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Dos Santos L, Carbone F, Pacreau E, Diarra S, Luka M, Pigat N, Baures M, Navarro E, Anract J, Barry Delongchamps N, Cagnard N, Bost F, Nemazanyy I, Petitjean O, Hamaï A, Ménager M, Palea S, Guidotti JE, Goffin V. Cell Plasticity in a Mouse Model of Benign Prostate Hyperplasia Drives Amplification of Androgen-Independent Epithelial Cell Populations Sensitive to Antioxidant Therapy. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:30-51. [PMID: 37827216 DOI: 10.1016/j.ajpath.2023.09.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 08/23/2023] [Accepted: 09/12/2023] [Indexed: 10/14/2023]
Abstract
Benign prostate hyperplasia (BPH) is caused by the nonmalignant enlargement of the transition zone of the prostate gland, leading to lower urinary tract symptoms. Although current medical treatments are unsatisfactory in many patients, the limited understanding of the mechanisms driving disease progression prevents the development of alternative therapeutic strategies. The probasin-prolactin (Pb-PRL) transgenic mouse recapitulates many histopathological features of human BPH. Herein, these alterations parallel urodynamic disturbance reminiscent of lower urinary tract symptoms. Single-cell RNA-sequencing analysis of Pb-PRL mouse prostates revealed that their epithelium mainly includes low-androgen signaling cell populations analogous to Club/Hillock cells enriched in the aged human prostate. These intermediate cells are predicted to result from the reprogramming of androgen-dependent luminal cells. Pb-PRL mouse prostates exhibited increased vulnerability to oxidative stress due to reduction of antioxidant enzyme expression. One-month treatment of Pb-PRL mice with anethole trithione (ATT), a specific inhibitor of mitochondrial ROS production, reduced prostate weight and voiding frequency. In human BPH-1 epithelial cells, ATT decreased mitochondrial metabolism, cell proliferation, and stemness features. ATT prevented the growth of organoids generated by sorted Pb-PRL basal and LSCmed cells, the two major BPH-associated, androgen-independent epithelial cell compartments. Taken together, these results support cell plasticity as a driver of BPH progression and therapeutic resistance to androgen signaling inhibition, and identify antioxidant therapy as a promising treatment of BPH.
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Affiliation(s)
- Leïla Dos Santos
- Institut Necker Enfants Malades, Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Paris, France
| | - Francesco Carbone
- Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Imagine Institute, Université Paris Cité, Atip-Avenir Team, INSERM UMR 1163, Paris, France; Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, Paris, France
| | - Emeline Pacreau
- Institut Necker Enfants Malades, Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Paris, France
| | - Sekou Diarra
- Humana Biosciences SAS, Prologue Biotech, Labège, France
| | - Marine Luka
- Institut Necker Enfants Malades, Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Paris, France; Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Imagine Institute, Université Paris Cité, Atip-Avenir Team, INSERM UMR 1163, Paris, France
| | - Natascha Pigat
- Institut Necker Enfants Malades, Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Paris, France
| | - Manon Baures
- Institut Necker Enfants Malades, Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Paris, France
| | - Emilie Navarro
- Institut Necker Enfants Malades, Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Paris, France
| | - Julien Anract
- Institut Necker Enfants Malades, Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Paris, France; Urology Department, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Nicolas Barry Delongchamps
- Institut Necker Enfants Malades, Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Paris, France; Urology Department, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Nicolas Cagnard
- Bioinformatics Core Platform, Université Paris Cité, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UAR3633, Paris, France
| | - Frédéric Bost
- C3M, INSERM U1065, Université Côte d'Azur, Equipe Labélisée Ligue Nationale contre le Cancer, Nice, France
| | - Ivan Nemazanyy
- Metabolomics Core Facility, Université de Paris-Structure Fédérative de Recherche Necker, INSERM US24/CNRS UAR3633, Paris, France
| | | | - Ahmed Hamaï
- Institut Necker Enfants Malades, Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Paris, France
| | - Mickaël Ménager
- Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Imagine Institute, Université Paris Cité, Atip-Avenir Team, INSERM UMR 1163, Paris, France; Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, Paris, France
| | - Stefano Palea
- Humana Biosciences SAS, Prologue Biotech, Labège, France
| | - Jacques-Emmanuel Guidotti
- Institut Necker Enfants Malades, Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Paris, France
| | - Vincent Goffin
- Institut Necker Enfants Malades, Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Paris, France.
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Vickman RE, Aaron-Brooks L, Zhang R, Lanman NA, Lapin B, Gil V, Greenberg M, Sasaki T, Cresswell GM, Broman MM, Paez JS, Petkewicz J, Talaty P, Helfand BT, Glaser AP, Wang CH, Franco OE, Ratliff TL, Nastiuk KL, Crawford SE, Hayward SW. TNF is a potential therapeutic target to suppress prostatic inflammation and hyperplasia in autoimmune disease. Nat Commun 2022; 13:2133. [PMID: 35440548 PMCID: PMC9018703 DOI: 10.1038/s41467-022-29719-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 03/24/2022] [Indexed: 11/08/2022] Open
Abstract
Autoimmune (AI) diseases can affect many organs; however, the prostate has not been considered to be a primary target of these systemic inflammatory processes. Here, we utilize medical record data, patient samples, and in vivo models to evaluate the impact of inflammation, as seen in AI diseases, on prostate tissue. Human and mouse tissues are used to examine whether systemic targeting of inflammation limits prostatic inflammation and hyperplasia. Evaluation of 112,152 medical records indicates that benign prostatic hyperplasia (BPH) prevalence is significantly higher among patients with AI diseases. Furthermore, treating these patients with tumor necrosis factor (TNF)-antagonists significantly decreases BPH incidence. Single-cell RNA-seq and in vitro assays suggest that macrophage-derived TNF stimulates BPH-derived fibroblast proliferation. TNF blockade significantly reduces epithelial hyperplasia, NFκB activation, and macrophage-mediated inflammation within prostate tissues. Together, these studies show that patients with AI diseases have a heightened susceptibility to BPH and that reducing inflammation with a therapeutic agent can suppress BPH.
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Affiliation(s)
- Renee E Vickman
- Department of Surgery, NorthShore University HealthSystem, an Academic Affiliate of the University of Chicago Pritzker School of Medicine, Evanston, IL, 60201, USA
| | - LaTayia Aaron-Brooks
- Department of Surgery, NorthShore University HealthSystem, an Academic Affiliate of the University of Chicago Pritzker School of Medicine, Evanston, IL, 60201, USA
- Department of Cancer Biology, Meharry Medical College, Nashville, TN, 37208, USA
| | - Renyuan Zhang
- Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Nadia A Lanman
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, 47907, USA
- Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA
| | - Brittany Lapin
- Biostatistics and Research Informatics, NorthShore University HealthSystem, Evanston, IL, 60201, USA
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Victoria Gil
- Department of Surgery, NorthShore University HealthSystem, an Academic Affiliate of the University of Chicago Pritzker School of Medicine, Evanston, IL, 60201, USA
| | - Max Greenberg
- Department of Surgery, NorthShore University HealthSystem, an Academic Affiliate of the University of Chicago Pritzker School of Medicine, Evanston, IL, 60201, USA
| | - Takeshi Sasaki
- Department of Surgery, NorthShore University HealthSystem, an Academic Affiliate of the University of Chicago Pritzker School of Medicine, Evanston, IL, 60201, USA
- Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, Mie, Japan
| | - Gregory M Cresswell
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, 47907, USA
- GW Cancer Center, The George Washington University, Washington, DC, 20052, USA
| | - Meaghan M Broman
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, 47907, USA
| | - J Sebastian Paez
- Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA
| | - Jacqueline Petkewicz
- Department of Surgery, NorthShore University HealthSystem, an Academic Affiliate of the University of Chicago Pritzker School of Medicine, Evanston, IL, 60201, USA
| | - Pooja Talaty
- Department of Surgery, NorthShore University HealthSystem, an Academic Affiliate of the University of Chicago Pritzker School of Medicine, Evanston, IL, 60201, USA
| | - Brian T Helfand
- Department of Surgery, NorthShore University HealthSystem, an Academic Affiliate of the University of Chicago Pritzker School of Medicine, Evanston, IL, 60201, USA
| | - Alexander P Glaser
- Department of Surgery, NorthShore University HealthSystem, an Academic Affiliate of the University of Chicago Pritzker School of Medicine, Evanston, IL, 60201, USA
| | - Chi-Hsiung Wang
- Department of Surgery, NorthShore University HealthSystem, an Academic Affiliate of the University of Chicago Pritzker School of Medicine, Evanston, IL, 60201, USA
- Biostatistics and Research Informatics, NorthShore University HealthSystem, Evanston, IL, 60201, USA
| | - Omar E Franco
- Department of Surgery, NorthShore University HealthSystem, an Academic Affiliate of the University of Chicago Pritzker School of Medicine, Evanston, IL, 60201, USA
| | - Timothy L Ratliff
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, 47907, USA
- Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA
| | - Kent L Nastiuk
- Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
- Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Susan E Crawford
- Department of Surgery, NorthShore University HealthSystem, an Academic Affiliate of the University of Chicago Pritzker School of Medicine, Evanston, IL, 60201, USA
| | - Simon W Hayward
- Department of Surgery, NorthShore University HealthSystem, an Academic Affiliate of the University of Chicago Pritzker School of Medicine, Evanston, IL, 60201, USA.
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Qian Y, Berryman DE, Basu R, List EO, Okada S, Young JA, Jensen EA, Bell SRC, Kulkarni P, Duran-Ortiz S, Mora-Criollo P, Mathes SC, Brittain AL, Buchman M, Davis E, Funk KR, Bogart J, Ibarra D, Mendez-Gibson I, Slyby J, Terry J, Kopchick JJ. Mice with gene alterations in the GH and IGF family. Pituitary 2022; 25:1-51. [PMID: 34797529 PMCID: PMC8603657 DOI: 10.1007/s11102-021-01191-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/21/2021] [Indexed: 01/04/2023]
Abstract
Much of our understanding of GH's action stems from animal models and the generation and characterization of genetically altered or modified mice. Manipulation of genes in the GH/IGF1 family in animals started in 1982 when the first GH transgenic mice were produced. Since then, multiple laboratories have altered mouse DNA to globally disrupt Gh, Ghr, and other genes upstream or downstream of GH or its receptor. The ability to stay current with the various genetically manipulated mouse lines within the realm of GH/IGF1 research has been daunting. As such, this review attempts to consolidate and summarize the literature related to the initial characterization of many of the known gene-manipulated mice relating to the actions of GH, PRL and IGF1. We have organized the mouse lines by modifications made to constituents of the GH/IGF1 family either upstream or downstream of GHR or to the GHR itself. Available data on the effect of altered gene expression on growth, GH/IGF1 levels, body composition, reproduction, diabetes, metabolism, cancer, and aging are summarized. For the ease of finding this information, key words are highlighted in bold throughout the main text for each mouse line and this information is summarized in Tables 1, 2, 3 and 4. Most importantly, the collective data derived from and reported for these mice have enhanced our understanding of GH action.
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Affiliation(s)
- Yanrong Qian
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
| | - Darlene E Berryman
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Reetobrata Basu
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
| | - Edward O List
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
| | - Shigeru Okada
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Pediatrics, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Jonathan A Young
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Elizabeth A Jensen
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
- Translational Biomedical Sciences Doctoral Program, Ohio University, Athens, OH, USA
| | - Stephen R C Bell
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Prateek Kulkarni
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biological Sciences, College of Arts and Sciences, Ohio University, Athens, OH, USA
- Molecular and Cellular Biology Program, Ohio University, Athens, OH, USA
| | | | - Patricia Mora-Criollo
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Translational Biomedical Sciences Doctoral Program, Ohio University, Athens, OH, USA
| | - Samuel C Mathes
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
| | - Alison L Brittain
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
- Molecular and Cellular Biology Program, Ohio University, Athens, OH, USA
| | - Mat Buchman
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Emily Davis
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biological Sciences, College of Arts and Sciences, Ohio University, Athens, OH, USA
- Molecular and Cellular Biology Program, Ohio University, Athens, OH, USA
| | - Kevin R Funk
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biological Sciences, College of Arts and Sciences, Ohio University, Athens, OH, USA
- Molecular and Cellular Biology Program, Ohio University, Athens, OH, USA
| | - Jolie Bogart
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biological Sciences, College of Arts and Sciences, Ohio University, Athens, OH, USA
| | - Diego Ibarra
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Chemistry and Biochemistry, College of Arts and Sciences, Ohio University, Athens, OH, USA
| | - Isaac Mendez-Gibson
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- College of Health Sciences and Professions, Ohio University, Athens, OH, USA
| | - Julie Slyby
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biological Sciences, College of Arts and Sciences, Ohio University, Athens, OH, USA
| | - Joseph Terry
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biological Sciences, College of Arts and Sciences, Ohio University, Athens, OH, USA
| | - John J Kopchick
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA.
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA.
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4
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Prostate luminal progenitor cells: from mouse to human, from health to disease. Nat Rev Urol 2022; 19:201-218. [DOI: 10.1038/s41585-021-00561-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/17/2021] [Indexed: 12/11/2022]
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5
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Park JJ, Kim JE, Jeon Y, Lee MR, Choi JY, Song BR, Park JW, Kang MJ, Choi HJ, Bae SJ, Lee H, Kang BC, Hwang DY. Deletion of NKX3.1 via CRISPR/Cas9 Induces Prostatic Intraepithelial Neoplasia in C57BL/6 Mice. Technol Cancer Res Treat 2020; 19:1533033820964425. [PMID: 33094683 PMCID: PMC7586030 DOI: 10.1177/1533033820964425] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Several techniques have been employed for deletion of the NKX3.1 gene, resulting in developmental defects of the prostate, including alterations in ductal branching morphogenesis and prostatic secretions as well as epithelial hyperplasia and dysplasia. To investigate whether the CRISPR/Cas9-mediated technique can be applied to study prostate carcinogenesis through exon I deletion of NKX3.1 gene, alterations in the prostatic intraepithelial neoplasia (PIN) and their regulatory mechanism were observed in the prostate of NKX3.1 knockout (KO) mice produced by the CRISPR/Cas9-mediated NKX3.1 mutant gene, at the ages of 16 and 24 weeks. The weight of dorsal-lateral prostate (DLP) and anterior prostate (AP) were observed to be increased in only the 24 weeks KO mice, although morphogenesis was constant in all groups. Obvious PIN 1 and 2 lesions were frequently detected in prostate of the 24 weeks KO mice, as compared with the same age wild type (WT) mice. Ki67, a key indicator for PIN, was densely stained in the epithelium of prostate in the 24 weeks KO mice, while the expression of p53 protein was suppressed in the same group. Also, both the 16 and 24 weeks KO mice reveal inhibition of the PI3K/AKT/mTOR pathway in the prostate. However, prostate specific antigen (PSA) levels and Bax/Bcl-2 expressions were decreased in the prostate of 16 weeks KO mice, and were increased in only the 24 weeks KO mice. Taken together, the results of the present study provide additional evidence that CRISPR/Cas9-mediated exon 1 deletion of the NKX3.1 gene successfully induces PIN lesions, along with significant alterations of Ki67 expression, EGFR signaling pathway, and cancer-regulated proteins.
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Affiliation(s)
- Jin Ju Park
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Ji Eun Kim
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Yoon Jeon
- Graduate School of Cancer Science and Policy, Research Institute, National Cancer Center, Goyang-si, Korea
| | - Mi Rim Lee
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Jun Young Choi
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Bo Ram Song
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Ji Won Park
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Mi Ju Kang
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Hyeon Jun Choi
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Su Ji Bae
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Ho Lee
- Graduate School of Cancer Science and Policy, Research Institute, National Cancer Center, Goyang-si, Korea
| | - Byeong Cheol Kang
- Graduate School of Translational Medicine, Seoul National University, College of Medicine/Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea
| | - Dae Youn Hwang
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
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6
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Adejumo BIG, Williams OL, Odigie EB, Unachukwu IG, Abdulrahman ON, Dimkpa U, Uzor S, Adebowale OM, Oke OM. Serum Levels of Reproductive Hormones and Their Relationship with Age in Men with Benign Prostatic Hyperplasia in Benin City, Edo State. Health (London) 2020. [DOI: 10.4236/health.2020.129082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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7
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STAT5a/b Deficiency Delays, but does not Prevent, Prolactin-Driven Prostate Tumorigenesis in Mice. Cancers (Basel) 2019; 11:cancers11070929. [PMID: 31269779 PMCID: PMC6678910 DOI: 10.3390/cancers11070929] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 06/28/2019] [Accepted: 06/28/2019] [Indexed: 11/28/2022] Open
Abstract
The canonical prolactin (PRL) Signal Transducer and Activator of Transcription (STAT) 5 pathway has been suggested to contribute to human prostate tumorigenesis via an autocrine/paracrine mechanism. The probasin (Pb)-PRL transgenic mouse models this mechanism by overexpressing PRL specifically in the prostate epithelium leading to strong STAT5 activation in luminal cells. These mice exhibit hypertrophic prostates harboring various pre-neoplastic lesions that aggravate with age and accumulation of castration-resistant stem/progenitor cells. As STAT5 signaling is largely predominant over other classical PRL-triggered pathways in Pb-PRL prostates, we reasoned that Pb-Cre recombinase-driven genetic deletion of a floxed Stat5a/b locus should prevent prostate tumorigenesis in so-called Pb-PRLΔSTAT5 mice. Anterior and dorsal prostate lobes displayed the highest Stat5a/b deletion efficiency with no overt compensatory activation of other PRLR signaling cascade at 6 months of age; hence the development of tumor hallmarks was markedly reduced. Stat5a/b deletion also reversed the accumulation of stem/progenitor cells, indicating that STAT5 signaling regulates prostate epithelial cell hierarchy. Interestingly, ERK1/2 and AKT, but not STAT3 and androgen signaling, emerged as escape mechanisms leading to delayed tumor development in aged Pb-PRLΔSTAT5 mice. Unexpectedly, we found that Pb-PRL prostates spontaneously exhibited age-dependent decline of STAT5 signaling, also to the benefit of AKT and ERK1/2 signaling. As a consequence, both Pb-PRL and Pb-PRLΔSTAT5 mice ultimately displayed similar pathological prostate phenotypes at 18 months of age. This preclinical study provides insight on STAT5-dependent mechanisms of PRL-induced prostate tumorigenesis and alternative pathways bypassing STAT5 signaling down-regulation upon prostate neoplasia progression.
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8
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Yun BY, Cho C, Cho BN. Differential activity of 16K rat prolactin in different organic systems. Anim Cells Syst (Seoul) 2019; 23:135-142. [PMID: 30949401 PMCID: PMC6440500 DOI: 10.1080/19768354.2018.1554543] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Revised: 11/06/2018] [Accepted: 11/26/2018] [Indexed: 01/08/2023] Open
Abstract
The 16K isoform of rat prolactin (16K rPRL) performs multiple functions in various systems including angiogenesis, tumorigenesis, and reproduction. Recently, 16K rPRL has attained prominence as a possible therapeutic target in pathophysiological conditions. However, the integral function and mechanism of 16K rPRL in various systems has not been elucidated. To this end, a transient gain-of-function animal model was adopted. An expression DNA plasmid containing 16K rPRL or rPRL gene was introduced into the muscle of adult mice by direct injection. The mRNA and protein expression levels of 16K rPRL were detected by initial RT–PCR and subsequent Southern blot and western blot, respectively. When the expression vector was introduced, the results were as follows: First, 16K rPRL combined with rPRL reduced angiogenesis in the testis whereas rPRL alone induced angiogenesis. Second, 16K rPRL combined with rPRL reduced WBC proliferation, whereas rPRL alone increased WBC proliferation. Third, 16K rPRL combined with rPRL reduced diestrus, whereas rPRL alone extended diestrus. Fourth, 16K rPRL combined with rPRL unexpectedly increased testosterone (T) levels, whereas rPRL alone did not increase T levels. Taken together, our data suggest that the 16K rPRL isoform performs integral functions in angiogenesis in the testis, WBC proliferation, and reproduction, although the action of 16K rPRL is not always antagonistic.
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Affiliation(s)
- Bo-Young Yun
- Department of Life Science, The Catholic University of Korea, Bucheon, Korea
| | - Chunghee Cho
- Department of Life Science Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Byung-Nam Cho
- Department of Life Science, The Catholic University of Korea, Bucheon, Korea
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9
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Pigat N, Reyes-Gomez E, Boutillon F, Palea S, Barry Delongchamps N, Koch E, Goffin V. Combined Sabal and Urtica Extracts (WS ® 1541) Exert Anti-proliferative and Anti-inflammatory Effects in a Mouse Model of Benign Prostate Hyperplasia. Front Pharmacol 2019; 10:311. [PMID: 30984003 PMCID: PMC6450068 DOI: 10.3389/fphar.2019.00311] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 03/14/2019] [Indexed: 12/19/2022] Open
Abstract
WS® 1541 is a phytopharmaceutical drug combination containing a lipophilic extract from fruits of Sabal serrulata (WS® 1473) and an aqueous ethanolic extract from roots of Urtica dioica (WS® 1031). It is approved in several countries worldwide for the treatment of lower urinary tract syndrome (LUTS) linked to benign prostate hyperplasia (BPH). Clinical studies have demonstrated the efficacy of this unique combination in the treatment of BPH-related LUTS. However, its mechanisms of action in vivo remain partly uncharacterized. The aim of this study was to take advantage of a validated mouse model of BPH to better characterize its growth-inhibitory and anti-inflammatory properties. We used the probasin–prolactin (Pb-PRL) transgenic mouse model in which prostate-specific overexpression of PRL results in several features of the human disease including tissue hypertrophy, epithelial hyperplasia, increased stromal cellularity, inflammation, and LUTS. Six-month-old heterozygous Pb-PRL male mice were randomly distributed to five groups (11–12 animals/group) orally treated for 28 consecutive days with WS® 1541 (300, 600, or 900 mg/kg/day), the 5α-reductase inhibitor finasteride used as reference (5 mg/kg/day) or vehicle (olive oil 5 ml/kg/day). Administration of WS® 1541 was well tolerated and caused a dose-dependent reduction of prostate weight (vs. vehicle) that was statistically significant at the two highest doses. This effect was accompanied by a reduction in prostate cell proliferation as assessed by lower Ki-67 expression (qPCR and immunohistochemistry). In contrast, finasteride had no or only a mild effect on these parameters. The growth-inhibitory activity of WS® 1541 was accompanied by a strong anti-inflammatory effect as evidenced by the reduced infiltration of cells expressing the leukocyte common antigen CD45. In sharp contrast, finasteride significantly increased the prostate inflammatory status according to this readout. Molecular profiling (qPCR) of 23 selected pro-inflammatory genes confirmed the strong anti-inflammatory potency of WS® 1541 compared to finasteride. Since treatment of WS® 1541 did not interfere with transgene expression and activity in the prostate of Pb-PRL mice, the effects observed in this study are entirely attributable to the intrinsic pharmacological action of the drug combination.
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Affiliation(s)
- Natascha Pigat
- PRL/GH Pathophysiology Laboratory, Institut Necker Enfants Malades, Unit 1151, Inserm, Paris, France.,Faculté de Médecine, Université Paris Descartes, Paris, France
| | - Edouard Reyes-Gomez
- Unité d'Histologie et d'Anatomie Pathologique, Laboratoire d'Anatomo-Cytopathologie, Biopôle Alfort, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France.,Inserm, U955 - IMRB, Ecole Nationale Vétérinaire d'Alfort, UPEC, Maisons-Alfort, France
| | - Florence Boutillon
- PRL/GH Pathophysiology Laboratory, Institut Necker Enfants Malades, Unit 1151, Inserm, Paris, France.,Faculté de Médecine, Université Paris Descartes, Paris, France
| | | | - Nicolas Barry Delongchamps
- PRL/GH Pathophysiology Laboratory, Institut Necker Enfants Malades, Unit 1151, Inserm, Paris, France.,Faculté de Médecine, Université Paris Descartes, Paris, France.,Urology Department, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Egon Koch
- Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany
| | - Vincent Goffin
- PRL/GH Pathophysiology Laboratory, Institut Necker Enfants Malades, Unit 1151, Inserm, Paris, France.,Faculté de Médecine, Université Paris Descartes, Paris, France
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10
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Genetic profile of ductal adenocarcinoma of the prostate. Hum Pathol 2017; 69:1-7. [DOI: 10.1016/j.humpath.2017.04.015] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 04/20/2017] [Accepted: 04/21/2017] [Indexed: 12/27/2022]
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11
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Goffin V. Prolactin receptor targeting in breast and prostate cancers: New insights into an old challenge. Pharmacol Ther 2017; 179:111-126. [DOI: 10.1016/j.pharmthera.2017.05.009] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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12
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The prostate response to prolactin modulation in adult castrated rats subjected to testosterone replacement. J Mol Histol 2017; 48:403-415. [PMID: 28988314 DOI: 10.1007/s10735-017-9738-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 09/27/2017] [Indexed: 12/22/2022]
Abstract
Despite the androgenic dependence, other hormones, growth factors, and cytokines are necessary to support prostatic growth and maintain the glandular structure; among them, prolactin is a non-steroidal hormone secreted mainly by the pituitary gland. However, extra-pituitary expression of prolactin, such as in the prostate, has also been demonstrated, highlighting the paracrine and autocrine actions of prolactin within the prostate. Here, we investigated whether prolactin modulation alters ventral prostate (VP) morphophysiology in adult castrated rats. Sprague Dawley rats were castrated and after 21 days, divided into ten experimental groups (n = 6/group): castrated control: castrated animals that did not receive treatment; castrated+testosterone: castrated animals that received T (4 mg/kg/day); castrated+PRL (PRL): castrated animals receiving prolactin (0.3 mg/kg/day); castrated+T+PRL: castrated animals that received a combination of testosterone and prolactin; and castrated+bromocriptine (BR): castrated animals that received bromocriptine (0.4 mg/kg/day). The control group included intact animals. The animals were treated for 3 or 10 consecutive days. At the end of experimental period, the animals were euthanized, and the blood and VP lobes were collected and analyzed by different methods. The main findings were that the administration of prolactin to castrated rats did not exert anabolic effects on the VP. Although we observed activation of downstream prolactin signaling after prolactin administration, this was not enough to overcome the prostatic androgen deficiency. Likewise, there was no additional glandular involution in the castrated group treated with bromocriptine. We concluded that despite stimulating the downstream signaling pathway, exogenous prolactin does not act on VP in the absence or presence of high levels of testosterone.
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13
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Xu D, Wang X, Jiang C, Ruan Y, Xia S, Wang X. The androgen receptor plays different roles in macrophage-induced proliferation in prostate stromal cells between transitional and peripheral zones of benign prostatic hypertrophy. EXCLI JOURNAL 2017; 16:939-948. [PMID: 28694768 PMCID: PMC5500834 DOI: 10.17179/excli2017-335] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 05/23/2017] [Indexed: 12/23/2022]
Abstract
Macrophages play a critical role in the process of excessive stromal proliferation of benign prostatic hyperplasia (BPH). In our previous study, we used a BPH mouse model to elucidate a potential mechanism whereby macrophage infiltration promotes stromal cell proliferation in the prostate via the androgen receptor (AR)/inflammatory cytokine CCL3-dependent pathway. In our present study, we used the co-culture system of human macrophages and various prostatic zone stromal cells to further demonstrate that infiltrating macrophages promote prostatic stromal cell proliferation through stromal AR-dependent pathways, and we show that the stroma of TZ and PZ respond to macrophages differently because of differences in stromal AR signaling; this could possibly be one of the key pathways for stromal expansion during BPH development and progression. We hypothesize that AR and different downstream inflammatory mediators between TZ and PZ could serve as potential targets for the future design of therapeutic agents for BPH and our results provide significant insights into the search for targeted therapeutic approaches to battle BPH.
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Affiliation(s)
- Dongliang Xu
- Department of Urology, Shanghai General Hospital, Address: No. 100 Haining Road, Hongkou district, Post code: 200080, Shanghai, China; Telephone: +86 13916482122 (Wang); Telephone: +86 15301655577 (Xia)
| | - Xingjie Wang
- Department of Urology, Shanghai General Hospital, Address: No. 100 Haining Road, Hongkou district, Post code: 200080, Shanghai, China; Telephone: +86 13916482122 (Wang); Telephone: +86 15301655577 (Xia)
| | - Chenyi Jiang
- Department of Urology, Shanghai General Hospital, Address: No. 100 Haining Road, Hongkou district, Post code: 200080, Shanghai, China; Telephone: +86 13916482122 (Wang); Telephone: +86 15301655577 (Xia)
| | - Yuan Ruan
- Department of Urology, Shanghai General Hospital, Address: No. 100 Haining Road, Hongkou district, Post code: 200080, Shanghai, China; Telephone: +86 13916482122 (Wang); Telephone: +86 15301655577 (Xia)
| | - Shujie Xia
- Department of Urology, Shanghai General Hospital, Address: No. 100 Haining Road, Hongkou district, Post code: 200080, Shanghai, China; Telephone: +86 13916482122 (Wang); Telephone: +86 15301655577 (Xia)
| | - Xiaohai Wang
- Department of Urology, Shanghai General Hospital, Address: No. 100 Haining Road, Hongkou district, Post code: 200080, Shanghai, China; Telephone: +86 13916482122 (Wang); Telephone: +86 15301655577 (Xia)
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14
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Seipel AH, Delahunt B, Samaratunga H, Egevad L. Ductal adenocarcinoma of the prostate: histogenesis, biology and clinicopathological features. Pathology 2016; 48:398-405. [DOI: 10.1016/j.pathol.2016.04.001] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 04/10/2016] [Accepted: 04/10/2016] [Indexed: 12/20/2022]
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15
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Agarwal N, Machiels JP, Suárez C, Lewis N, Higgins M, Wisinski K, Awada A, Maur M, Stein M, Hwang A, Mosher R, Wasserman E, Wu G, Zhang H, Zieba R, Elmeliegy M. Phase I Study of the Prolactin Receptor Antagonist LFA102 in Metastatic Breast and Castration-Resistant Prostate Cancer. Oncologist 2016; 21:535-6. [PMID: 27091421 PMCID: PMC4861370 DOI: 10.1634/theoncologist.2015-0502] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 01/11/2016] [Indexed: 11/17/2022] Open
Abstract
LESSONS LEARNED Despite evidence for a role for prolactin signaling in breast and prostate tumorigenesis, a prolactin receptor-binding monoclonal antibody has not produced clinical efficacy.Increased serum prolactin levels may be a biomarker for prolactin receptor inhibition.Results from the pharmacokinetic and pharmacodynamics (PD) studies suggest that inappropriately long dosing intervals and insufficient exposure to LFA102 may have resulted in lack of antitumor efficacy.Based on preclinical data, combination therapy of LFA102 with those novel agents targeting hormonal pathways in metastatic castration-resistant prostate cancer and metastatic breast cancer is promising.Given the PD evidence of prolactin receptor blockade by LFA102, this drug has the potential to be used in conditions such as hyperprolactinemia that are associated with high prolactin levels. BACKGROUND Prolactin receptor (PRLR) signaling is implicated in breast and prostate cancer. LFA102, a humanized monoclonal antibody (mAb) that binds to and inhibits the PRLR, has exhibited promising preclinical antitumor activity. METHODS Patients with PRLR-positive metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (mCRPC) received doses of LFA102 at 3-60 mg/kg intravenously once every 4 weeks. Objectives were to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) to investigate the safety/tolerability of LFA102 and to assess pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. RESULTS A total of 73 patients were enrolled at 5 dose levels. The MTD was not reached because of lack of dose-limiting toxicities. The RDE was established at 60 mg/kg based on PK and PD analysis and safety data. The most common all-cause adverse events (AEs) were fatigue (44%) and nausea (33%) regardless of relationship. Grade 3/4 AEs reported to be related to LFA102 occurred in 4% of patients. LFA102 exposure increased approximately dose proportionally across the doses tested. Serum prolactin levels increased in response to LFA102 administration, suggesting its potential as a biomarker for PRLR inhibition. No antitumor activity was detected. CONCLUSION Treatment with LFA102 was safe and well tolerated, but did not show antitumor activity as monotherapy at the doses tested.
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Affiliation(s)
- Neeraj Agarwal
- Huntsman Cancer Institute, Division of Medical Oncology, Department of Medicine, University of Utah, Salt Lake City, Utah, USA
| | - Jean-Pascal Machiels
- Roi Albert II Institute, Medical Oncology Service, University Clinic Saint Luc and Institute of Experimental and Clinical Research (Pôle Molecular Imaging, Radiotherapy & Oncology), Catholic University of Louvain, Brussels, Belgium
| | - Cristina Suárez
- Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - Nancy Lewis
- Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Michaela Higgins
- Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Kari Wisinski
- University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
| | | | - Michela Maur
- Oncology Unit, Department of Oncology, Hematology and Respiratory Disease, University Hospital Policlinico of Modena, Modena, Italy
| | - Mark Stein
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA
| | - Andy Hwang
- Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA
| | | | | | - Gang Wu
- Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA
| | - Hefei Zhang
- Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA
| | - Renata Zieba
- Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA
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16
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Singh S, Pan C, Wood R, Yeh CR, Yeh S, Sha K, Krolewski JJ, Nastiuk KL. Quantitative volumetric imaging of normal, neoplastic and hyperplastic mouse prostate using ultrasound. BMC Urol 2015; 15:97. [PMID: 26391476 PMCID: PMC4578765 DOI: 10.1186/s12894-015-0091-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2015] [Accepted: 09/14/2015] [Indexed: 12/22/2022] Open
Abstract
Background Genetically engineered mouse models are essential to the investigation of the molecular mechanisms underlying human prostate pathology and the effects of therapy on the diseased prostate. Serial in vivo volumetric imaging expands the scope and accuracy of experimental investigations of models of normal prostate physiology, benign prostatic hyperplasia and prostate cancer, which are otherwise limited by the anatomy of the mouse prostate. Moreover, accurate imaging of hyperplastic and tumorigenic prostates is now recognized as essential to rigorous pre-clinical trials of new therapies. Bioluminescent imaging has been widely used to determine prostate tumor size, but is semi-quantitative at best. Magnetic resonance imaging can determine prostate volume very accurately, but is expensive and has low throughput. We therefore sought to develop and implement a high throughput, low cost, and accurate serial imaging protocol for the mouse prostate. Methods We developed a high frequency ultrasound imaging technique employing 3D reconstruction that allows rapid and precise assessment of mouse prostate volume. Wild-type mouse prostates were examined (n = 4) for reproducible baseline imaging, and treatment effects on volume were compared, and blinded data analyzed for intra- and inter-operator assessments of reproducibility by correlation and for Bland-Altman analysis. Examples of benign prostatic hyperplasia mouse model prostate (n = 2) and mouse prostate implantation of orthotopic human prostate cancer tumor and its growth (n = 6) are also demonstrated. Results Serial measurement volume of the mouse prostate revealed that high frequency ultrasound was very precise. Following endocrine manipulation, regression and regrowth of the prostate could be monitored with very low intra- and interobserver variability. This technique was also valuable to monitor the development of prostate growth in a model of benign prostatic hyperplasia. Additionally, we demonstrate accurate ultrasound image-guided implantation of orthotopic tumor xenografts and monitoring of subsequent tumor growth from ~10 to ~750 mm3 volume. Discussion High frequency ultrasound imaging allows precise determination of normal, neoplastic and hyperplastic mouse prostate. Low cost and small image size allows incorporation of this imaging modality inside clean animal facilities, and thereby imaging of immunocompromised models. 3D reconstruction for volume determination is easily mastered, and both small and large relative changes in volume are accurately visualized. Ultrasound imaging does not rely on penetration of exogenous imaging agents, and so may therefore better measure poorly vascularized or necrotic diseased tissue, relative to bioluminescent imaging (IVIS). Conclusions Our method is precise and reproducible with very low inter- and intra-observer variability. Because it is non-invasive, mouse models of prostatic disease states can be imaged serially, reducing inter-animal variability, and enhancing the power to detect small volume changes following therapeutic intervention.
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Affiliation(s)
- Shalini Singh
- Departments of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. .,Current address: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, 14263, NY, USA.
| | - Chunliu Pan
- Departments of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. .,Current address: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, 14263, NY, USA.
| | - Ronald Wood
- Departments of Neurobiology and Anatomy and Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. .,Department of Urology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
| | - Chiuan-Ren Yeh
- Department of Urology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
| | - Shuyuan Yeh
- Departments of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. .,Department of Urology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
| | - Kai Sha
- Departments of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. .,Current address: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, 14263, NY, USA.
| | - John J Krolewski
- Departments of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. .,Current address: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, 14263, NY, USA.
| | - Kent L Nastiuk
- Departments of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. .,Current address: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, 14263, NY, USA.
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17
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Sackmann-Sala L, Angelergues A, Boutillon F, d'Acremont B, Maidenberg M, Oudard S, Goffin V. Human and murine prostate basal/stem cells are not direct targets of prolactin. Gen Comp Endocrinol 2015; 220:133-42. [PMID: 25888939 DOI: 10.1016/j.ygcen.2015.04.007] [Citation(s) in RCA: 3] [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] [Received: 09/03/2014] [Revised: 03/25/2015] [Accepted: 04/07/2015] [Indexed: 10/23/2022]
Abstract
Local overexpression of prolactin (PRL) in the prostate of Pb-PRL transgenic mice induces benign prostate tumors exhibiting marked amplification of the epithelial basal/stem cell compartment. However, PRL-activated intracellular signaling seems to be restricted to luminal cells, suggesting that basal/stem cells may not be direct targets of PRL. Given their described role as prostate cancer-initiating cells, it is important to understand the mechanisms that regulate basal/stem cells. In this study, we evaluated whether PRL can act directly on these cells, by growing them as prostaspheres. For this, primary 3D prostasphere cultures were prepared from unfractionated cells isolated from freshly harvested human and mouse benign prostate tissues and subjected to PRL stimulation in vitro. None of the various concentrations of PRL tested showed any effects on the sizes or numbers of the prostaspheres generated. In addition, neither activation of canonical PRL-induced signaling pathways (Stat5, Stat3 or Erk1/2) nor increased expression of the proliferation marker Ki-67 were detected by immunostaining in PRL-stimulated prostaspheres. Consistent with the absence of response, PRL receptor mRNA levels were generally undetectable in mouse sphere cells. We conclude that human and mouse prostate basal/stem cells are not direct targets of PRL action. The observed amplification of basal/stem cells in Pb-PRL prostates might be due to paracrine mechanisms originating from PRL action on other cell compartments. Our current efforts are aimed at unraveling these mechanisms.
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Affiliation(s)
- Lucila Sackmann-Sala
- Institut Necker Enfants Malades (INEM), Inserm U1151 - CNRS UMR 8253, Equipe "Physiopathologie des hormones PRL/GH", Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 14 rue Maria Helena Vieira da Silva - CS 61431, Bâtiment Leriche, 75993 Paris Cedex 14, France.
| | - Antoine Angelergues
- Institut Necker Enfants Malades (INEM), Inserm U1151 - CNRS UMR 8253, Equipe "Physiopathologie des hormones PRL/GH", Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 14 rue Maria Helena Vieira da Silva - CS 61431, Bâtiment Leriche, 75993 Paris Cedex 14, France; Service de Cancérologie Médicale, Hôpital Européen Georges Pompidou, Université Paris Descartes, 20 rue Leblanc, 75015 Paris, France.
| | - Florence Boutillon
- Institut Necker Enfants Malades (INEM), Inserm U1151 - CNRS UMR 8253, Equipe "Physiopathologie des hormones PRL/GH", Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 14 rue Maria Helena Vieira da Silva - CS 61431, Bâtiment Leriche, 75993 Paris Cedex 14, France
| | - Bruno d'Acremont
- Service d'Urologie, Fondation Saint Jean de Dieu - Clinique Oudinot, 19 rue Oudinot, 75007 Paris, France.
| | - Marc Maidenberg
- Service d'Urologie, Fondation Saint Jean de Dieu - Clinique Oudinot, 19 rue Oudinot, 75007 Paris, France.
| | - Stéphane Oudard
- Service de Cancérologie Médicale, Hôpital Européen Georges Pompidou, Université Paris Descartes, 20 rue Leblanc, 75015 Paris, France.
| | - Vincent Goffin
- Institut Necker Enfants Malades (INEM), Inserm U1151 - CNRS UMR 8253, Equipe "Physiopathologie des hormones PRL/GH", Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 14 rue Maria Helena Vieira da Silva - CS 61431, Bâtiment Leriche, 75993 Paris Cedex 14, France.
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18
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Abstract
Prolactin (PRL) is a hormone, mainly secreted by lactotroph cells of the anterior pituitary gland. Recent studies have shown it may also be produced by many extrapituitary cells. Its well-recognized PRL plays an important role in lactation during pregnancy, but it is involved in other biological functions such as angiogenesis, immunoregulation and osmoregulation. Hyperprolactinemia is a typical condition producing reproductive dysfunction in both sexes, resulting in hypogonadism, infertility and galactorrhea. It may be also asymptomatic. Lactotroph adenomas (prolactinoma) is one of the most common cause of PRL excess, representing approximately 40% of all pituitary tumors. Several other conditions should be excluded before a clear diagnosis of hyperprolactinemia is made. Hyperprolactinemia may be secondary to pharmacological or pathological interruption of hypothalamic-pituitary dopaminergic pathways or idiopathic. Stress, renal failure or hypothyroidism are other frequent conditions to exclude in patients with hyperprolactinemia. We will review biochemical characteristics and physiological functions of that hormone. Clinical and pharmacological approach to hyperprolactinemia will also be discussed.
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Affiliation(s)
- Anna Capozzi
- a Department of Endocrinology and Metabolism and
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19
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Goffin V, Touraine P. The prolactin receptor as a therapeutic target in human diseases: browsing new potential indications. Expert Opin Ther Targets 2015; 19:1229-44. [PMID: 26063597 DOI: 10.1517/14728222.2015.1053209] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
INTRODUCTION Prolactin (PRL) signaling has emerged as a relevant target in breast and prostate cancers. This has encouraged various laboratories to develop compounds targeting the PRL receptor (PRLR). As the latter is widely distributed, it is timely to address whether other conditions could also benefit from such inhibitors. AREAS COVERED The authors briefly overview the two classes of PRLR blockers, which involve: i) PRL-core based analogs that have been validated as competitive antagonists in various preclinical models, and ii) anti-PRLR neutralizing antibodies that are currently in clinical Phase I for advanced breast and prostate cancers. The main purpose of this review is to discuss the multiple organs/diseases that may be considered as potential targets/indications for such inhibitors. This is done in light of reports suggesting that PRLR expression/signaling is increased in disease, and/or that systemic or locally elevated PRL levels correlate with (or promote) organ pathogenesis. EXPERT OPINION The two immediate challenges in the field are i) to provide the scientific community with potent anti-prolactin receptor antibodies to map prolactin receptor expression in target organs, and ii) to take advantage of the availability of functionally validated PRLR blockers to establish the relevance of these potential indications in humans.
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Affiliation(s)
- Vincent Goffin
- Research Director at Inserm, Head of the 'PRL/GH Pathophysiology: Translational Approaches' Laboratory,University Paris Descartes, Institut Necker Enfants Malades (INEM), Inserm Unit 1151, Faculté de Médecine Paris Descartes , Bâtiment Leriche, 14 Rue Maria Helena Vieira Da Silva, CS61431, 75993 Paris Cedex 14 , France +33 1 72 60 63 68 +33 1 72 60 64 01 ;
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20
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Gorvin CM. The prolactin receptor: Diverse and emerging roles in pathophysiology. JOURNAL OF CLINICAL AND TRANSLATIONAL ENDOCRINOLOGY 2015; 2:85-91. [PMID: 29204371 PMCID: PMC5685068 DOI: 10.1016/j.jcte.2015.05.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 05/10/2015] [Indexed: 12/21/2022]
Abstract
Investigations over two decades have revised understanding of the prolactin hormone. Long thought to be merely a lactogenic hormone, its list of functions has been extended to include: reproduction, islet differentiation, adipocyte control and immune modulation. Prolactin functions by binding cell-surface expressed prolactin receptor, initiating signaling cascades, primarily utilizing Janus kinase-signal transducer and activator of transcription (JAK-STAT). Pathway disruption has been implicated in tumorigenesis, reproductive abnormalities, and diabetes. Prolactin can also be secreted from extrapituitary sources adding complexity to understanding of its physiological functions. This review aims to describe how prolactin exerts its pathophysiological roles by endocrine and autocrine means.
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Affiliation(s)
- Caroline M Gorvin
- Academic Endocrine Unit, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, Oxford, OX3 7LJ, UK
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21
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Bernichtein S, Pigat N, Capiod T, Boutillon F, Verkarre V, Camparo P, Viltard M, Méjean A, Oudard S, Souberbielle JC, Friedlander G, Goffin V. High milk consumption does not affect prostate tumor progression in two mouse models of benign and neoplastic lesions. PLoS One 2015; 10:e0125423. [PMID: 25938513 PMCID: PMC4418739 DOI: 10.1371/journal.pone.0125423] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Accepted: 03/23/2015] [Indexed: 01/25/2023] Open
Abstract
Epidemiological studies that have investigated whether dairy (mainly milk) diets are associated with prostate cancer risk have led to controversial conclusions. In addition, no existing study clearly evaluated the effects of dairy/milk diets on prostate tumor progression, which is clinically highly relevant in view of the millions of men presenting with prostate pathologies worldwide, including benign prostate hyperplasia (BPH) or high-grade prostatic intraepithelial neoplasia (HGPIN). We report here a unique interventional animal study to address this issue. We used two mouse models of fully penetrant genetically-induced prostate tumorigenesis that were investigated at the stages of benign hyperplasia (probasin-Prl mice, Pb-Prl) or pre-cancerous PIN lesions (KIMAP mice). Mice were fed high milk diets (skim or whole) for 15 to 27 weeks of time depending on the kinetics of prostate tumor development in each model. Prostate tumor progression was assessed by tissue histopathology examination, epithelial proliferation, stromal inflammation and fibrosis, tumor invasiveness potency and expression of various tumor markers relevant for each model (c-Fes, Gprc6a, activated Stat5 and p63). Our results show that high milk consumption (either skim or whole) did not promote progression of existing prostate tumors when assessed at early stages of tumorigenesis (hyperplasia and neoplasia). For some parameters, and depending on milk type, milk regimen could even exhibit slight protective effects towards prostate tumor progression by decreasing the expression of tumor-related markers like Ki-67 and Gprc6a. In conclusion, our study suggests that regular milk consumption should not be considered detrimental for patients presenting with early-stage prostate tumors.
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Affiliation(s)
- Sophie Bernichtein
- Inserm, U1151, Institut Necker Enfants Malades, PRL/GH Pathophysiology Laboratory, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
| | - Natascha Pigat
- Inserm, U1151, Institut Necker Enfants Malades, PRL/GH Pathophysiology Laboratory, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
| | - Thierry Capiod
- Inserm, U1151, Institut Necker Enfants Malades, PRL/GH Pathophysiology Laboratory, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
| | - Florence Boutillon
- Inserm, U1151, Institut Necker Enfants Malades, PRL/GH Pathophysiology Laboratory, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
| | - Virginie Verkarre
- Pathology Department, Hôpital Necker, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
- Assistance Publique Hôpitaux de Paris, Paris, France
| | - Philippe Camparo
- Inserm, U1151, Institut Necker Enfants Malades, PRL/GH Pathophysiology Laboratory, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
| | - Mélanie Viltard
- Institute for European Expertise in Physiology, Paris, France
| | - Arnaud Méjean
- Urology Department, Hôpital Européen Georges Pompidou, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
- Assistance Publique Hôpitaux de Paris, Paris, France
| | - Stéphane Oudard
- Medical Oncology Department, Hôpital Européen Georges Pompidou, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
- Assistance Publique Hôpitaux de Paris, Paris, France
| | - Jean-Claude Souberbielle
- Inserm, U1151, Institut Necker Enfants Malades, Phosphate Homeostasis Laboratory, Paris, France
- Physiology Department, Hôpital Européen Georges Pompidou, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
- Assistance Publique Hôpitaux de Paris, Paris, France
| | - Gérard Friedlander
- Inserm, U1151, Institut Necker Enfants Malades, Phosphate Homeostasis Laboratory, Paris, France
- Physiology Department, Hôpital Européen Georges Pompidou, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
- Assistance Publique Hôpitaux de Paris, Paris, France
| | - Vincent Goffin
- Inserm, U1151, Institut Necker Enfants Malades, PRL/GH Pathophysiology Laboratory, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
- * E-mail:
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22
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Bernichtein S, Pigat N, Camparo P, Latil A, Viltard M, Friedlander G, Goffin V. Anti-inflammatory properties of Lipidosterolic extract of Serenoa repens (Permixon®) in a mouse model of prostate hyperplasia. Prostate 2015; 75:706-22. [PMID: 25683150 DOI: 10.1002/pros.22953] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 11/25/2014] [Accepted: 12/01/2014] [Indexed: 12/29/2022]
Abstract
BACKGROUND Permixon®, the hexanic lipidosterolic extract of saw palmetto Serenoa repens (LSESr), has shown properties that highlight its benefit in the management of benign prostate hyperplasia (BPH). To address its actual anti-inflammatory potency, we used a unique pro-inflammatory mouse model of prostate hyperplasia involving prostate-specific over-expression of prolactin transgene (Pb-Prl). METHODS Six month-old Pb-Prl males were administered with Permixon® per os at the daily dose of 100 mg/kg for 28 days. Body and prostate weights were measured weekly and at sacrifice, respectively. Prostate histology was carefully assessed by a pathologist and detailed quantifications of epithelial and stromal compartments were performed using image analysis software. Luminal cell proliferation index was determined using Ki-67 immunostaining, and apoptosis using Bax/Bcl2 mRNA ratio. Tissue inflammation and fibrosis were assessed by histological analyses then quantified using CD45 immunostaining and picrosirius staining, respectively. Expression profiling of selected pro-inflammatory cytokines, chemokines, and chemokine receptors was performed by quantitative RT-PCR. RESULTS In this model, Permixon® significantly decreased tissue weight and proliferation index specifically in the ventral lobe. Although treatment had no noticeable effect on epithelial histology of any lobe, it markedly reduced the histological hallmarks of inflammation in all lobes. This was confirmed by the global down-regulation of prostate pro-inflammatory cytokine profile, with significant reduction of CCR7, CXCL6, IL-6, and IL-17 expression. CONCLUSIONS In this mouse model of prostate hyperplasia, Permixon® exerted potent anti-inflammatory properties in the whole prostate while anti-androgenic effects were lobe-specific, suggesting that distinct LSESr components may be involved in these effects. Our results support the beneficial role of Permixon® treatment for BPH. The relevance of CCR7, CXCL6, IL-6, and IL-17 as potential biomarkers to follow up BPH inflammatory status needs to be assessed.
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23
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Sackmann-Sala L, Guidotti JE, Goffin V. Minireview: prolactin regulation of adult stem cells. Mol Endocrinol 2015; 29:667-81. [PMID: 25793405 DOI: 10.1210/me.2015-1022] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Adult stem/progenitor cells are found in many tissues, where their primary role is to maintain homeostasis. Recent studies have evaluated the regulation of adult stem/progenitor cells by prolactin in various target tissues or cell types, including the mammary gland, the prostate, the brain, the bone marrow, the hair follicle, and colon cancer cells. Depending on the tissue, prolactin can either maintain stem cell quiescence or, in contrast, promote stem/progenitor cell expansion and push their progeny towards differentiation. In many instances, whether these effects are direct or involve paracrine regulators remains debated. This minireview aims to overview the current knowledge in the field.
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Affiliation(s)
- Lucila Sackmann-Sala
- Institut Necker Enfants Malades, Inserm Unité1151, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8253, Team Prolactin/Growth Hormone Pathophysiology, Faculty of Medicine, University Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France
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Prolactin-Induced Prostate Tumorigenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 846:221-42. [DOI: 10.1007/978-3-319-12114-7_10] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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25
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Sackmann-Sala L, Chiche A, Mosquera-Garrote N, Boutillon F, Cordier C, Pourmir I, Pascual-Mathey L, Kessal K, Pigat N, Camparo P, Goffin V. Prolactin-Induced Prostate Tumorigenesis Links Sustained Stat5 Signaling with the Amplification of Basal/Stem Cells and Emergence of Putative Luminal Progenitors. THE AMERICAN JOURNAL OF PATHOLOGY 2014; 184:3105-19. [DOI: 10.1016/j.ajpath.2014.07.020] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Revised: 06/10/2014] [Accepted: 07/10/2014] [Indexed: 12/28/2022]
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26
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Lai KP, Huang CK, Fang LY, Izumi K, Lo CW, Wood R, Kindblom J, Yeh S, Chang C. Targeting stromal androgen receptor suppresses prolactin-driven benign prostatic hyperplasia (BPH). Mol Endocrinol 2013; 27:1617-31. [PMID: 23893956 DOI: 10.1210/me.2013-1207] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Stromal-epithelial interaction plays a pivotal role to mediate the normal prostate growth, the pathogenesis of benign prostatic hyperplasia (BPH), and prostate cancer development. Until now, the stromal androgen receptor (AR) functions in the BPH development, and the underlying mechanisms remain largely unknown. Here we used a genetic knockout approach to ablate stromal fibromuscular (fibroblasts and smooth muscle cells) AR in a probasin promoter-driven prolactin transgenic mouse model (Pb-PRL tg mice) that could spontaneously develop prostate hyperplasia to partially mimic human BPH development. We found Pb-PRL tg mice lacking stromal fibromuscular AR developed smaller prostates, with more marked changes in the dorsolateral prostate lobes with less proliferation index. Mechanistically, prolactin mediated hyperplastic prostate growth involved epithelial-stromal interaction through epithelial prolactin/prolactin receptor signals to regulate granulocyte macrophage-colony stimulating factor expression to facilitate stromal cell growth via sustaining signal transducer and activator of transcription-3 activity. Importantly, the stromal fibromuscular AR could modulate such epithelial-stromal interacting signals. Targeting stromal fibromuscular AR with the AR degradation enhancer, ASC-J9(®), led to the reduction of prostate size, which could be used in future therapy.
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Affiliation(s)
- Kuo-Pao Lai
- George Whipple Distinguished University of Rochester Medical Center, 601 Elmwood Avenue, Box 626, Rochester, New York 14642.
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27
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Kitazawa T. Contractile signaling pathways in mouse prostate smooth muscle. Prostate 2013; 73:996-1006. [PMID: 23389830 DOI: 10.1002/pros.22647] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2012] [Accepted: 01/08/2013] [Indexed: 12/31/2022]
Abstract
BACKGROUND Prostate smooth muscle plays an important role in the physiological ejection of prostatic fluid and also in the pathogenesis of benign prostate hyperplasia. Although mouse is the best genetically engineered animal model to identify potential molecular targets for human diseases, only fragmentary information is available for basic mechanism of mouse prostate contraction. METHODS Small smooth muscle tubular rings were excised from four mouse prostate lobes to measure their isometric contractions. High K(+) , noradrenaline (NA), or acetylcholine (ACh) was applied with and without various antagonists and/or inhibitors to examine the contractile signaling pathways. RESULTS Maximum amplitude of agonist-induced contractions varied greatly with different lobes but not with different locations or orientations within each lobe. Both NA and ACh produced large contractions in ventral and dorsal rings, whereas only small contractions were elicited in lateral and anterior rings. Combination of alpha-1 and muscarinic antagonists suppressed K(+) depolarization-induced contraction potently in ventral rings, but slightly in anterior rings. Blocking of either Ca(2+) -release or Ca(2+) -influx reduced agonist-induced contraction of ventral rings, however, a considerable amount of contractility remained even with both blockers. Inhibitors of ROCK and PKC partially inhibited NA-induced contractions, whereas a combination of Ca(2+) -blockers and Ca(2+) -sensitization inhibitors strongly suppressed the contraction. CONCLUSIONS The ejection of prostatic fluid is differentially regulated in each prostate lobe. In ventral prostate smooth muscle, Ca(2+) -release, Ca(2+) -influx, and ROCK- and PKC-mediated Ca(2+) -sensitizations are all involved in NA-induced contractions. This finding is a useful step toward the understanding of the phenotypic changes in the smooth muscle of BPH prostate.
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Affiliation(s)
- Toshio Kitazawa
- Boston Biomedical Research Institute, Watertown, Massachusetts 02472, USA.
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28
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Affiliation(s)
- Andrzej Bartke
- Department of Physiology, Southern Illinois University School of Medicine, 801 N Rutledge, Springfield, IL 62794-9628, USA.
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29
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Wolf K, Kayacelebi H, Urhausen C, Piechotta M, Mischke R, Kramer S, Einspanier A, Oei CHY, Günzel-Apel A. Testicular Steroids, Prolactin, Relaxin and Prostate Gland Markers in Peripheral Blood and Seminal Plasma of Normal Dogs and Dogs with Prostatic Hyperplasia. Reprod Domest Anim 2012; 47 Suppl 6:243-6. [DOI: 10.1111/rda.12083] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Accepted: 06/27/2012] [Indexed: 11/28/2022]
Affiliation(s)
- K Wolf
- University of Veterinary Medicine; Hannover; Germany
| | - H Kayacelebi
- University of Veterinary Medicine; Hannover; Germany
| | - C Urhausen
- University of Veterinary Medicine; Hannover; Germany
| | - M Piechotta
- University of Veterinary Medicine; Hannover; Germany
| | - R Mischke
- University of Veterinary Medicine; Hannover; Germany
| | - S Kramer
- University of Veterinary Medicine; Hannover; Germany
| | - A Einspanier
- Faculty of Veterinary Medicine; University of Leipzig; Leipzig; Germany
| | - CHY Oei
- Faculty of Veterinary Medicine; University of Utrecht; Utrecht; The Netherlands
| | - A Günzel-Apel
- University of Veterinary Medicine; Hannover; Germany
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30
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Nicholson TM, Ricke EA, Marker PC, Miano JM, Mayer RD, Timms BG, vom Saal FS, Wood RW, Ricke WA. Testosterone and 17β-estradiol induce glandular prostatic growth, bladder outlet obstruction, and voiding dysfunction in male mice. Endocrinology 2012; 153:5556-65. [PMID: 22948219 PMCID: PMC3473198 DOI: 10.1210/en.2012-1522] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Benign prostatic hyperplasia (BPH) and bladder outlet obstruction (BOO) are common in older men and can contribute to lower urinary tract symptoms that significantly impact quality of life. Few existing models of BOO and BPH use physiological levels of hormones associated with disease progression in humans in a genetically manipulable organism. We present a model of BPH and BOO induced in mice with testosterone (T) and 17β-estradiol (E(2)). Male mice were surgically implanted with slow-releasing sc pellets containing 25 mg T and 2.5 mg E(2) (T+E(2)). After 2 and 4 months of hormone treatment, we evaluated voiding patterns and examined the gross morphology and histology of the bladder, urethra, and prostate. Mice treated with T+E(2) developed significantly larger bladders than untreated mice, consistent with BOO. Some mice treated with T+E(2) had complications in the form of bladder hypertrophy, diverticula, calculi, and eventual decompensation with hydronephrosis. Hormone treatment caused a significant decrease in the size of the urethral lumen, increased prostate mass, and increased number of prostatic ducts associated with the prostatic urethra, compared with untreated mice. Voiding dysfunction was observed in mice treated with T+E(2), who exhibited droplet voiding pattern with significantly decreased void mass, shorter void duration, and fewer sustained voids. The constellation of lower urinary tract abnormalities, including BOO, enlarged prostates, and voiding dysfunction seen in male mice treated with T+E(2) is consistent with BPH in men. This model is suitable for better understanding molecular mechanisms and for developing novel strategies to address BPH and BOO.
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31
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Effects of metoclopramide on mRNA levels of steroid 5α-reductase isozymes in prostate of adult rats. J Physiol Biochem 2012; 69:133-40. [DOI: 10.1007/s13105-012-0197-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2012] [Accepted: 06/28/2012] [Indexed: 10/28/2022]
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32
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Wang X, Lin WJ, Izumi K, Jiang Q, Lai KP, Xu D, Fang LY, Lu T, Li L, Xia S, Chang C. Increased infiltrated macrophages in benign prostatic hyperplasia (BPH): role of stromal androgen receptor in macrophage-induced prostate stromal cell proliferation. J Biol Chem 2012; 287:18376-85. [PMID: 22474290 DOI: 10.1074/jbc.m112.355164] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Infiltrated macrophages may play important roles in the development and progression of benign prostatic hyperplasia (BPH), but the underlying mechanisms remain largely unknown. We found increased macrophages infiltration in human and mouse BPH tissues. By establishing a co-culture transwell system, we found increased migration of macrophages and proliferation of prostate stromal cells during co-culture. Importantly, stromal androgen receptor (AR) could enhance the migration of macrophages and macrophage-mediated stromal cell proliferation. We identified CCL3 as an AR downstream player, and found CCL3 levels were notably increased in human and mouse BPH prostates. Ablation of prostate stromal AR in a mouse BPH model significantly reduced CCL3 expression levels in prostates. Consistently, targeting AR via an AR degradation enhancer, ASC-J9®, or neutralization of CCL3 with an antibody, resulted in suppression of macrophage migration and prostate stromal cell growth. Our study provides mechanistic insights on the regulation of prostate stromal cells by macrophages via stromal AR/CCL3 signaling pathways, which could potentially allow the development of therapeutic approaches for battling BPH with persistent inflammation.
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Affiliation(s)
- Xiaohai Wang
- Department of Pathology, University of Rochester Medical Center, Rochester, New York 14642, USA
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33
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Harvey S, Arámburo C, Sanders EJ. Extrapituitary production of anterior pituitary hormones: an overview. Endocrine 2012; 41:19-30. [PMID: 22169962 DOI: 10.1007/s12020-011-9557-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2011] [Accepted: 11/14/2011] [Indexed: 10/15/2022]
Abstract
Protein hormones from the anterior pituitary gland have well-established endocrine roles in their peripheral target glands. It is, however, now known that these proteins are also produced within many of their target tissues, in which they act as local autocrine or paracrine factors, with physiological and/or pathophysiological significance. This emerging concept is the focus of this brief review.
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Affiliation(s)
- S Harvey
- Department of Physiology, University of Alberta, Edmonton, AB, T6G 2H7, Canada,
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34
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Abstract
Prolactin is best known for its actions on the mammary gland. However, circulating prolactin is also detected in males and its receptor (PRLR) is expressed in the prostate, suggesting that the prostate is a target of prolactin. Germline knockout of prolactin or its receptor has failed to reveal a key role for prolactin signaling in mouse prostate physiology. However, several studies involving rodent models and human prostate cell lines and specimens have supported the contribution of the canonical PRLR-Jak2-Stat5a/b pathway to prostate cancer tumorigenesis and progression. Increased expression of prolactin in the prostate itself (rather than changes in circulating prolactin levels) and crosstalk with androgen receptor (AR) signaling are potential mechanisms for increased Stat5a/b signaling in prostate cancer. In the mouse prostate, prolactin overexpression results in disorganized expansion of the basal/stem cell compartment, which has been proposed to house putative prostate tumor-initiating cells. These findings provide new insight into the molecular and cellular targets by which locally produced prolactin could contribute to prostate cancer initiation and progression. A number of pharmacological inhibitors targeting various levels of the PRLR-Jak2-Stat5a/b pathway have been developed and are entering clinical trials for advanced prostate cancer.
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35
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Hargreaves A, Harleman J. Preclinical risk assessment of drug-induced hypo- and hyperprolactinemia. J Appl Toxicol 2011; 31:599-607. [DOI: 10.1002/jat.1723] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2011] [Revised: 07/08/2011] [Accepted: 07/08/2011] [Indexed: 11/08/2022]
Affiliation(s)
- Adam Hargreaves
- Pathology Department; Safety Assessment, Astrazeneca Pharmaceuticals; Alderley Park; Cheshire; SK10 4TG; UK
| | - Johannes Harleman
- Pathology Department; Safety Assessment, Astrazeneca Pharmaceuticals; Alderley Park; Cheshire; SK10 4TG; UK
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36
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Nicholson TM, Ricke WA. Androgens and estrogens in benign prostatic hyperplasia: past, present and future. Differentiation 2011; 82:184-99. [PMID: 21620560 DOI: 10.1016/j.diff.2011.04.006] [Citation(s) in RCA: 218] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2011] [Revised: 04/19/2011] [Accepted: 04/26/2011] [Indexed: 01/28/2023]
Abstract
Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are common clinical problems in urology. While the precise molecular etiology remains unclear, sex steroids have been implicated in the development and maintenance of BPH. Sufficient data exists linking androgens and androgen receptor pathways to BPH and use of androgen reducing compounds, such as 5α-reductase inhibitors which block the conversion of testosterone into dihydrotestosterone, are a component of the standard of care for men with LUTS attributed to an enlarged prostate. However, BPH is a multifactorial disease and not all men respond well to currently available treatments, suggesting factors other than androgens are involved. Testosterone, the primary circulating androgen in men, can also be metabolized via CYP19/aromatase into the potent estrogen, estradiol-17β. The prostate is an estrogen target tissue and estrogens directly and indirectly affect growth and differentiation of prostate. The precise role of endogenous and exogenous estrogens in directly affecting prostate growth and differentiation in the context of BPH is an understudied area. Estrogens and selective estrogen receptor modulators (SERMs) have been shown to promote or inhibit prostate proliferation signifying potential roles in BPH. Recent research has demonstrated that estrogen receptor signaling pathways may be important in the development and maintenance of BPH and LUTS; however, new models are needed to genetically dissect estrogen regulated molecular mechanisms involved in BPH. More work is needed to identify estrogens and associated signaling pathways in BPH in order to target BPH with dietary and therapeutic SERMs.
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Affiliation(s)
- Tristan M Nicholson
- University of Rochester School of Medicine & Dentistry, Rochester, NY, United States
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37
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Tam NNC, Szeto CYY, Freudenberg JM, Fullenkamp AN, Medvedovic M, Ho SM. Research resource: estrogen-driven prolactin-mediated gene-expression networks in hormone-induced prostatic intraepithelial neoplasia. Mol Endocrinol 2010; 24:2207-17. [PMID: 20861223 DOI: 10.1210/me.2010-0179] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Cotreatment with testosterone (T) and 17β-estradiol (E2) is an established regimen for inducing of prostatic intraepithelial neoplasia (PIN) and prostate cancer in rodent models. We previously used the pure antiestrogen ICI 182,780 (ICI) and bromocriptine, a dopamine receptor agonist, to inhibit PIN induction and systemic hyperprolactinemia in Noble rats and found that the carcinogenic action of T+E2 is mediated directly by the effects of E2 on the prostate and/or indirectly via E2-induced hyperprolactinemia. In this study, we delineate the specific action(s) of E2 and prolactin (PRL) in early prostate carcinogenesis by an integrated approach combining global transcription profiling, gene ontology, and gene-network mapping. We identified 2504 differentially expressed genes in the T+E2-treated lateral prostate. The changes in expression of a subset of 1990 genes (∼80%) were blocked upon cotreatment with ICI and bromocriptine, respectively, whereas those of 262 genes (∼10%) were blocked only by treatment with ICI, suggesting that E2-induced pituitary PRL is the primary mediator of the prostatic transcriptional response to the altered hormone milieu. Bioinformatics analyses identified hormone-responsive gene networks involved in immune responses, stromal tissue remodeling, and the ERK pathway. In particular, our data suggest that IL-1β may mediate, at least in part, hormone-induced changes in gene expression during PIN formation. Together, these data highlight the importance of pituitary PRL in estrogen-induced prostate tumorigenesis. The identification of both E2- and pituitary PRL-responsive genes provides a comprehensive resource for future investigations of the complex mechanisms by which changes in the endocrine milieu contribute to prostate carcinogenesis in vivo.
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Affiliation(s)
- Neville N C Tam
- Department of Environmental Health, University of Cincinnati Medical Center, Kettering Laboratory, Suite 128, 3223 Eden Avenue, Cincinnati, Ohio 45267-0056, USA
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38
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Hansen MJK, Olsen JG, Bernichtein S, O'Shea C, Sigurskjold BW, Goffin V, Kragelund BB. Development of prolactin receptor antagonists with reduced pH-dependence of receptor binding. J Mol Recognit 2010; 24:533-47. [PMID: 20842635 DOI: 10.1002/jmr.1064] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2010] [Revised: 05/26/2010] [Accepted: 05/26/2010] [Indexed: 01/03/2023]
Abstract
The cytokine hormone prolactin has a vast number of diverse functions. Unfortunately, it also exhibits tumor growth promoting properties, which makes the development of prolactin receptor antagonists a priority. Prolactin binds to its cognate receptor with much lower affinity at low pH than at physiological pH and since the extracellular environment around solid tumors often is acidic, it is desirable to develop antagonists that have improved binding affinity at low pH. The pK(a) value of a histidine side chain is ∼6.8 making histidine residues obvious candidates for examination. From evaluation of known molecular structures of human prolactin, of the prolactin receptor and of different complexes of the two, three histidine residues in the hormone-receptor binding site 1 were selected for mutational studies. We analyzed 10 variants by circular dichroism spectroscopy, affinity and thermodynamic characterization of receptor binding by isothermal titration calorimetry combined with in vitro bioactivity in living cells. Histidine residue 27 was recognized as a central hot spot for pH sensitivity and conservative substitutions at this site resulted in strong receptor binding at low pH. Pure antagonists were developed earlier and the histidine mutations were introduced within such background. The antagonistic properties were maintained and the high affinity at low pH conserved. The implications of these findings may open new areas of research in the field of prolactin cancer biology.
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Affiliation(s)
- Mathilde J Kaas Hansen
- Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark
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Local prolactin is a target to prevent expansion of basal/stem cells in prostate tumors. Proc Natl Acad Sci U S A 2010; 107:15199-204. [PMID: 20699217 DOI: 10.1073/pnas.0911651107] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Androgen-independent recurrence is the major limit of androgen ablation therapy for prostate cancer. Identification of alternative pathways promoting prostate tumor growth is thus needed. Stat5 has been recently shown to promote human prostate cancer cell survival/proliferation and to be associated with early prostate cancer recurrence. Stat5 is the main signaling pathway triggered by prolactin (PRL), a growth factor whose local production is also increased in high-grade prostate cancers. The first aim of this study was to use prostate-specific PRL transgenic mice to address the mechanisms by which local PRL induces prostate tumorogenesis. We report that (i) Stat5 is the major signaling cascade triggered by local PRL in the mouse dorsal prostate, (ii) this model recapitulates prostate tumorogenesis from precancer lesions to invasive carcinoma, and (iii) tumorogenesis involves dramatic accumulation and abnormal spreading of p63-positive basal cells, and of stem cell antigen-1-positive cells identified as a stem/progenitor-like subpopulation. Because basal epithelial stem cells are proposed to serve as tumor-initiating cells, we challenged the relevance of local PRL as a previously unexplored therapeutic target. Using a double-transgenic approach, we show that Delta1-9-G129R-hPRL, a competitive PRL-receptor antagonist, prevented early stages of prostate tumorogenesis by reducing or inhibiting Stat5 activation, cell proliferation, abnormal basal-cell pattern, and frequency or grade of intraepithelial neoplasia. This study identifies PRL receptor/Stat5 as a unique pathway, initiating prostate tumorogenesis by altering basal-/stem-like cell subpopulations, and strongly supports the importance of further developing strategies to target locally overexpressed PRL in human prostate cancer.
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Transgenic expression of 15-lipoxygenase 2 (15-LOX2) in mouse prostate leads to hyperplasia and cell senescence. Oncogene 2010; 29:4261-75. [PMID: 20514017 PMCID: PMC3042242 DOI: 10.1038/onc.2010.197] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
15-Lipoxygenase 2 (15-LOX2), a lipid-peroxidizing enzyme, is mainly expressed in the luminal compartment of the normal human prostate, and is often decreased or lost in prostate cancer. Previous studies from our lab implicate 15-LOX2 as a functional tumor suppressor. To better understand the biological role of 15-LOX2 in vivo, we generated prostate-specific 15-LOX2 transgenic mice using the ARR2PB promoter. Unexpectedly, transgenic expression of 15-LOX2 or 15-LOX2sv-b, a splice variant that lacks arachidonic acid-metabolizing activity, resulted in age-dependent prostatic hyperplasia and enlargement of the prostate. Prostatic hyperplasia induced by both 15-LOX2 and 15-LOX2sv-b was associated with an increase in luminal and Ki-67(+) cells; however, 15-LOX2-transgenic prostates also showed a prominent increase in basal cells. Microarray analysis revealed distinct gene expression profiles that could help explain the prostate phenotypes. Strikingly, 15-LOX2, but not 15-LOX2sv-b, transgenic prostate showed upregulation of several well-known stem or progenitor cell molecules including Sca-1, Trop2, p63, Nkx3.1 and Psca. Prostatic hyperplasia caused by both 15-LOX2 and 15-LOX2sv-b did not progress to prostatic intraprostate neoplasia or carcinoma and, mechanistically, prostate lobes (especially those of 15-LOX2 mice) showed a dramatic increase in senescent cells as revealed by increased SA-betagal, p27(Kip1) and heterochromatin protein 1gamma staining. Collectively, our results suggest that 15-LOX2 expression in mouse prostate leads to hyperplasia and also induces cell senescence, which may, in turn, function as a barrier to tumor development.
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Huang KT, Walker AM. Long term increased expression of the short form 1b prolactin receptor in PC-3 human prostate cancer cells decreases cell growth and migration, and causes multiple changes in gene expression consistent with reduced invasive capacity. Prostate 2010; 70:37-47. [PMID: 19739126 PMCID: PMC2787886 DOI: 10.1002/pros.21036] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
BACKGROUND We have shown that treatment of human prostate cancer cells with the selective prolactin (PRL) receptor modulator, S179D PRL, inhibits growth in vitro, and the initiation and growth of xenografts in vivo. S179D PRL treatment also upregulates expression of the short form 1b (SF1b) PRL receptor, activation of which upregulates expression of the cell cycle-regulating protein, p21. METHODS We examined the consequences of long term increased expression and activation of SF1b, at levels comparable to those resulting from treatment with S179D PRL, by creating PC-3-derived stable cell lines expressing a constitutively active form of SF1b, DeltaS2 SF1b. RESULTS Increased expression of DeltaS2 SF1b decreased growth and migration of the cells. This was accompanied by an increase in cell-matrix interactions, and cell-cell aggregation when cells were plated on basement membrane components. Real-time PCR evaluated the expression of genes related to invasive capacity. Of particular interest was decreased expression of the protease, urokinase-type plaminogen activator, and its receptor, uPAR, and increased expression of its inhibitors, PAI-1 and 2. Also decreased in cells with increased expression of DeltaS2 SF1b was expression of basic fibroblast growth factor and vascular endothelial growth factor. CONCLUSION We conclude that at least part of the beneficial effects of S179D PRL is the result of increased expression of SF1b, and that the effects of increased expression and activation of SF1b continue to be of potential benefit in the long term.
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Affiliation(s)
- Kuang-tzu Huang
- Division of Biomedical Sciences, University of California, Riverside, Riverside, California 92521, USA
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Liao Z, Lutz J, Nevalainen MT. Transcription factor Stat5a/b as a therapeutic target protein for prostate cancer. Int J Biochem Cell Biol 2009; 42:186-92. [PMID: 19914392 DOI: 10.1016/j.biocel.2009.11.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2009] [Revised: 11/02/2009] [Accepted: 11/03/2009] [Indexed: 10/20/2022]
Abstract
Prostate cancer is the most common non-cutaneous cancer in Western males. The majority of prostate cancer fatalities are caused by development of castration-resistant growth and metastatic spread of the primary tumor. The average duration of the response of primary prostate cancer to hormonal ablation is less than 3 years, and 75% of prostate cancers in the United States progress to castration-resistant disease. The existing pharmacological therapies for metastatic and/or castration-resistant prostate cancer do not provide significant survival benefit. This review summarizes the importance of transcription factor Stat5 signaling in the pathogenesis of prostate cancer and discusses the molecular basis of Stat5a/b inhibition as a therapeutic strategy for prostate cancer.
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Affiliation(s)
- Zhiyong Liao
- Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, 233 S. 10th Street, Philadelphia, PA 19107, USA
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Abstract
Ductal adenocarcinoma is an uncommon variant of prostatic adenocarcinoma with a generally more aggressive clinical course than usual acinar adenocarcinoma. However, the molecular distinction between ductal and acinar adenocarcinomas is not well characterized. The aim of this investigation was to evaluate the relatedness of ductal versus acinar prostatic adenocarcinoma by comparative gene expression profiling. Archived, de-identified, snap frozen tumor tissue from 5 ductal adenocarcinomas, 3 mixed ductal-acinar adenocarcinomas, and 11 acinar adenocarcinomas cases were analyzed. All cases of acinar and ductal adenocarcinomas were matched by Gleason grade. RNA from whole tissue sections of the 5 ductal and 11 acinar adenocarcinomas cases were subjected to gene expression profiling on Affymetrix U133Plus2 microarrays. Independently, laser-capture microdissection was also performed on the three mixed ductal-acinar cases and five pure acinar cases to isolate homogeneous populations of ductal and acinar carcinoma cells from the same tumor. Seven of these laser-capture microdissected samples (three ductal and four acinar cell populations) were similarly analyzed on U133Plus2 arrays. Analysis of data from whole sections of ductal and acinar carcinomas identified only 25 gene transcripts whose expression was significantly and at least two-fold different between ductal and acinar adenocarcinomas. A similar analysis of microdissected cell populations identified 10 transcripts, including the prolactin receptor, with more significant differences in expression of 5- to 27-fold between ductal and acinar adenocarcinomas cells. Overexpression of prolactin receptor protein in ductal versus acinar adenocarcinoma was confirmed by immunohistochemistry in an independent set of tumors. We conclude that ductal and acinar adenocarcinomas of the prostate are strikingly similar at the level of gene expression. However, several of the genes identified in this study, including the prolactin receptor, represent targets for further investigations on the molecular basis for histomorphological and clinical behavioral differences between acinar and ductal adenocarcinomas.
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Gómez V, Ingelmo I, Martín R, Codesal J, Rodríguez R, Pozuelo JM, Santamaría L. Effect of Prolactin on the Population of Epithelial Cells From Ventral Prostate of Intact and Cyproterone Acetate-Treated Peripubertal Rats: Stereological and Immunohistochemical Study. Anat Rec (Hoboken) 2009; 292:746-55. [DOI: 10.1002/ar.20879] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Yatkin E, Bernoulli J, Talvitie EM, Santti R. Inflammation and epithelial alterations in rat prostate: impact of the androgen to oestrogen ratio. ACTA ACUST UNITED AC 2008; 32:399-410. [PMID: 19515173 DOI: 10.1111/j.1365-2605.2008.00930.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Chronic non-bacterial prostatitis may offer new insights into the pathogenesis of human benign prostatic hyperplasia and prostate cancer and the strategies for their treatment and prevention. The potential significance of androgen replacement therapy in terms of the reversal of oestradiol (E(2))-induced inflammatory reaction was studied in the dorsolateral prostate (DLP) of the Noble rat. Castrated Noble rats were treated with E(2) and different doses of androgens [dihydrotestosterone (DHT) and testosterone (T)] to achieve an elevated concentration of E(2) and a wide range of the androgen-to-oestradiol ratios in serum. After the 3-week treatment, inflammatory changes in the DLP were classified and counted. Oestrogen receptor alpha (ER alpha), progesterone receptor (PR), fos-related antigen-2 (Fra2), Ki-67 and P63 were immunocytochemically stained. T, E(2) and prolactin concentrations in serum were measured and the relative weights of the seminal vesicles and pituitary glands and microscopic structures of the DLP and seminal vesicle ducts were determined. Hypoandrogenic doses of DHT (judged on the basis of seminal vesicle weight gain), dose-dependently increased the number of perivascular and stromal inflammatory infiltrates. T and DHT were anti-inflammatory at the doses which normalized or over stimulated the growth of the seminal vesicles. As signs of anti-oestrogenicity, androgens dose-dependently decreased the number and distribution of the ER alpha and PR-positive cells at proinflammatory concentrations. Anti-inflammatory concentrations were needed to reduce the expression of Fra2, E(2)-increased prolactin concentration in serum and pituitary weight. The androgen concentrations required to prevent proinflammatory and epithelial responses to E(2) in the presence of elevated E(2) concentrations may subject the accessory sex glands to more intense androgenic stimulation than is normal for the male. The androgen-resistant endpoints of oestrogen action (body weight reduction and hyperplasia of seminal vesicle ducts) further indicate limitations in the possible preventive effects of androgen-replacement therapy.
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Affiliation(s)
- Emrah Yatkin
- Department of Cell Biology and Anatomy, Institute of Biomedicine, University of Turku, Turku, Finland.
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Yatkin E, Bernoulli J, Lammintausta R, Santti R. Fispemifene [Z-2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)-phenoxy]ethoxy}-ethanol], a novel selective estrogen receptor modulator, attenuates glandular inflammation in an animal model of chronic nonbacterial prostatitis. J Pharmacol Exp Ther 2008; 327:58-67. [PMID: 18583549 DOI: 10.1124/jpet.108.139501] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2025] Open
Abstract
The anti-inflammatory and antiestrogenic action of fispemifene [Z-2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}-ethanol], a novel selective estrogen receptor modulator (SERM), was tested on the Noble rat model of chronic nonbacterial prostatic inflammation with cellular composition and inflammation patterns similar to those described in human prostatitis. Inflammation was assessed by counting perivascular and stromal infiltrates and the number of inflamed acini. Furthermore, the aggressiveness of inflammation was assessed on the basis of the relation of lymphocytes to the acinar epithelium. The immunohistochemical expression of progesterone receptor (PR) and Fos-related antigen 2 (Fra2), prolactin concentration in serum, and the weights of the seminal vesicles and pituitary glands were used as endpoints of estrogen action. Fispemifene significantly attenuated the glandular form of inflammation induced in the dorsolateral prostatic lobes (DLP) in the hormonal milieu of the decreased androgen/estrogen ratio. The anti-inflammatory action was seen in the decreased number of acini containing intraluminal neutrophils. As signs of antiestrogenic action, fispemifene blocked estrogen-induced expression of PR and Fra2 in the acinar epithelium of the DLP, and it decreased prolactin concentration in serum and the relative weights of the seminal vesicles and pituitary glands. Because fispemifene exhibited both antiestrogenic and anti-inflammatory action in the prostate, this experimental study suggests that SERMs could be considered as a new therapeutic option in the treatment and prevention of prostatic inflammation.
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Affiliation(s)
- Emrah Yatkin
- University of Turku, Institute of Biomedicine, Department of Cell Biology and Anatomy, Kiinamyllynkatu 10, FIN-20520, Turku, Finland.
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Abstract
Advances in science and technology have allowed us to manipulate the mouse genome and analyse the effect of specific genetic alterations on the development of prostate cancer in vivo. We can now analyse the molecular basis of initiation, invasion and progression to metastatic disease. The current mouse models utilise knockout, knock-in or conditional regulation of expression using Cre-loxP technology. Genes that have been targeted include homeobox genes, tumour suppressors and oncogenes, growth factors (and their receptors), steroid hormones and cell-cycle regulators, as well as pro- and anti-apoptotic proteins. Bigenic models indicate that that two 'hits' are required for progression from intra-epithelial neoplasia (PIN) to invasion carcinoma, and two to five hits are needed for metastasis. Here, we discuss the numerous models that mimic various aspects of the disease process, such as PIN, locally invasive adenocarcinoma and metastatic disease. Currently the PB-Cre4 x PTEN(loxP/loxP) mouse is the only model that spans the entire continuum from initiation to local invasion and metastasis. Such mouse models increase our understanding of the disease process and provide targets for novel therapeutic approaches. Hopefully, the transgenic models will become inducible and ultimately allow both temporal and spatial gene inactivation. Compound mutational models will also develop further, with double and triple knock-in or knockout systems adding to our knowledge of the interaction between different signalling cascades.
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Tan SH, Nevalainen MT. Signal transducer and activator of transcription 5A/B in prostate and breast cancers. Endocr Relat Cancer 2008; 15:367-90. [PMID: 18508994 PMCID: PMC6036917 DOI: 10.1677/erc-08-0013] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Protein kinase signaling pathways, such as Janus kinase 2-Signal transducer and activator of transcription 5A/B (JAK2-STAT5A/B), are of significant interest in the search for new therapeutic strategies in both breast and prostate cancers. In prostate cancer, the components of the JAK2-STAT5A/B signaling pathway provide molecular targets for small-molecule inhibition of survival and growth signals of the cells. At the same time, new evidence suggests that the STAT5A/B signaling pathway is involved in the transition of organ-confined prostate cancer to hormone-refractory disease. This implies that the active JAK2-STAT5A/B signaling pathway potentially provides the means for pharmacological intervention of clinical prostate cancer progression. In addition, active STAT5A/B may serve as a prognostic marker for identification of those primary prostate cancers that are likely to progress to aggressive disease. In breast cancer, the role of STAT5A/B is more complex. STAT5A/B may have a dual role in the regulation of malignant mammary epithelium. Data accumulated from mouse models of breast cancer suggest that in early stages of breast cancer STAT5A/B may promote malignant transformation and enhance growth of the tumor. This is in contrast to established breast cancer, where STAT5A/B may mediate the critical cues for maintaining the differentiation of mammary epithelium. In addition, present data suggest that activation of STAT5A/B in breast cancer predicts favorable clinical outcome. The dual nature of STAT5A/B action in breast cancer makes the therapeutic use of STAT5 A/B more complex.
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Affiliation(s)
- Shyh-Han Tan
- Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, BLSB 309, Philadelphia, Pennsylvania 19107, USA
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Dagvadorj A, Kirken RA, Leiby B, Karras J, Nevalainen MT. Transcription factor signal transducer and activator of transcription 5 promotes growth of human prostate cancer cells in vivo. Clin Cancer Res 2008; 14:1317-24. [PMID: 18316550 DOI: 10.1158/1078-0432.ccr-07-2024] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Signal transducer and activator of transcription 5a/b (Stat5a/b) is the key mediator of prolactin effects in prostate cancer cells via activation of Janus-activated kinase 2. Prolactin is a locally produced growth factor in human prostate cancer. Prolactin protein expression and constitutive activation of Stat5a/b are associated with high histologic grade of clinical prostate cancer. Moreover, activation of Stat5a/b in primary prostate cancer predicts early disease recurrence. Here, we inhibited Stat5a/b by several different methodologic approaches. Our goal was to establish a proof of principle that Stat5a/b is critical for prostate cancer cell viability in vitro and for prostate tumor growth in vivo. EXPERIMENTAL DESIGN We inhibited Stat5a/b protein expression by antisense oligonucleotides or RNA interference and transcriptional activity of Stat5a/b by adenoviral expression of a dominant-negative mutant of Stat5a/b in prostate cancer cells in culture. Moreover, Stat5a/b activity was suppressed in human prostate cancer xenograft tumors in nude mice. Stat5a/b regulation of Bcl-X(L) and cyclin D1 protein levels was shown by antisense suppression of Stat5a/b protein expression followed by Western blotting. RESULTS AND CONCLUSIONS We show here that inhibition of Stat5a/b by antisense oligonucleotides, RNA interference, or adenoviral expression of dominant-negative Stat5a/b effectively kills prostate cancer cells. Moreover, we show that Stat5a/b is critical for human prostate cancer xenograft growth in nude mice. The effects of Stat5a/b on the viability of prostate cancer cells involve Stat5a/b regulation of Bcl-X(L) and cyclin D1 protein levels but not the expression or activation of Stat3. This work establishes Stat5a/b as a therapeutic target protein for prostate cancer. Pharmacologic inhibition of Stat5a/b in prostate cancer can be achieved by small-molecule inhibitors of transactivation, dimerization, or DNA binding of Stat5a/b.
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Affiliation(s)
- Ayush Dagvadorj
- Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
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50
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Abstract
Hyperprolactinaemia is a frequent cause of reproductive problems encountered in clinical practice. A variety of pathophysiological conditions can lead to hyperprolactinaemia; therefore, pregnancy, drug effects, hypothyroidism and polycystic ovary syndrome should be excluded before investigating for prolactin-secreting pituitary tumours. Prolactinomas are mainly diagnosed in women aged 20-40 years. They present with clinical features of hyperprolactinaemia (galactorrhoea, gonadal dysfunction), and more rarely with large tumours, headache and visual field loss due to optic chiasm compression. Medical therapy with dopamine agonists is the treatment of choice for both micro- and macroprolactinomas. Tumour shrinkage and restoration of gonadal function are achieved in the majority of cases with dopamine agonists. A trial of withdrawal of medical therapy may be considered in many patients with close follow-up. Pituitary surgery and radiotherapy currently have very limited indications. Pregnancies in patients with prolactinomas need careful planning and close monitoring.
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Affiliation(s)
- V K B Prabhakar
- Department of Endocrinology, Manchester Royal Infirmary, Manchester M13 9WL, UK
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