race to men without IBD (controls=9306). All patients had undergone at least one prostate-specific antigen (PSA) screening test. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Kaplan-Meier and multivariable Cox proportional hazard models, stratified by age and race, evaluated the relationship between IBD and the incidence of any PCa and clinically significant PCa (Gleason grade group ≥2). A mixed-effect regression model assessed the association of IBD with PSA level. RESULTS AND LIMITATIONS PCa incidence at 10yr was 4.4% among men with IBD and 0.65% among controls (hazard ratio [HR] 4.84 [3.34-7.02] [3.19-6.69], p<0.001). Clinically significant PCa incidence at 10yr was 2.4% for men with IBD and 0.42% for controls (HR 4.04 [2.52-6.48], p<0.001). After approximately age 60, PSA values were higher among patients with IBD (fixed-effect interaction of age and patient group: p=0.004). Results are limited by the retrospective nature of the analysis and lack of external validity. CONCLUSIONS Men with IBD had higher rates of clinically significant PCa when compared with age- and race-matched controls. PATIENT SUMMARY This study of over 10000 men treated at a large medical center suggests that men with inflammatory bowel disease may be at a higher risk of prostate cancer than the general population.
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Affiliation(s)
- Jacob A Burns
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Adam B Weiner
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - William J Catalona
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Eric V Li
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Edward M Schaeffer
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Stephen B Hanauer
- Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Scott Strong
- Division of Gastrointestinal Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - James Burns
- Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Maha H A Hussain
- Division of Hematology Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Shilajit D Kundu
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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19
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An allometric approach of tumor-angiogenesis. Med Hypotheses 2018; 116:74-78. [DOI: 10.1016/j.mehy.2018.03.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 03/13/2018] [Accepted: 03/25/2018] [Indexed: 01/27/2023]
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20
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Macrophage Cytokines Enhance Cell Proliferation of Normal Prostate Epithelial Cells through Activation of ERK and Akt. Sci Rep 2018; 8:7718. [PMID: 29769604 PMCID: PMC5955920 DOI: 10.1038/s41598-018-26143-8] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2018] [Accepted: 04/10/2018] [Indexed: 12/20/2022] Open
Abstract
Macrophage infiltrations (inflammation) are associated with prostate disorders such as prostatitis, prostatic hyperplasia and prostate cancer. All prostate disorders have elevated cell proliferation, and are initiated from normal prostate epithelial cells. To date, the mechanism of how macrophages regulate normal prostate epithelial cell proliferation remains largely unknown. Using a 3D co-culture system, we here show that Raw 264.7 macrophages increased cell proliferation of normal prostate epithelial PZ-HPV-7 cells. In addition, these Raw 264.7 macrophages expressed higher levels of Ym1 and CD206. We further identify macrophage-secreted cytokines including CCL3, IL-1ra, osteopontin, M-CSF1 and GDNF as mediators for potentiating PZ-HPV-7 cell proliferation in 3D. All these cytokines differentially activated ERK and Akt. Blockade of both kinases through their inhibitors hindered macrophage-induced cell proliferation of PZ-HPV-7 cells. Hence, our data provide mechanistic insight of how inflammation may contribute to development of prostatic diseases at a very early stage through augment of cell proliferation of normal prostate epithelial cells.
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21
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Pavone C, Abbadessa D, Tarantino M, Oxenius I, Laganà A, Lupo A, Rinella M. Associating Serenoa Repens, Urtica Dioica and Pinus Pinaster. Safety and Efficacy in the Treatment of Lower Urinary Tract Symptoms. Prospective Study on 320 Patients. Urologia 2018. [DOI: 10.1177/039156031007700108] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Introduction Serenoa repens (saw palmetto) has been employed for the treatment of lower urinary tract symptoms (LUTS) for several years. Its mechanism of action is believed to be due to antiandrogenic, antiproliferative and antinflammatory properties. An association of Serenoa with the nettle “Urtica dioica” showing antiproliferative activity and the pine “Pinus pinaster” derivative, showing antinflammatory action, has been proposed in recent years. Such an action is hoped to act not only by reducing LUTS but also by preventing the development of prostate cancer. Material and Methods During the years 2007 and 2008, 320 patients suffering from LUTS were treated with an association of Serenoa repens 320 mg, Urtica dioica 120 mg and Pinus pinaster 5 mg, named IPBTRE. This treatment was administered to all patients for a minimal duration of 30 days to a maximum of a year, either alone or in association with antibiotics or alpha-blockers, if needed. Outcome analysis was based on evaluation of symptoms, prostate volume and maximum flow rate (Qmax). Results From a careful analysis of the data collected in our database, the following observations can be made: ages varied between 19 and 78 years. The patients were affected by BPH in 46% of cases, chronic prostatitis syndrome in 43%, chronic genital-pelvic pain in 7% and other conditions in 4%, the absolute numbers being 147, 138, 22 and 7 patients, respectively. No untoward side effect was reported in any case. Variations in symptom score could be fully evaluated only in 80 of 320 patients (25%), of whom 68 (85%) reported a significant benefit, with special reference to an improvement of pain, urgency, strangury and nocturia. Data on variations in prostate volume, as measured by digital rectal examination, were available in 84 (26.5%) patients. No significant change was observed. Qmax after treatment was measured in 83 (26%) patients. It did not show significant changes from the initial values. Discussion The association tested in our study appeared to be safe and well tolerated. No changes in flow rate and prostate volume were observed, but a marked reduction of LUTS was observed in 85% of evaluable cases, especially with regard to pain and irritative symptoms. Whether or not such an association may display a prevention of prostate cancer, may be investigated in additional studies.
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Affiliation(s)
| | | | - M.L. Tarantino
- Dip. Di Medicina Interna, Malattie Cardiovascolari e Nefrourologiche Università degli Studi di Palermo
| | | | - A. Laganà
- Dip. Di Medicina Interna, Malattie Cardiovascolari e Nefrourologiche Università degli Studi di Palermo
| | - A. Lupo
- Dip. Di Medicina Interna, Malattie Cardiovascolari e Nefrourologiche Università degli Studi di Palermo
| | - M. Rinella
- Dip. Di Medicina Interna, Malattie Cardiovascolari e Nefrourologiche Università degli Studi di Palermo
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22
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The molecular biology of prostate cancer: current understanding and clinical implications. Prostate Cancer Prostatic Dis 2017; 21:22-36. [PMID: 29282359 DOI: 10.1038/s41391-017-0023-8] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 10/11/2017] [Accepted: 11/02/2017] [Indexed: 01/07/2023]
Abstract
BACKGROUND With continuous progress over the past few decades in understanding diagnosis, treatment, and genetics, much has been learned about the prostate cancer-diagnosed genome. METHODS A comprehensive MEDLINE® and Google scholar literature search was conducted using keyword variations relating to the genetics of prostate cancer such as chromosomal alterations, androgen receptor, castration-resistant, inheritance, polymorphisms, oncogenes, metastasis, biomarkers, and immunotherapy. RESULTS Traditionally, androgen receptors (AR) have been the focus of research. Recently, identification of recurrent chromosomal alterations that lead to either multiplication of regions (gain-of-function) or deletion of regions (loss-of-function) has opened the door to greater genetic accessibility. These chromosomal aberrations lead to variation in copy number and gene expression. Some of these chromosomal alterations are inherited, while others undergo somatic mutations during disease progression. Inherited gene mutations that make one susceptible to prostate cancer have been identified with familial-linked studies. Somatic genes that progress tumorigenesis have also been identified. Research on the molecular biology of prostate cancer has characterized these genes into tumor suppressor genes or oncogenes. Additionally, genome-wide assay studies have identified many high-risk single-nucleotide polymorphisms recurrent throughout the prostate cancer-diagnosed genome. Castration-resistant prostate cancer is the most aggressive form of prostate cancer, and its research has elucidated many types of mutations associated with AR itself, including enhanced expression and amplification, point mutations, and alternative splicing. Understanding the molecular biology of prostate cancer has permitted more accurate identification using advanced biomarkers and therapy for aggressive forms using immunotherapy. CONCLUSIONS An age-related disease, prostate cancer commands profound attention. With increasing life expectancy and the continuous pursuit of it, prostate cancer is a powerful obstacle best defeated using targeted therapies specifically designed for the unique molecular profile of the malignancy.
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Sfanos KS, Yegnasubramanian S, Nelson WG, De Marzo AM. The inflammatory microenvironment and microbiome in prostate cancer development. Nat Rev Urol 2017; 15:11-24. [PMID: 29089606 DOI: 10.1038/nrurol.2017.167] [Citation(s) in RCA: 314] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Chronic inflammation promotes the development of several types of solid cancers and might contribute to prostate carcinogenesis. This hypothesis partly originates in the frequent observation of inflammatory cells in the prostate microenvironment of adult men. Inflammation is associated with putative prostate cancer precursor lesions, termed proliferative inflammatory atrophy. Inflammation might drive prostate carcinogenesis via oxidative stress and generation of reactive oxygen species that induce mutagenesis. Additionally, inflammatory stress might cause epigenetic alterations that promote neoplastic transformation. Proliferative inflammatory atrophy is enriched for proliferative luminal epithelial cells of intermediate phenotype that might be prone to genomic alterations leading to prostatic intraepithelial neoplasia and prostate cancer. Studies in animals suggest that inflammatory changes in the prostate microenvironment contribute to reprogramming of prostate epithelial cells, a possible step in tumour initiation. Prostatic infection, concurrent with epithelial barrier disruption, might be a key driver of an inflammatory microenvironment; the discovery of a urinary microbiome indicates a potential source of frequent exposure of the prostate to a diverse number of microorganisms. Hence, current evidence suggests that inflammation and atrophy are involved in prostate carcinogenesis and suggests a role for the microbiome in establishing an inflammatory prostate microenvironment that might promote prostate cancer development and progression.
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Affiliation(s)
- Karen S Sfanos
- Department of Pathology, Johns Hopkins University School of Medicine.,Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, 1550 Orleans Street, Baltimore, Maryland 21231, USA.,Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, Maryland 21287, USA
| | - Srinivasan Yegnasubramanian
- Department of Pathology, Johns Hopkins University School of Medicine.,Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, 1550 Orleans Street, Baltimore, Maryland 21231, USA
| | - William G Nelson
- Department of Pathology, Johns Hopkins University School of Medicine.,Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, 1550 Orleans Street, Baltimore, Maryland 21231, USA.,Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, Maryland 21287, USA
| | - Angelo M De Marzo
- Department of Pathology, Johns Hopkins University School of Medicine.,Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, 1550 Orleans Street, Baltimore, Maryland 21231, USA.,Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, Maryland 21287, USA
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C-reactive protein binds to integrin α2 and Fcγ receptor I, leading to breast cell adhesion and breast cancer progression. Oncogene 2017; 37:28-38. [PMID: 28846105 DOI: 10.1038/onc.2017.298] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 06/19/2017] [Accepted: 07/20/2017] [Indexed: 12/12/2022]
Abstract
C-reactive protein (CRP) is an acute phase protein synthesized upon the inflammatory responses, associated with breast cancer. The process of tumor cell invasion and metastasis involves the adherence of cells to the extracellular matrix via integrin as a receptor for matrix molecules. The present study investigated the role of CRP in the adhesive phenotype of breast cells and the underlying mechanisms. Here, we first showed that CRP induces adhesion of MCF10A human breast epithelial cells through the activation of integrin α2 signaling. Expression of integrin α2 was induced by CRP in which transcription factors c-fos and SP1 may be involved. Binding of CRP with integrin α2 leads to the activation of focal adhesion kinase (FAK), paxillin and ERKs. CRP also binds to an Fcγ receptor Fcγ receptor I (FcγRI), and induces activation of paxillin, FAK and ERKs. Integrin α2 and FAK have crucial roles in the adhesive and invasive phenotypes as well as MMP-9 upregulation induced by CRP in MCF10A cells. Treatment with an inflammatory lipid sphingosine-1-phosphate induced CRP, which may be secreted and exert an autocrine effect by binding to FcγRI and integrin α2. Involvement of CRP in adhesion, invasion, anchorage-independent growth and upregulation of integrin α2, paxillin and FAK was observed in MDA-MB-231 triple-negative human breast cancer (TNBC) cells. Using an in vivo invasion model and an orthotopic mouse tumor model with MDA-MB-231 cells, we showed that CRP has an important role in intravasation and tumor growth in vivo, demonstrating the in vivo relevance of our in vitro results. The present study elucidates a critical molecular basis between CRP, integrin α2 and FcγRI pathways in MCF10A breast cells and MDA-MB-231 TNBC cells, thereby providing useful information on CRP-induced aggressiveness of breast cells in the inflammatory microenvironment.
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Kirk PS, Govani S, Borza T, Hollenbeck BK, Davis J, Shumway D, Waljee AK, Skolarus TA. Implications of Prostate Cancer Treatment in Men With Inflammatory Bowel Disease. Urology 2017; 104:131-136. [PMID: 28163082 PMCID: PMC5520802 DOI: 10.1016/j.urology.2017.01.030] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Revised: 01/24/2017] [Accepted: 01/27/2017] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To investigate the influences of inflammatory bowel disease (IBD), a rare but morbid disease with increasing incidence, on prostate cancer management decisions. We examined whether prostate cancer treatment differed for men with IBD, and whether treatment choice was associated with risk of IBD flare. MATERIALS AND METHODS Using Veterans Health Administration cancer registry and administrative data, we identified 52,311 men diagnosed with prostate cancer from 2005 to 2008. We used International Classification of Diseases-9 codes and pharmacy and utilization data to identify IBD diagnoses, IBD-directed therapy, and flares (glucocorticoid escalation, hospitalization, and surgical intervention). We compared characteristics across men with and without IBD, and used multivariable regression to examine IBD flares after treatment according to treatment type. RESULTS Two hundred and forty men (0.5%) had IBD prior to prostate cancer diagnosis. Compared to non-IBD patients, IBD patients were more likely Caucasian (P < .001) with lower-risk cancer (P = .02). Surgery was more common in IBD patients (41% vs 28%, P < .001). In the year following prostate cancer treatment, 18% of IBD patients experienced flares. After adjustment, the only predictor of flare in the year after treatment was flare in the year prior to treatment (adjusted odds ratio, 12.5; 95% confidence interval, 5.4-29.2). CONCLUSION IBD patients were more likely to have lower-risk disease and be treated with surgery. Choice of prostate cancer treatment did not predict flares in the subsequent year. Better understanding of the intersection of IBD and prostate cancer can help inform treatment decisions for the increasing number of men managing both diseases.
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Affiliation(s)
- Peter S Kirk
- Dow Division of Health Services Research, Department of Urology, University of Michigan Health System, Ann Arbor, MI
| | - Shail Govani
- Department of Gastroenterology, Division of Internal Medicine, University of Michigan Health System, Ann Arbor, MI
| | - Tudor Borza
- Dow Division of Health Services Research, Department of Urology, University of Michigan Health System, Ann Arbor, MI
| | - Brent K Hollenbeck
- Dow Division of Health Services Research, Department of Urology, University of Michigan Health System, Ann Arbor, MI
| | - Jennifer Davis
- VA Health Services Research and Development, Center for Clinical Management Research, VA Ann Arbor Healthcare System, Ann Arbor, MI
| | - Dean Shumway
- Department of Radiation Oncology, University of Michigan Health System, Ann Arbor, MI
| | - Akbar K Waljee
- Department of Gastroenterology, Division of Internal Medicine, University of Michigan Health System, Ann Arbor, MI; VA Health Services Research and Development, Center for Clinical Management Research, VA Ann Arbor Healthcare System, Ann Arbor, MI
| | - Ted A Skolarus
- Dow Division of Health Services Research, Department of Urology, University of Michigan Health System, Ann Arbor, MI; VA Health Services Research and Development, Center for Clinical Management Research, VA Ann Arbor Healthcare System, Ann Arbor, MI.
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Hempel HA, Cuka NS, Kulac I, Barber JR, Cornish TC, Platz EA, De Marzo AM, Sfanos KS. Low Intratumoral Mast Cells Are Associated With a Higher Risk of Prostate Cancer Recurrence. Prostate 2017; 77:412-424. [PMID: 27868214 DOI: 10.1002/pros.23280] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Accepted: 11/01/2016] [Indexed: 12/18/2022]
Abstract
BACKGROUND Mast cells are of interest in prostate cancer because they possess both pro- and anti-tumorigenic properties and are present in the tumor microenvironment. We studied the association of mast cell count and densities with prostate cancer recurrence using tissue microarrays (TMAs) for 462 men who recurred (cases) and 462 controls that were matched to the cases nested in a cohort of radical prostatectomy patients. METHODS Dual-immunostaining for mast cell tryptase and epithelial cytokeratin-8 and whole slide image analysis were used to assess total mast cell number, mast cell density (mast cell number/tissue area), and mast cell number per epithelial or stromal area in TMA spots containing tumor (up to 4 per man). We used conditional logistic regression to estimate the odds ratio (OR) and 95% confidence interval of recurrence for the mean, minimum, and maximum mast cell parameters in tumor tissue among each man's TMA spots. RESULTS After taking into account matching factors of age, race, Gleason sum, and pathologic stage, higher minimum mast cell density in the tumor (comparing highest to lowest quartiles: OR = 0.58, 95% CI 0.40-0.86; P-trend = 0.004) was associated with a lower risk of recurrence. Patterns for mast cell number and ratio of mast cell number to epithelial or stromal area were similar to those for mast cell density. CONCLUSIONS Our results suggest that intratumoral mast cells may be protective against prostate cancer recurrence and could potentially serve as a prognostic biomarker after prostatectomy. Prostate 77: 412-424, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Heidi A Hempel
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Nathan S Cuka
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ibrahim Kulac
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - John R Barber
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Toby C Cornish
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Elizabeth A Platz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Angelo M De Marzo
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Karen S Sfanos
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
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Kelly SP, Graubard BI, Andreotti G, Younes N, Cleary SD, Cook MB. Prediagnostic Body Mass Index Trajectories in Relation to Prostate Cancer Incidence and Mortality in the PLCO Cancer Screening Trial. J Natl Cancer Inst 2017; 109:2905639. [PMID: 27754927 PMCID: PMC5074530 DOI: 10.1093/jnci/djw225] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 07/25/2016] [Accepted: 08/30/2016] [Indexed: 12/16/2022] Open
Abstract
Background Evidence suggests that obesity in adulthood is associated with increased risk of "clinically significant" prostate cancer. However, studies of body mass index (BMI) across the adult life course and prostate cancer risks remain limited. Methods In a prospective cohort of 69 873 men in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, we examined associations of prediagnostic BMI across the adult life course with risk of incident prostate cancer and fatal prostate cancer (prostate cancer-specific mortality). At 13 years of follow-up, we identified 7822 incident prostate cancer cases, of which 3078 were aggressive and 255 fatal. BMI trajectories were determined using latent-class trajectory modeling. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results BMI at age 20 years, 50 years, and baseline questionnaire (mean age = 63 years) were associated with increased risks of fatal prostate cancer (HRs = 1.27-1.32 per five-unit increase). In five BMI trajectories identified, fatal prostate cancer risk was increased in men who had a normal BMI (HR = 1.95, 95% CI = 1.21 to 3.12) or who were overweight (HR = 2.65, 95% CI = 1.35 to 5.18) at age 20 years and developed obesity by baseline compared with men who maintained a normal BMI. Aggressive and nonaggressive prostate cancer were not associated with BMI, and modest inverse associations were seen for total prostate cancer. Conclusions Our results suggest that BMI trajectories during adulthood that result in obesity lead to an elevated risk of fatal prostate cancer.
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Affiliation(s)
- Scott P Kelly
- Affiliations of authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD (SPK, BIG, GA, MBC); Department of Epidemiology and Biostatistics, Milken Institute School of Public Health, The George Washington University, Washington, DC (SPK, NY, SDC)
| | - Barry I Graubard
- Affiliations of authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD (SPK, BIG, GA, MBC); Department of Epidemiology and Biostatistics, Milken Institute School of Public Health, The George Washington University, Washington, DC (SPK, NY, SDC)
| | - Gabriella Andreotti
- Affiliations of authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD (SPK, BIG, GA, MBC); Department of Epidemiology and Biostatistics, Milken Institute School of Public Health, The George Washington University, Washington, DC (SPK, NY, SDC)
| | - Naji Younes
- Affiliations of authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD (SPK, BIG, GA, MBC); Department of Epidemiology and Biostatistics, Milken Institute School of Public Health, The George Washington University, Washington, DC (SPK, NY, SDC)
| | - Sean D Cleary
- Affiliations of authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD (SPK, BIG, GA, MBC); Department of Epidemiology and Biostatistics, Milken Institute School of Public Health, The George Washington University, Washington, DC (SPK, NY, SDC)
| | - Michael B Cook
- Affiliations of authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD (SPK, BIG, GA, MBC); Department of Epidemiology and Biostatistics, Milken Institute School of Public Health, The George Washington University, Washington, DC (SPK, NY, SDC)
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Lim H, Moon A. Inflammatory fibroblasts in cancer. Arch Pharm Res 2016; 39:1021-31. [DOI: 10.1007/s12272-016-0787-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Accepted: 06/22/2016] [Indexed: 01/07/2023]
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Davidsson S, Mölling P, Rider JR, Unemo M, Karlsson MG, Carlsson J, Andersson SO, Elgh F, Söderquis B, Andrén O. Frequency and typing of Propionibacterium acnes in prostate tissue obtained from men with and without prostate cancer. Infect Agent Cancer 2016; 11:26. [PMID: 27284286 PMCID: PMC4899914 DOI: 10.1186/s13027-016-0074-9] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 04/29/2016] [Indexed: 11/25/2022] Open
Abstract
Background Prostate cancer is the most common cancer among men in Western countries but the exact pathogenic mechanism of the disease is still largely unknown. An infectious etiology and infection-induced inflammation has been suggested to play a role in prostate carcinogenesis and Propionibacterium acnes has been reported as the most prevalent microorganism in prostatic tissue. We investigated the frequency and types of P. acnes isolated from prostate tissue samples from men with prostate cancer and from control patients without the disease. Methods We included 100 cases and 50 controls in this study. Cases were men diagnosed with prostate cancer undergoing radical prostatectomy and controls were men undergoing surgery for bladder cancer without any histological findings of prostate cancer. Six biopsies taken from each patient’s prostate gland at the time of surgery were used for cultivation and further characterization of P. acnes. Results The results revealed that P. acnes was more common in men with prostate carcinoma than in controls, with the bacteria cultured in 60 % of the cases vs. 26 % of the controls (p = 0.001). In multivariable analyses, men with P. acnes had a 4-fold increase in odds of a prostate cancer diagnosis after adjustment for age, calendar year of surgery and smoking status (OR: 4.46; 95 % CI: 1.93–11.26). To further support the biologic plausibility for a P. acnes infection as a contributing factor in prostate cancer development, we subsequently conducted cell-based experiments. P. acnes- isolates were co-cultured with the prostate cell line PNT1A. An increased cell proliferation and cytokine/chemokine secretion in infected cells was observed. Conclusion The present study provides further evidence for a role of P. acnes in prostate cancer development. Electronic supplementary material The online version of this article (doi:10.1186/s13027-016-0074-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Sabina Davidsson
- Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden ; A Member of the Transdisciplinary Prostate Cancer Partnership (TopCaP), Örebro, Sweden ; Department of Urology, Örebro University Hospital, SE-701 85 Örebro, Sweden
| | - Paula Mölling
- Department of Laboratory Medicine, Clinical Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Jennifer R Rider
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA USA ; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA ; A Member of the Transdisciplinary Prostate Cancer Partnership (TopCaP), Örebro, Sweden
| | - Magnus Unemo
- Department of Laboratory Medicine, Clinical Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Mats G Karlsson
- Department of Laboratory Medicine, Pathology, Örebro University Hospital, Örebro, Sweden ; Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Jessica Carlsson
- Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden ; A Member of the Transdisciplinary Prostate Cancer Partnership (TopCaP), Örebro, Sweden
| | - Swen-Olof Andersson
- Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden ; A Member of the Transdisciplinary Prostate Cancer Partnership (TopCaP), Örebro, Sweden
| | - Fredrik Elgh
- Department of Clinical Microbiology, Umeå University, Umeå, Sweden
| | - Bo Söderquis
- Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Ove Andrén
- Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden ; A Member of the Transdisciplinary Prostate Cancer Partnership (TopCaP), Örebro, Sweden
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Stark T, Livas L, Kyprianou N. Inflammation in prostate cancer progression and therapeutic targeting. Transl Androl Urol 2016; 4:455-63. [PMID: 26816843 PMCID: PMC4708587 DOI: 10.3978/j.issn.2223-4683.2015.04.12] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Chronic inflammation contributes to the onset and progression of human cancer, via modifications in the tumor microenvironment by remodeling the extracellular matrix (ECM) and initiating epithelial mesenchymal transition (EMT). At the biological level, chronically inflamed cells release cytokines that are functionally dictating a constitutively active stroma, promoting tumor growth and metastasis. In prostate cancer, inflammation correlates with increased development of “risk factor” lesions or proliferative inflammatory atrophy (PIA). Chronic inflammation in benign prostate biopsy specimens can be associated with high-grade prostate tumors in adjacent areas. In this article, we discuss the current understanding of the incidence of inflammation in prostate cancer progression and the significance of the process in therapeutic targeting of specific inflammatory signaling pathways and critical effectors during tumor progression. Further understanding of the process of chronic inflammation in prostate tumor progression to metastasis will enable development and optimization of novel therapeutic modalities for the treatment of high-risk patients with advanced disease.
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Affiliation(s)
- Timothy Stark
- 1 Department of Urology, 2 Department of Molecular Biochemistry, 3 Department of Pathology, 4 The Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA
| | - Lydia Livas
- 1 Department of Urology, 2 Department of Molecular Biochemistry, 3 Department of Pathology, 4 The Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA
| | - Natasha Kyprianou
- 1 Department of Urology, 2 Department of Molecular Biochemistry, 3 Department of Pathology, 4 The Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA
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Yeh CR, Slavin S, Da J, Hsu I, Luo J, Xiao GQ, Ding J, Chou FJ, Yeh S. Estrogen receptor α in cancer associated fibroblasts suppresses prostate cancer invasion via reducing CCL5, IL6 and macrophage infiltration in the tumor microenvironment. Mol Cancer 2016; 15:7. [PMID: 26790618 PMCID: PMC4721150 DOI: 10.1186/s12943-015-0488-9] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Accepted: 12/16/2015] [Indexed: 02/07/2023] Open
Abstract
Background Cancer associated fibroblasts (CAF) play important roles in tumor growth that involves inflammation and epithelial cell differentiation. Early studies suggested that estrogen receptor alpha (ERα) was expressed in stromal cells in normal prostates and prostate cancer (PCa), but the detailed functions of stromal ERα in the PCa remain to be further elucidated. Methods Migration and invasion assays demonstrated the presence of high levels of ERα in CAF cells (CAF.ERα(+)) suppressed PCa invasion via influencing the infiltration of tumor associated macrophages. ERα decreased CAF CCL5 secretion via suppressing the CCL5 promoter activity was examined by luciferase assay. ERα decreased CCL5 and IL-6 expression in conditioned media that was collected from CAF cell only or CAF cell co-cultured with macrophages as measured by ELISA assay. Results Both in vitro and in vivo studies demonstrated CAF.ERα(+) led to a reduced macrophage migration toward PCa via inhibiting CAF cells secreted chemokine CCL5. This CAF.ERα(+) suppressed macrophage infiltration affected the neighboring PCa cells invasion and the reduced invasiveness of PCa cells are at least partly due to reduced IL6 expression in the macrophages and CAF. Conclusion Our data suggest that CAF ERα could be applied as a prognostic marker to predict cancer progression, and targeting CCL5 and IL6 may be applied as an alternative therapeutic approach to reduce M2 type macrophages and PCa invasion in PCa patients with low or little ERα expression in CAF cells. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0488-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Chiuan-Ren Yeh
- George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY, 14642, USA
| | - Spencer Slavin
- George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY, 14642, USA
| | - Jun Da
- George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY, 14642, USA
| | - Iawen Hsu
- George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY, 14642, USA
| | - Jie Luo
- George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY, 14642, USA
| | - Guang-Qian Xiao
- Department of Pathology, University of Rochester Medical Center, Rochester, NY, 14642, USA
| | - Jie Ding
- George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY, 14642, USA
| | - Fu-Ju Chou
- George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY, 14642, USA
| | - Shuyuan Yeh
- George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY, 14642, USA.
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An EP4 antagonist ONO-AE3-208 suppresses cell invasion, migration, and metastasis of prostate cancer. Cell Biochem Biophys 2015; 70:521-7. [PMID: 24744183 DOI: 10.1007/s12013-014-9951-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
EP4 is one of the prostaglandin E2 receptors, which is the most common prostanoid and is associated with inflammatory disease and cancer. We previously reported that over-expression of EP4 was one of the mechanisms responsible for progression to castration-resistant prostate cancer, and an EP4 antagonist ONO-AE3-208 in vivo suppressed the castration-resistant progression regulating the activation of androgen receptor. The aim of this study was to analyze the association of EP4 with prostate cancer metastasis and the efficacy of ONO-AE3-208 for suppressing the metastasis. The expression levels of EP4 mRNA were evaluated in prostate cancer cell lines, LNCaP, and PC3. EP4 over-expressing LNCaP was established, and their cell invasiveness was compared with the control LNCaP (LNCaP/mock). The in vitro cell proliferation, invasion, and migration of these cells were examined under different concentrations of ONO-AE3-208. An in vivo bone metastatic mouse model was constructed by inoculating luciferase expressing PC3 cells into left ventricle of nude mice. Their bone metastasis was observed by bioluminescent imaging with or without ONO-AE3-208 administration. The EP4 mRNA expression levels were higher in PC3 than in LNCaP, and EP4 over-expression of LNCaP cells enhanced their cell invasiveness. The in vitro cell invasion and migration were suppressed by ONO-AE3-208 in a dose-dependent manner without affecting cell proliferation. The in vivo bone metastasis of PC3 was also suppressed by ONO-AE3-208 treatment. EP4 expression levels were correlated with prostate cancer cell invasiveness and EP4 specific antagonist ONO-AE3-208 suppressed cell invasion, migration, and bone metastasis, indicating that it is a potential novel therapeutic modality for the treatment of metastatic prostate cancer.
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Fernández-Martínez AB, Lucio-Cazaña J. Intracellular EP2 prostanoid receptor promotes cancer-related phenotypes in PC3 cells. Cell Mol Life Sci 2015; 72:3355-73. [PMID: 25828575 PMCID: PMC11113933 DOI: 10.1007/s00018-015-1891-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Revised: 03/10/2015] [Accepted: 03/19/2015] [Indexed: 12/23/2022]
Abstract
Prostaglandin E2 (PGE2) and hypoxia-inducible factor-1α (HIF-1α) affect many mechanisms that have been involved in the pathogenesis of prostate cancer (PC). HIF-1α, which is up-regulated by PGE2 in LNCaP cells and PC3 cells, has been shown to contribute to metastasis and chemo-resistance of castrate-resistant PC (a lethal form of PC) and to promote in PC cells migration, invasion, angiogenesis and chemoresistance. The selective blockade of PGE2-EP2 signaling pathway in PC3 cells results in inhibition of cancer cell proliferation and invasion. PGE2 affects many mechanisms that have been shown to play a role in carcinogenesis such as proliferation, apoptosis, migration, invasion and angiogenesis. Recently, we have found in PC3 cells that most of these PGE2-induced cancer-related features are due to intracellular PGE2 (iPGE2). Here, we aimed to study in PC3 cells the role of iPGE2-intracellular EP2 (iEP2)-HIF-1α signaling in several events linked to PC progression using an experimental approach involving pharmacological inhibition of the prostaglandin uptake transporter and EGFR and pharmacological and genetic modulation of EP2 receptor and HIF-1α. We found that iPGE2 increases HIF-1α expression through iEP2-dependent EGFR transactivation and that inhibition of any of the axis iEP2-EGFR-HIF-1α in cells treated with PGE2 or EP2 agonist results in prevention of the increase in PC3 cell proliferation, adhesion, migration, invasion and angiogenesis in vitro. Of note, PGE2 induced EP2 antagonist-sensitive DNA synthesis in nuclei isolated from PC3 cells, which indicates that they have functional EP2 receptors. These results suggest that PGE2-EP2 dependent intracrine mechanisms involving EGFR and HIF-1α play a role in PC.
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Affiliation(s)
- Ana Belén Fernández-Martínez
- Departamento de Biología de Sistemas, Facultad de Medicina, Universidad de Alcalá, Alcalá de Henares, 28871, Madrid, Spain,
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Atala A. Re: A Human Prostatic Bacterial Isolate Alters the Prostatic Microenvironment and Accelerates Prostate Cancer Progression. J Urol 2015; 194:849. [PMID: 26292899 DOI: 10.1016/j.juro.2015.06.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Moreira DM, Bostwick DG, Andriole GL, Peterson BL, Cohen HJ, Castro-Santamaria R, Freedland SJ. Baseline Prostate Atrophy is Associated with Reduced Risk of Prostate Cancer in Men Undergoing Repeat Prostate Biopsy. J Urol 2015; 194:1241-6. [PMID: 26165588 DOI: 10.1016/j.juro.2015.05.103] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/29/2015] [Indexed: 12/23/2022]
Abstract
PURPOSE We evaluated whether the presence and severity of baseline prostate atrophy in men with initial biopsy negative for prostate cancer was associated the risk of subsequent prostate cancer detection in a clinical trial with scheduled study mandated biopsies. MATERIALS AND METHODS We retrospectively analyzed the records of 3,084 men 50 to 75 years old with prostate specific antigen between 2.5 and 10 ng/ml, and a prior negative biopsy in the placebo arm of the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) study who completed at least 1 per-protocol biopsy. Prostate cancer (defined as present or absent) and prostate atrophy (graded as absent, mild or moderate/marked) was assessed by central pathology review. The association of baseline atrophy with positive 2 and 4-year repeat biopsies was evaluated with logistic regression, controlling for baseline covariates. RESULTS Baseline prostate atrophy was detected in 2,143 men (70%) and graded as mild and moderate/marked in 1,843 (60%) and 300 (10%) baseline biopsies, respectively. Patients with atrophy were older and had a larger prostate, and more acute and chronic prostate inflammation. At 2-year biopsy the prostate cancer incidence was 17% (508 cases). Baseline atrophy was significantly associated with lower prostate cancer risk (univariable and multivariable OR 0.60, 95% CI 0.50-0.74 and OR 0.67, 95% CI 0.54-0.83, p <0.001, respectively) at the 2-year biopsy. These results were similar at the 4-year biopsy (univariable and multivariable OR 0.70, 95% CI 0.53-0.93 and OR 0.72, 95% CI 0.53-0.97, p = 0.03, respectively). Relative to no atrophy the prostate cancer risk at the 2-year repeat biopsy was lower for mild atrophy (OR 0.69, 95% CI 0.55-0.86) and moderate/marked atrophy (OR 0.51, 95% CI 0.34-0.76, each p <0.001). CONCLUSIONS Baseline prostate atrophy in men with a prostate biopsy negative for prostate cancer was independently associated with subsequent lower prostate cancer detection.
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Affiliation(s)
| | | | - Gerald L Andriole
- Division of Urologic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - Bercedis L Peterson
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina
| | - Harvey J Cohen
- Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | | | - Stephen J Freedland
- Urology Section, Veterans Affairs Medical Center, Durham, North Carolina; Division of Urology, Department of Surgery, Cedars Sinai Medical Center, Los Angeles, California
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Erdrich S, Bishop KS, Karunasinghe N, Han DY, Ferguson LR. A pilot study to investigate if New Zealand men with prostate cancer benefit from a Mediterranean-style diet. PeerJ 2015; 3:e1080. [PMID: 26157638 PMCID: PMC4493678 DOI: 10.7717/peerj.1080] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2014] [Accepted: 06/14/2015] [Indexed: 12/23/2022] Open
Abstract
Carcinoma of the prostate is the most commonly diagnosed malignancy and the third leading cause of mortality in New Zealand men, making it a significant health issue in this country. Global distribution patterns suggest that diet and lifestyle factors may be linked to the development and progression of this cancer. Twenty men with diagnosed prostate cancer adhered to a Mediterranean diet, with specific adaptations, for three months. Prostate-specific antigen, C-reactive protein and DNA damage were evaluated at baseline and after three months of following the diet. Dietary data were collated from diet diaries and an adaptation of a validated Mediterranean diet questionnaire. A significant reduction in DNA damage compared to baseline was apparent, with particular benefit noted for overall adherence to the diet (p = 0.013), increased intake of folate (p = 0.023), vitamin C (p = 0.007), legumes (p = 0.004) and green tea (p = 0.002). Higher intakes of red meat and dairy products were inversely associated with DNA damage (p = 0.003 and p = 0.008 respectively). The results from this small feasibility study suggest that a high-antioxidant diet, modelled on Mediterranean traditions, may be of benefit for men with prostate cancer. Protection against DNA damage appears to be associated with the diet implemented, ostensibly due to reduction in reactive oxidant species. These findings warrant further exploration in a longer trial, with a larger cohort.
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Affiliation(s)
- Sharon Erdrich
- Discipline of Nutrition, FM&HS, University of Auckland , Auckland , New Zealand
| | - Karen S Bishop
- Auckland Cancer Society Research Centre, FM & HS, University of Auckland , Auckland , New Zealand
| | - Nishi Karunasinghe
- Auckland Cancer Society Research Centre, FM & HS, University of Auckland , Auckland , New Zealand
| | - Dug Yeo Han
- Nutrigenomics New Zealand, University of Auckland , Auckland , New Zealand
| | - Lynnette R Ferguson
- Discipline of Nutrition, FM&HS, University of Auckland , Auckland , New Zealand ; Auckland Cancer Society Research Centre, FM & HS, University of Auckland , Auckland , New Zealand ; Nutrigenomics New Zealand, University of Auckland , Auckland , New Zealand
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Bowen C, Zheng T, Gelmann EP. NKX3.1 Suppresses TMPRSS2-ERG Gene Rearrangement and Mediates Repair of Androgen Receptor-Induced DNA Damage. Cancer Res 2015; 75:2686-98. [PMID: 25977336 DOI: 10.1158/0008-5472.can-14-3387] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Accepted: 04/17/2015] [Indexed: 02/02/2023]
Abstract
TMPRSS2 gene rearrangements occur at DNA breaks formed during androgen receptor-mediated transcription and activate expression of ETS transcription factors at the early stages of more than half of prostate cancers. NKX3.1, a prostate tumor suppressor that accelerates the DNA repair response, binds to androgen receptor at the ERG gene breakpoint and inhibits both the juxtaposition of the TMPRSS2 and ERG gene loci and also their recombination. NKX3.1 acts by accelerating DNA repair after androgen-induced transcriptional activation. NKX3.1 influences the recruitment of proteins that promote homology-directed DNA repair. Loss of NKX3.1 favors recruitment to the ERG gene breakpoint of proteins that promote error-prone nonhomologous end-joining. Analysis of prostate cancer tissues showed that the presence of a TMPRSS2-ERG rearrangement was highly correlated with lower levels of NKX3.1 expression consistent with the role of NKX3.1 as a suppressor of the pathogenic gene rearrangement.
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Affiliation(s)
- Cai Bowen
- Department of Medicine, Columbia University, Herbert Irving Comprehensive Cancer Center, New York, New York
| | - Tian Zheng
- Department of Statistics, Columbia University, Herbert Irving Comprehensive Cancer Center, New York, New York
| | - Edward P Gelmann
- Department of Medicine, Columbia University, Herbert Irving Comprehensive Cancer Center, New York, New York. Department of Pathology, Columbia University, Herbert Irving Comprehensive Cancer Center, New York, New York.
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Nash SH, Schenk JM, Kristal AR, Goodman PJ, Lucia MS, Parnes HL, Thompson IM, Lippman SM, Song X, Gurel B, De Marzo A, Platz EA. Association between Serum Phospholipid Fatty Acids and Intraprostatic Inflammation in the Placebo Arm of the Prostate Cancer Prevention Trial. Cancer Prev Res (Phila) 2015; 8:590-6. [PMID: 25926387 DOI: 10.1158/1940-6207.capr-14-0398] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 04/06/2015] [Indexed: 01/01/2023]
Abstract
Inflammation may play an etiologic role in prostate cancer. Several dietary factors influence inflammation; studies have shown that long-chain n-3 polyunsaturated fatty acids are anti-inflammatory, whereas n-6 and trans fatty acids are proinflammatory. We evaluated whether serum phospholipid n-3, n-6, and trans fatty acids were associated with intraprostatic inflammation, separately in 191 prostate cancer cases and 247 controls from the placebo arm of the Prostate Cancer Prevention Trial (PCPT). Men without a prostate cancer diagnosis underwent prostate biopsy at trial end, and benign prostate tissue inflammation was evaluated in approximately three biopsy cores per man; this was expressed as no, some, or all cores with inflammation. In controls, serum eicosapentaenoic acid [OR of all cores with inflammation versus none (95% CI), 0.35 (0.14-0.89)] and docosahexaenoic acid [OR (95% CI), 0.42 (0.17-1.02)] were inversely associated with, whereas linoleic acid [OR (95% CI), 3.85 (1.41-10.55)] was positively associated with intraprostatic inflammation. Serum trans fatty acids were not associated with intraprostatic inflammation. No significant associations were observed in cases; however, we could not rule out a positive association with linoleic acid and an inverse association with arachidonic acid. Thus, in the PCPT, we found that serum n-3 fatty acids were inversely, n-6 fatty acids were positively, and trans fatty acids were not associated with intraprostatic inflammation in controls. Although, in theory, inflammation could mediate associations of serum fatty acids with prostate cancer risk, our findings cannot explain the epidemiologic associations observed with n-3 and n-6 fatty acids.
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Affiliation(s)
- Sarah H Nash
- Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland
| | - Jeannette M Schenk
- Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Alan R Kristal
- Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | | | - M Scott Lucia
- Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Denver, Colorado
| | - Howard L Parnes
- Prostate and Urologic Cancer Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland
| | - Ian M Thompson
- Department of Urology, School of Medicine, University of Texas Health Science Center, San Antonio, Texas
| | - Scott M Lippman
- Office of the Director, Moores Cancer Center, University of California at San Diego, San Diego, California
| | - Xiaoling Song
- Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Bora Gurel
- Department of Pathology, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Angelo De Marzo
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland. James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland
| | - Elizabeth A Platz
- Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland. James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
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Simons BW, Durham NM, Bruno TC, Grosso JF, Schaeffer AJ, Ross AE, Hurley PJ, Berman DM, Drake CG, Thumbikat P, Schaeffer EM. A human prostatic bacterial isolate alters the prostatic microenvironment and accelerates prostate cancer progression. J Pathol 2015; 235:478-89. [PMID: 25348195 DOI: 10.1002/path.4472] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2014] [Revised: 10/14/2014] [Accepted: 10/22/2014] [Indexed: 01/10/2023]
Abstract
Inflammation is associated with several diseases of the prostate including benign enlargement and cancer, but a causal relationship has not been established. Our objective was to characterize the prostate inflammatory microenvironment after infection with a human prostate-derived bacterial strain and to determine the effect of inflammation on prostate cancer progression. To this end, we mimicked typical human prostate infection with retrograde urethral instillation of CP1, a human prostatic isolate of Escherichia coli. CP1 bacteria were tropic for the accessory sex glands and induced acute inflammation in the prostate and seminal vesicles, with chronic inflammation lasting at least 1 year. Compared to controls, infection induced both acute and chronic inflammation with epithelial hyperplasia, stromal hyperplasia, and inflammatory cell infiltrates. In areas of inflammation, epithelial proliferation and hyperplasia often persist, despite decreased expression of androgen receptor (AR). Inflammatory cells in the prostates of CP1-infected mice were characterized at 8 weeks post-infection by flow cytometry, which showed an increase in macrophages and lymphocytes, particularly Th17 cells. Inflammation was additionally assessed in the context of carcinogenesis. Multiplex cytokine profiles of inflamed prostates showed that distinct inflammatory cytokines were expressed during prostate inflammation and cancer, with a subset of cytokines synergistically increased during concurrent inflammation and cancer. Furthermore, CP1 infection in the Hi-Myc mouse model of prostate cancer accelerated the development of invasive prostate adenocarcinoma, with 70% more mice developing cancer by 4.5 months of age. This study provides direct evidence that prostate inflammation accelerates prostate cancer progression and gives insight into the microenvironment changes induced by inflammation that may accelerate tumour initiation or progression.
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Affiliation(s)
- Brian W Simons
- The Brady Urological Institute, Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Madrigal-Martínez A, Cazaña FJL, Fernández-Martínez YAB. Role of intracellular prostaglandin E₂ in cancer-related phenotypes in PC3 cells. Int J Biochem Cell Biol 2014; 59:52-61. [PMID: 25462156 DOI: 10.1016/j.biocel.2014.11.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Revised: 10/20/2014] [Accepted: 11/03/2014] [Indexed: 11/25/2022]
Abstract
Prostaglandin E2 (PGE2) and hypoxia-inducible factor-1α (HIF-1α) affect many mechanisms that have been shown to play a role in prostate cancer. In PGE2-treated LNCaP cells, up-regulation of HIF-1α requires the internalization of PGE2, which is in sharp contrast with the generally accepted view that PGE2 acts through EP receptors located at the cell membrane. Here we aimed to study in androgen-independent PC3 cells the role of intracellular PGE2 in several events linked to prostate cancer progression. To this end, we used bromocresol green, an inhibitor of prostaglandin uptake that blocked the immediate rise in intracellular immunoreactive PGE2 following treatment with 16,16-dimethyl-PGE2. Bromocresol green prevented the stimulatory effect of 16,16-dimethyl-PGE on cell proliferation, adhesion, migration and invasion and on HIF-1α expression and activity, the latter assessed as the HIF-dependent activation of (i) a hypoxia response element-luciferase plasmid construct, (ii) production of angiogenic factor vascular endothelial growth factor-A and (iii) in vitro angiogenesis. The basal phenotype of PC3 cells was also affected by bromocresol green, that substantially lowered expression of HIF-1α, production of vascular endothelial growth factor-A and cell proliferation. These results, and the fact that we found functional intracellular EP receptors in PC3 cells, suggest that PGE2-dependent intracrine mechanisms play a role in prostate cancer Therefore, inhibition of the prostaglandin uptake transporter might be a novel therapeutic approach for the treatment of prostate cancer.
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Markt SC, Rider JR, Penney KL, Schumacher FR, Epstein MM, Fall K, Sesso HD, Stampfer MJ, Mucci LA. Genetic variation across C-reactive protein and risk of prostate cancer. Prostate 2014; 74:1034-42. [PMID: 24844401 PMCID: PMC4063346 DOI: 10.1002/pros.22820] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 04/15/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND Inflammation has been hypothesized to play an important etiological role in the initiation or progression of prostate cancer. Circulating levels of the systemic inflammation marker C-reactive protein (CRP) have been associated with increased risk of prostate cancer. We investigated the role of genetic variation in CRP and prostate cancer, under the hypothesis that variants may alter risk of disease. METHODS We undertook a case-control study nested within the prospective Physicians' Health Study among 1,286 men with incident prostate cancer and 1,264 controls. Four single-nucleotide polymorphisms (SNPs) were selected to capture the common genetic variation across CRP (r(2) > 0.8). We used unconditional logistic regression to assess the association between each SNP and risk of prostate cancer. Linear regression models explored associations between each genotype and plasma CRP levels. RESULTS None of the CRP SNPs were associated with prostate cancer overall. Individuals with one copy of the minor allele (C) in rs1800947 had an increased risk of high-grade prostate cancer (OR: 1.7; 95% CI: 1.1-2.8), and significantly lower mean CRP levels (P-value <0.001), however, we found no significant association with lethal disease. Mean CRP levels were significantly elevated in men with one or two copies of the minor allele in rs3093075 and rs1417939, but these were unrelated to prostate cancer risk. CONCLUSION Our findings suggest that SNPs in the CRP gene are not associated with risk of overall or lethal prostate cancer. Polymorphisms in CRP rs1800947 may be associated with higher grade disease, but our results require replication in other cohorts.
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Affiliation(s)
- Sarah C. Markt
- Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
| | - Jennifer R. Rider
- Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Kathryn L. Penney
- Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Fredrick R. Schumacher
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Mara M. Epstein
- Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Katja Fall
- Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
- Clinical Epidemiology and Biostatistics, Örebro University, Sweden
| | - Howard D. Sesso
- Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School
| | - Meir J. Stampfer
- Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Lorelei A. Mucci
- Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
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Qarro A, Ammani A, Bazine K, Najoui M, Samir J, Alami M. Synchronous primary malignancies of the male urogenital tract. Can Urol Assoc J 2014; 8:E353-5. [PMID: 24940463 DOI: 10.5489/cuaj.1532] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The finding of prostate cancer after a cystoprostatectomy for a bladder tumour can occur in up to 70% of cases. The incidence of prostate cancer in patients with a bladder tumour is 18 times higher than in the general population; moreover, the incidence of bladder cancer in patients with prostate cancer is 19 times higher than in the general population. This association can be explained by the common embryological origin of these organs, with molecular similarities. Other similarities between these two cancers are noted. They are multifocal and may be secondary to urinary stasis. However, this association does not seem responsible for an increased risk of progression of both diseases. The prognosis is related to the extension of each cancer. The stage and grade of bladder cancer are, in terms of prognosis, greater than those of prostate cancer. Most often, this is insignificant prostate cancer. Despite this, the prostate-specific antigen test should be administered to monitor patients after cystoprostatectomy.
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Affiliation(s)
| | - Abdelghani Ammani
- Department of Urology, Military Hospital Moulay Ismail, Meknes, Morocco
| | - Khalil Bazine
- Department of Urology, Military Hospital Moulay Ismail, Meknes, Morocco
| | - Mohammed Najoui
- Department of Urology, Military Hospital Moulay Ismail, Meknes, Morocco
| | - Jamaleddine Samir
- Department of Urology, Military Hospital Moulay Ismail, Meknes, Morocco
| | - Mohammed Alami
- Department of Urology, Military Hospital Moulay Ismail, Meknes, Morocco
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Mukherjee S, Siddiqui MA, Dayal S, Ayoub YZ, Malathi K. Epigallocatechin-3-gallate suppresses proinflammatory cytokines and chemokines induced by Toll-like receptor 9 agonists in prostate cancer cells. J Inflamm Res 2014; 7:89-101. [PMID: 24971028 PMCID: PMC4070858 DOI: 10.2147/jir.s61365] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Chronic inflammation of the prostate contributes to the increased risk of prostate cancer. Microbial pathogens in the prostate cause inflammation that leads to prostatitis and proliferative inflammatory atrophy frequently associated with the development of prostate cancer. Bacterial lipopolysaccharides and DNA mediate immune responses by engaging Toll-like receptor (TLR) 4 and 9, respectively. Synthetic oligodeoxynucleotides containing CpG motifs (CpG-ODN) mimic bacterial DNA and signal through TLR9 to initiate innate immune responses. Here, we show that stimulation of DU145, PC3, or LnCap prostate cancer cells by the TLR9 agonists, CpG-ODN, induces mRNA expression of IL-6, IL-8, CXCL1, IP-10, CCL5, and TGFβ. In addition, activity of matrix metalloproteinase (MMP)-9 and -2 and cell migration increased on CpG-ODN treatment. Induction of cytokines and chemokines was mediated by NF-κB activation and translocation to the nucleus. Treatment with epigallocatechin-3-gallate (EGCG), the major constituent of green tea, prior to CpG-ODN stimulation, inhibits cytokine and chemokine gene induction, activity of MMP-9 and -2, and cell migration. EGCG treatment sequesters the p65 subunit of transcription factor NF-κB in the cytoplasm and inhibits transcriptional activity of the NF-κB-driven promoter in response to CpG-ODN. Our results suggest that the ability of the TLR9 agonists, CpG-ODN, to induce cytokines, chemokines, and MMP activity, as well as suppression by EGCG are independent of the androgen receptor and p53 status of the cells. EGCG may provide protective effects against inflammation in the prostate and benefit prostate cancer treatment.
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Affiliation(s)
| | | | - Shubham Dayal
- Department of Biological Sciences, University of Toledo, Toledo, OH, USA
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Grindel BJ, Martinez JR, Pennington CL, Muldoon M, Stave J, Chung LW, Farach-Carson MC. Matrilysin/matrix metalloproteinase-7(MMP7) cleavage of perlecan/HSPG2 creates a molecular switch to alter prostate cancer cell behavior. Matrix Biol 2014; 36:64-76. [PMID: 24833109 DOI: 10.1016/j.matbio.2014.04.005] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 04/16/2014] [Accepted: 04/17/2014] [Indexed: 01/17/2023]
Abstract
Perlecan/HSPG2, a large heparan sulfate (HS) proteoglycan, normally is expressed in the basement membrane (BM) underlying epithelial and endothelial cells. During prostate cancer (PCa) cell invasion, a variety of proteolytic enzymes are expressed that digest BM components including perlecan. An enzyme upregulated in invasive PCa cells, matrilysin/matrix metalloproteinase-7 (MMP-7), was examined as a candidate for perlecan proteolysis both in silico and in vitro. Purified perlecan showed high sensitivity to MMP-7 digestion even when fully decorated with HS or when presented in native context connected with other BM proteins. In both conditions, MMP-7 produced discrete perlecan fragments corresponding to an origin in immunoglobulin (Ig) repeat region domain IV. While not predicted by in silico analysis, MMP-7 cleaved every subpart of recombinantly generated perlecan domain IV. Other enzymes relevant to PCa that were tested had limited ability to cleave perlecan including prostate specific antigen, hepsin, or fibroblast activation protein α. A long C-terminal portion of perlecan domain IV, Dm IV-3, induced a strong clustering phenotype in the metastatic PCa cell lines, PC-3 and C4-2. MMP-7 digestion of Dm IV-3 reverses the clustering effect into one favoring cell dispersion. In a C4-2 Transwell® invasion assay, perlecan-rich human BM extract that was pre-digested with MMP-7 showed loss of barrier function and permitted a greater level of cell penetration than untreated BM extract. We conclude that enzymatic processing of perlecan in the BM or territorial matrix by MMP-7 as occurs in the invasive tumor microenvironment acts as a molecular switch to alter PCa cell behavior and favor cell dispersion and invasiveness.
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Affiliation(s)
- B J Grindel
- Department of Biochemistry and Cell Biology, Rice University, Houston, TX, 77005, USA
| | - J R Martinez
- Department of Biochemistry and Cell Biology, Rice University, Houston, TX, 77005, USA
| | - C L Pennington
- Shared Equipment Authority, Rice University, Houston, TX 77005
| | - M Muldoon
- Strategic Diagnostics Inc, Newark, DE, 19702, USA
| | - J Stave
- Strategic Diagnostics Inc, Newark, DE, 19702, USA
| | - L W Chung
- Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - M C Farach-Carson
- Department of Biochemistry and Cell Biology, Rice University, Houston, TX, 77005, USA; Department of Bioengineering, Rice University, Houston, TX 77005, USA.
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Balkan F, Onal ED, Usluogullari A, Tuzun D, Ozdemir D, Inancli SS, Ersoy R, Cakir B. "Is there any association between insulin resistance and thyroid cancer? : A case control study". Endocrine 2014; 45:55-60. [PMID: 23564559 DOI: 10.1007/s12020-013-9942-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2013] [Accepted: 03/23/2013] [Indexed: 12/31/2022]
Abstract
Insulin stimulates proliferation of thyroid cells in culture. The presence of insulin resistance (IR) is associated with larger thyroid gland volume and an increased prevalence of thyroid nodules. The aim of this study was to investigate the presence of any possible association between IR and thyroid cancer. Forty-one patients with diffuse thyroid cancer (Group 1) were matched for age and gender with 41 patients with nodular goiter (Group 2). Both groups were compared in terms of frequency of IR, as estimated by the homeostasis model assessment, as well as other parameters of the metabolic syndrome (MetS). Fourteen patients (34.1 %) in each group had MetS. Twelve patients (29.3 %) in group 1 had IR compared to 10 (24.4 %) in group 2. Mean HOMA-IR scores in group 1 and 2 were 2.5 ± 2.2 and 1.8 ± 1.1, respectively. Thirty-two patients (78 %) in group 1 had a body mass index (BMI) of more than 25 compared to 33 patients (80.5 %) in group 2. The difference between groups with regard to HOMA-IR, the frequency of IR, BMI, and any of the parameters of MetS was statistically insignificant (p > 0.05). A subgroup analysis based on tumor size did not reveal a significant difference between patients with microcarcinoma (≤10 mm) and macrocarcinoma (>10 mm) in terms of any of the study parameters (p > 0.05). Neither MetS nor IR was a significant risk factor for thyroid cancer following logistic regression analysis (p > 0.05). IR is not more prevalent in patients with thyroid cancer. Some other pathologic mechanisms may be more prominent during thyroid carcinogenesis.
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Affiliation(s)
- Fevzi Balkan
- Department of Endocrinology and Metabolism, Yildirim Beyazit University Medical School Ataturk Teaching and Research Hospital, Bilkent, Ankara, Turkey,
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Moreira DM, Nickel JC, Gerber L, Muller RL, Andriole GL, Castro-Santamaria R, Freedland SJ. Baseline prostate inflammation is associated with a reduced risk of prostate cancer in men undergoing repeat prostate biopsy: results from the REDUCE study. Cancer 2013; 120:190-6. [PMID: 24323568 DOI: 10.1002/cncr.28349] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Revised: 07/21/2013] [Accepted: 07/24/2013] [Indexed: 11/08/2022]
Abstract
BACKGROUND The current study was performed to evaluate whether baseline acute and chronic prostate inflammation among men with an initial negative biopsy for prostate cancer (PCa) increased the risk of subsequent PCa detection in a clinical trial with systematic biopsies. METHODS A retrospective analysis was performed of 6238 men aged 50 years to 75 years with prostate-specific antigen levels between 2.5 ng/mL and 10 ng/mL and a prior negative biopsy in the REduction by DUtasteride of PCa Events study who completed a 2-year biopsy. PCa, acute prostate inflammation, and chronic prostate inflammation were assessed by central review. The association between inflammation in baseline prostate biopsies and positive 2-year and 4-year repeat biopsies was evaluated with the chi-square test and logistic regression analysis adjusting for baseline covariates. RESULTS Acute and chronic inflammation and both were detected in 46 baseline biopsies (1%), 3931 baseline biopsies (63%), and 892 baseline biopsies (14%), respectively. Acute and chronic inflammation were found to be significantly associated with each other (P<.001). Acute inflammation at baseline biopsy was associated with younger age, lower prostate-specific antigen levels, and a smaller prostate (all P<.01), whereas chronic inflammation was associated with older age and larger prostate glands (all P<0.01). At the 2-year biopsy, the prevalence of PCa was 14% (N=900 patients). On univariable and multivariable analysis, both acute and chronic inflammation were found to be significantly associated with a lower PCa risk (acute univariable: odds ratio [OR], 0.65 [P<.001] and multivariable: OR, 0.75 [P=.012] and chronic univariable: OR, 0.61 [P<.001] and multivariable: OR, 0.65 [P<.001]). At the time of 4-year biopsy, only acute inflammation was found to be associated with a lower PCa risk. CONCLUSIONS Baseline acute and chronic inflammation were both found to be independently associated with a lower PCa risk. From a clinical standpoint, inflammation in negative biopsies for PCa may lower the risk of subsequent PCa detection.
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Affiliation(s)
- Daniel M Moreira
- The Arthur Smith Institute for Urology, North Shore Long Island Jewish Health System, New Hyde Park, New York
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48
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Tsilidis KK, Rohrmann S, McGlynn KA, Nyante SJ, Lopez DS, Bradwin G, Feinleib M, Joshu CE, Kanarek N, Nelson WG, Selvin E, Platz EA. Association between endogenous sex steroid hormones and inflammatory biomarkers in US men. Andrology 2013; 1:919-28. [PMID: 24124163 DOI: 10.1111/j.2047-2927.2013.00129.x] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Revised: 07/10/2013] [Accepted: 08/03/2013] [Indexed: 11/25/2022]
Abstract
Sex steroid hormones and inflammatory biomarkers are both associated with the development and progression of chronic diseases, but their interrelationship is relatively uncharacterized. We examined the association of sex hormones and sex hormone-binding globulin (SHBG) with biomarkers of inflammation, C-reactive protein (CRP) and white blood cell (WBC) count. The study included data from 809 adult men in the National Health and Nutrition Examination Survey 1999-2004. Geometric means and 95% confidence intervals were estimated separately for CRP and WBC concentrations by sex steroid hormones and SHBG using weighted linear regression models. Higher concentrations of total (slope per one quintile in concentration, -0.18; p-trend, 0.001) and calculated free (slope, -0.13; p-trend, 0.03) testosterone were statistically significantly associated with lower concentrations of CRP, but not with WBC count. Men in the bottom quintile of total testosterone (≤3.3 ng/mL), who might be considered to have clinically low testosterone, were more likely to have elevated CRP (≥3 mg/L) compared with men in the top four quintiles (OR, 1.61; 95% CI, 1.00-2.61). Total and calculated free estradiol (E2) were positively associated with both CRP (Total E2: slope, 0.14; p-trend, <0.001; Free E2: slope, 0.15; p-trend, <0.001) and WBC (Total E2: slope, 0.02; p-trend, 0.08; Free E2: slope, 0.02; p-trend, 0.02) concentrations. SHBG concentrations were inversely associated with WBC count (slope, -0.03; p-trend, 0.04), but not with CRP. These cross-sectional findings are consistent with the hypothesis that higher androgen and lower oestrogen concentrations may have an anti-inflammatory effect in men.
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Affiliation(s)
- K K Tsilidis
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
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49
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Savoy RM, Ghosh PM. Linking inflammation and neuroendocrine differentiation: the role of macrophage migration inhibitory factor-mediated signaling in prostate cancer. Endocr Relat Cancer 2013; 20:C1-4. [PMID: 23612613 DOI: 10.1530/erc-13-0133] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
A new paper by Tawadros et al. in Endocrine-Related Cancer demonstrates a link between macrophage migration inhibitory factor and neuroendocrine differentiation in prostate cancer. This paper may have implications in explaining the effect of prostatitis and chronic inflammation on the development of aggressive prostate cancer.
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Affiliation(s)
- Rosalinda M Savoy
- Department of Urology, University of California Davis, Sacramento, California, USA
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50
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Jin F, Irshad S, Yu W, Belakavadi M, Chekmareva M, Ittmann MM, Abate-Shen C, Fondell JD. ERK and AKT signaling drive MED1 overexpression in prostate cancer in association with elevated proliferation and tumorigenicity. Mol Cancer Res 2013; 11:736-47. [PMID: 23538858 DOI: 10.1158/1541-7786.mcr-12-0618] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
MED1 is a key coactivator of the androgen receptor (AR) and other signal-activated transcription factors. Whereas MED1 is overexpressed in prostate cancer cell lines and is thought to coactivate distinct target genes involved in cell-cycle progression and castration-resistant growth, the underlying mechanisms by which MED1 becomes overexpressed and its oncogenic role in clinical prostate cancer have remained unclear. Here, we report that MED1 is overexpressed in the epithelium of clinically localized human prostate cancer patients, which correlated with elevated cellular proliferation. In a Nkx3.1:Pten mutant mouse model of prostate cancer that recapitulates the human disease, MED1 protein levels were markedly elevated in the epithelium of both invasive and castration-resistant adenocarcinoma prostate tissues. Mechanistic evidence showed that hyperactivated ERK and/or AKT signaling pathways promoted MED1 overexpression in prostate cancer cells. Notably, ectopic MED1 overexpression in prostate cancer xenografts significantly promoted tumor growth in nude mice. Furthermore, MED1 expression in prostate cancer cells promoted the expression of a number of novel genes involved in inflammation, cell proliferation, and survival. Together, these findings suggest that elevated MED1 is a critical molecular event associated with prostate oncogenesis.
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Affiliation(s)
- Feng Jin
- Department of Physiology and Biophysics, Robert Wood Johnson Medical School, UMDNJ, 683 Hoes Lane, Piscataway, New Jersey 08854, USA
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