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Arriojas A, Patalano S, Macoska J, Zarringhalam K. A Bayesian noisy logic model for inference of transcription factor activity from single cell and bulk transcriptomic data. NAR Genom Bioinform 2023; 5:lqad106. [PMID: 38094309 PMCID: PMC10716740 DOI: 10.1093/nargab/lqad106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 11/12/2023] [Accepted: 11/24/2023] [Indexed: 12/20/2023] Open
Abstract
The advent of high-throughput sequencing has made it possible to measure the expression of genes at relatively low cost. However, direct measurement of regulatory mechanisms, such as transcription factor (TF) activity is still not readily feasible in a high-throughput manner. Consequently, there is a need for computational approaches that can reliably estimate regulator activity from observable gene expression data. In this work, we present a noisy Boolean logic Bayesian model for TF activity inference from differential gene expression data and causal graphs. Our approach provides a flexible framework to incorporate biologically motivated TF-gene regulation logic models. Using simulations and controlled over-expression experiments in cell cultures, we demonstrate that our method can accurately identify TF activity. Moreover, we apply our method to bulk and single cell transcriptomics measurements to investigate transcriptional regulation of fibroblast phenotypic plasticity. Finally, to facilitate usage, we provide user-friendly software packages and a web-interface to query TF activity from user input differential gene expression data: https://umbibio.math.umb.edu/nlbayes/.
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Affiliation(s)
- Argenis Arriojas
- Department of Mathematics, University of Massachusetts Boston, Boston, MA 02125, USA
- Department of Physics, University of Massachusetts Boston, Boston, MA 02125, USA
- Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA 02125, USA
| | - Susan Patalano
- Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA 02125, USA
| | - Jill Macoska
- Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA 02125, USA
| | - Kourosh Zarringhalam
- Department of Mathematics, University of Massachusetts Boston, Boston, MA 02125, USA
- Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA 02125, USA
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Arriojas A, Patalano S, Macoska J, Zarringhalam K. A Bayesian Noisy Logic Model for Inference of Transcription Factor Activity from Single Cell and Bulk Transcriptomic Data. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.03.539308. [PMID: 37205561 PMCID: PMC10187261 DOI: 10.1101/2023.05.03.539308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
The advent of high-throughput sequencing has made it possible to measure the expression of genes at relatively low cost. However, direct measurement of regulatory mechanisms, such as Transcription Factor (TF) activity is still not readily feasible in a high-throughput manner. Consequently, there is a need for computational approaches that can reliably estimate regulator activity from observable gene expression data. In this work, we present a noisy Boolean logic Bayesian model for TF activity inference from differential gene expression data and causal graphs. Our approach provides a flexible framework to incorporate biologically motivated TF-gene regulation logic models. Using simulations and controlled over-expression experiments in cell cultures, we demonstrate that our method can accurately identify TF activity. Moreover, we apply our method to bulk and single cell transcriptomics measurements to investigate transcriptional regulation of fibroblast phenotypic plasticity. Finally, to facilitate usage, we provide user-friendly software packages and a web-interface to query TF activity from user input differential gene expression data: https://umbibio.math.umb.edu/nlbayes/.
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Affiliation(s)
- Argenis Arriojas
- Department of Mathematics, University of Massachusetts Boston, Boston, MA 02125, USA
- Department of Physics, University of Massachusetts Boston, Boston, MA 02125, USA
- Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA 02125, USA
| | - Susan Patalano
- Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA 02125, USA
| | - Jill Macoska
- Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA 02125, USA
| | - Kourosh Zarringhalam
- Department of Mathematics, University of Massachusetts Boston, Boston, MA 02125, USA
- Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA 02125, USA
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The IL-4/IL-13 signaling axis promotes prostatic fibrosis. PLoS One 2022; 17:e0275064. [PMID: 36201508 PMCID: PMC9536598 DOI: 10.1371/journal.pone.0275064] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 09/09/2022] [Indexed: 11/05/2022] Open
Abstract
Background Lower urinary tract symptoms (LUTS) are a costly and pervasive medical problem for millions of aging men. Recent studies have showed that peri-urethral tissue fibrosis is an untreated pathobiology contributing to LUTS. Fibrosis results from excessive extracellular matrix deposition which increases transition zone and peri-urethral tissue stiffness and compromises prostatic urethral flexibility and compliance, producing urinary obstructive symptoms. Inflammatory cells, including neutrophils, macrophages, and T-lymphocytes, secrete a medley of pro-fibrotic proteins into the prostatic microenvironment, including IFNγ, TNFα, CXC-type chemokines, and interleukins, all of which have been implicated in inflammation-mediated fibrosis. Among these, IL-4 and IL-13 are of particular interest because they share a common signaling axis that, as shown here for the first time, promotes the expression and maintenance of IL-4, IL-13, their cognate receptors, and ECM components by prostate fibroblasts, even in the absence of immune cells. Based on studies presented here, we hypothesize that the IL-4/IL-13 axis promotes prostate fibroblast activation to ECM-secreting cells. Methods N1 or SFT1 immortalized prostate stromal fibroblasts were cultured and treated, short- or long-term, with pro-fibrotic proteins including IL-4, IL-13, TGF-β, TNF-α, IFNγ, with or without prior pre-treatment with antagonists or inhibitors. Protein expression was assessed by immunohistochemistry, immunofluorescence, ELISA, immunoblot, or Sircoll assays. Transcript expression levels were determined by qRT-PCR. Intact cells were counted using WST assays. Results IL-4Rα, IL-13Rα1, and collagen are concurrently up-regulated in human peri-urethral prostate tissues from men with LUTS. IL-4 and IL-13 induce their own expression as well as that of their cognate receptors, IL-4Rα and IL-13Rα1. Low concentrations of IL-4 or IL-13 act as cytokines to promote prostate fibroblast proliferation, but higher (>40ng/ml) concentrations repress cellular proliferation. Both IL-4 and IL-13 robustly and specifically promote collagen transcript and protein expression by prostate stromal fibroblasts in a JAK/STAT-dependent manner. Moreover, IL-4 and IL-13-mediated JAK/STAT signaling is coupled to activation of the IL-4Rα receptor. Conclusions Taken together, these studies show that IL-4 and IL-13 signal through the IL-4Rα receptor to activate JAK/STAT signaling, thereby promoting their own expression, that of their cognate receptors, and collagens. These finding suggest that the IL-4/IL-13 signaling axis is a powerful, but therapeutically targetable, pro-fibrotic mechanism in the lower urinary tract.
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Han C, Zhu L, Liu X, Ma S, Liu Y, Wang X. Differential diagnosis of uncommon prostate diseases: combining mpMRI and clinical information. Insights Imaging 2021; 12:79. [PMID: 34132898 PMCID: PMC8208342 DOI: 10.1186/s13244-021-01024-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 05/31/2021] [Indexed: 01/03/2023] Open
Abstract
The differential diagnosis of abnormalities in the prostate is broad, covering common (acinar adenocarcinoma, benign prostatic hyperplasia, chronic prostatitis, hemorrhage, cysts, calcifications, atrophy and fibrosis) and less common conditions (tumors other than acinar adenocarcinoma, granulomatous prostatitis containing tuberculosis, abscesses and other conditions, and idiopathic disorders such as amyloidosis and exophytic benign prostatic hyperplasia). Recent advances in magnetic resonance imaging (MRI) of the prostate gland and imaging guidelines, such as the Prostate Imaging Reporting and Data System version 2.1 (PI-RADS v2.1), have dramatically improved the ability to distinguish common abnormalities, especially the ability to detect clinically significant prostate cancer (csPCa). Overlap can exist in the clinical history and imaging features associated with various common/uncommon prostate abnormalities, and biopsy is often required but is invasive. Prostate abnormalities can be divided into two categories: category 1, diseases for which PI-RADS scores are suitable for use, and category 2, diseases for which PI-RADS scores are unsuitable for use. Radiologists must have an intimate knowledge of other diseases, especially uncommon conditions. Past relevant history, symptoms, age, serum prostate-specific antigen (PSA) levels, MRI manifestations, and the applicability of the PI-RADS assessment should be considered when diagnosing prostate abnormalities.
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Affiliation(s)
- Chao Han
- Department of Radiology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, China
| | - Lina Zhu
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe Road, ZhengzhouHenan Province, 450052, China
| | - Xiang Liu
- Department of Radiology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, China
| | - Shuai Ma
- Department of Radiology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, China
| | - Yi Liu
- Department of Radiology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, China
| | - Xiaoying Wang
- Department of Radiology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, China.
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Liu YT, Song FX, Xiang L, Chang H. Solitary fibrous tumor of the prostate: a case report and 5-year follow-up. Asian J Androl 2020; 21:421-422. [PMID: 30950411 PMCID: PMC6628732 DOI: 10.4103/aja.aja_18_19] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Affiliation(s)
- Ya-Ting Liu
- Department of Medical Oncology, Lanzhou University Second Hospital, Lanzhou 730030, China
| | - Fei-Xue Song
- Department of Medical Oncology, Lanzhou University Second Hospital, Lanzhou 730030, China
| | - Lin Xiang
- Department of Pathology, Lanzhou University Second Hospital, Lanzhou 730030, China
| | - Hong Chang
- Department of Urology, Lanzhou University Second Hospital, Lanzhou 730030, China.,Institute of Urology, Lanzhou University Second Hospital, Key Laboratory of Urological Diseases in Gansu Province, Gansu Nephro-Urological Clinical Center, Lanzhou 730030, China.,Department of Clinical Laboratory Center, The Second Clinical Medical College of Lanzhou University, Lanzhou 730030, China
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Macoska JA, Uchtmann KS, Leverson GE, McVary KT, Ricke WA. Prostate Transition Zone Fibrosis is Associated with Clinical Progression in the MTOPS Study. J Urol 2019; 202:1240-1247. [PMID: 31188728 PMCID: PMC7339116 DOI: 10.1097/ju.0000000000000385] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/04/2019] [Indexed: 11/25/2022]
Abstract
PURPOSE Medications targeting androgen receptor activity (eg finasteride) or smooth muscle contractility (eg doxazosin) do not resolve lower urinary tract symptoms indicative of lower urinary tract dysfunction in an important subgroup of men. Recently fibrosis has been implicated as another pathobiology contributing to male lower urinary tract symptoms but to our knowledge no systematic studies have been done to assess fibrosis in the context of medical treatment. We determine whether fibrotic changes in the prostate transition zone are associated with an increased risk of clinical progression in participants treated with doxazosin, finasteride or finasteride plus doxazosin in the MTOPS (Medical Therapy of Prostatic Symptoms) study. MATERIALS AND METHODS Transition zone biopsy tissues from men who did or did not experience clinical progression on placebo, doxazosin, finasteride or combination therapy were assessed for collagen content and architectural changes using picrosirius red birefringence and CT-FIRE (Curvelet Transform-Fiber Extraction) analysis. Correlations were made with annotated demographic and clinical data. Statistical analyses were done with the Pearson correlation coefficient, ANOVA and the t-test. RESULTS High levels of wavy, aligned prostate transition zone collagen significantly correlated with an increased risk of clinical progression among MTOPS trial participants treated with doxazosin plus finasteride, particularly those with a high body mass index. CONCLUSIONS Fibrotic changes in the prostate transition zone are associated with an increased risk of clinical progression in men treated with doxazosin plus finasteride. Antifibrotic therapeutics might provide a new treatment approach in men with lower urinary tract dysfunction who do not respond to current medical treatment approaches.
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Affiliation(s)
- Jill A. Macoska
- Center for Personalized Cancer Therapy, University of Massachusetts, Boston, MA, USA
- George M. O’Brien Center for Benign Urologic Research, University of Wisconsin, Madison, WI, USA
| | - Kristen S. Uchtmann
- George M. O’Brien Center for Benign Urologic Research, University of Wisconsin, Madison, WI, USA
- Department of Urology, The University of Wisconsin, Madison, WI, USA
| | - Glen E. Leverson
- Department of Urology, The University of Wisconsin, Madison, WI, USA
| | - Kevin T. McVary
- Department of Urology, Loyola University Medical Center, Maywood, IL, USA
| | - William A. Ricke
- George M. O’Brien Center for Benign Urologic Research, University of Wisconsin, Madison, WI, USA
- Department of Urology, The University of Wisconsin, Madison, WI, USA
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Almanza D, Gharaee-Kermani M, Zhilin-Roth A, Rodriguez-Nieves JA, Colaneri C, Riley T, Macoska JA. Nonalcoholic Fatty Liver Disease Demonstrates a Pre-fibrotic and Premalignant Molecular Signature. Dig Dis Sci 2019; 64:1257-1269. [PMID: 30519850 PMCID: PMC6512804 DOI: 10.1007/s10620-018-5398-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 11/27/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Metabolic syndrome contributing to nonalcoholic fatty liver disease (NAFLD) can lead to hepatic dysfunction, steatohepatitis, cirrhosis, and hepatocellular carcinoma. AIMS In this study, we tested whether diet-induced fatty liver in a mouse model physiologically mimicked human NAFLD, and whether transcriptional alterations in mouse fatty liver signified risk for the development of hepatitis, cirrhosis, and/or hepatocellular carcinoma. METHODS SAMP6 strain mice were fed a low-fat diet or high-fat diet (HFD) for 6 months. Mouse livers were isolated and subjected to histology, immunohistochemistry, and whole transcriptome RNA sequencing. Sequences were aligned to the mouse reference genome, and gene expression signatures were analyzed using bioinformatics tools including Cufflinks, Pathview, Cytoscape, ClueGO, and GOstats. RESULTS Consistent with NAFLD, livers from HFD-fed mice demonstrated steatosis, high levels of inflammation, an up-regulation of genes encoding proteins associated with the complement pathway and immune responses, and down-regulation of those associated with metabolic processes. These livers also showed an up-regulation of genes associated with fibrosis and malignant transformation but no histological evidence of either pathobiology or DNA damage. CONCLUSIONS HFD-fed mice exhibited NAFLD that had incompletely transitioned from fatty liver to NASH. Importantly, bioinformatics approaches identified pre-fibrotic and premalignant signatures, suggesting that the pathogenesis of both fibrosis and cancer may initiate in fatty livers well before associated histological changes are evident.
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Affiliation(s)
- Diego Almanza
- 0000 0004 0386 3207grid.266685.9Department of Biology, University of Massachusetts Boston, Boston, USA ,0000 0004 0386 3207grid.266685.9Center for Personalized Cancer Therapy, The University of Massachusetts Boston, Room 4601, Integrated Sciences Complex, 100 Morrissey Blvd., Boston, MA 02125 USA
| | - Mehrnaz Gharaee-Kermani
- 0000 0004 0386 3207grid.266685.9Department of Biology, University of Massachusetts Boston, Boston, USA ,0000 0004 0386 3207grid.266685.9Center for Personalized Cancer Therapy, The University of Massachusetts Boston, Room 4601, Integrated Sciences Complex, 100 Morrissey Blvd., Boston, MA 02125 USA
| | - Alisa Zhilin-Roth
- 0000 0004 0386 3207grid.266685.9Department of Biology, University of Massachusetts Boston, Boston, USA ,0000 0004 0386 3207grid.266685.9Center for Personalized Cancer Therapy, The University of Massachusetts Boston, Room 4601, Integrated Sciences Complex, 100 Morrissey Blvd., Boston, MA 02125 USA
| | - Jose A. Rodriguez-Nieves
- 0000 0004 0386 3207grid.266685.9Center for Personalized Cancer Therapy, The University of Massachusetts Boston, Room 4601, Integrated Sciences Complex, 100 Morrissey Blvd., Boston, MA 02125 USA
| | - Cory Colaneri
- 0000 0004 0386 3207grid.266685.9Department of Biology, University of Massachusetts Boston, Boston, USA
| | - Todd Riley
- 0000 0004 0386 3207grid.266685.9Department of Biology, University of Massachusetts Boston, Boston, USA ,0000 0004 0386 3207grid.266685.9Center for Personalized Cancer Therapy, The University of Massachusetts Boston, Room 4601, Integrated Sciences Complex, 100 Morrissey Blvd., Boston, MA 02125 USA
| | - Jill A. Macoska
- 0000 0004 0386 3207grid.266685.9Department of Biology, University of Massachusetts Boston, Boston, USA ,0000 0004 0386 3207grid.266685.9Center for Personalized Cancer Therapy, The University of Massachusetts Boston, Room 4601, Integrated Sciences Complex, 100 Morrissey Blvd., Boston, MA 02125 USA
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8
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Mesenchymal tumors of the prostate. Mod Pathol 2018; 31:S133-142. [PMID: 29297486 DOI: 10.1038/modpathol.2017.155] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 09/19/2017] [Accepted: 09/21/2017] [Indexed: 12/12/2022]
Abstract
Mesenchymal tumors of the prostate are rare but often cause considerable diagnostic difficulty when encountered. These may be either benign or malignant and can arise within the prostate gland or in adjacent tissues. This review covers prostatic stromal proliferations (prostatic stromal tumor of uncertain malignant potential and stromal sarcoma), solitary fibrous tumor, myofibroblastic proliferations, smooth muscle neoplasms (leiomyoma and leiomyosarcoma), gastrointestinal stromal tumor, schwannoma, rhabdomyosarcoma, sarcomatoid carcinoma, postradiation sarcoma, and mixed epithelial stromal tumor of the seminal vesicle. Differential diagnostic considerations are emphasized, including descriptions of helpful histological and/or clinical clues and the use of adjuvant diagnostic techniques.
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Wegner KA, Cadena MT, Trevena R, Turco AE, Gottschalk A, Halberg RB, Guo J, McMahon JA, McMahon AP, Vezina CM. An immunohistochemical identification key for cell types in adult mouse prostatic and urethral tissue sections. PLoS One 2017; 12:e0188413. [PMID: 29145476 PMCID: PMC5690684 DOI: 10.1371/journal.pone.0188413] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 11/06/2017] [Indexed: 02/07/2023] Open
Abstract
Though many methods can be used to identify cell types contained in complex tissues, most require cell disaggregation and destroy information about where cells reside in relation to their microenvironment. Here, we describe a polytomous key for cell type identification in intact sections of adult mouse prostate and prostatic urethra. The key is organized as a decision tree and initiates with one round of immunostaining for nerve, epithelial, fibromuscular/hematolymphoid, or vascular associated cells. Cell identities are recursively eliminated by subsequent staining events until the remaining pool of potential cell types can be distinguished by direct comparison to other cells. We validated our identification key using wild type adult mouse prostate and urethra tissue sections and it currently resolves sixteen distinct cell populations which include three nerve fiber types as well as four epithelial, five fibromuscular/hematolymphoid, one nerve-associated, and three vascular-associated cell types. We demonstrate two uses of this novel identification methodology. We first used the identification key to characterize prostate stromal cell type changes in response to constitutive phosphatidylinositide-3-kinase activation in prostate epithelium. We then used the key to map cell lineages in a new reporter mouse strain driven by Wnt10aem1(cre/ERT2)Amc. The identification key facilitates rigorous and reproducible cell identification in prostate tissue sections and can be expanded to resolve additional cell types as new antibodies and other resources become available.
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Affiliation(s)
- Kyle A. Wegner
- George M. O’Brien Benign Urology Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Molecular and Environmental Toxicology Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Mark T. Cadena
- George M. O’Brien Benign Urology Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Ryan Trevena
- George M. O’Brien Benign Urology Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Anne E. Turco
- George M. O’Brien Benign Urology Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Molecular and Environmental Toxicology Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Adam Gottschalk
- School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Richard B. Halberg
- Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Jinjin Guo
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad-CIRM Center for Regenerative Medicine and Stem Cell Research, W.M. Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States of America
| | - Jill A. McMahon
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad-CIRM Center for Regenerative Medicine and Stem Cell Research, W.M. Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States of America
| | - Andrew P. McMahon
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad-CIRM Center for Regenerative Medicine and Stem Cell Research, W.M. Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States of America
| | - Chad M. Vezina
- George M. O’Brien Benign Urology Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Molecular and Environmental Toxicology Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- * E-mail:
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Jernigan NL, Naik JS, Weise-Cross L, Detweiler ND, Herbert LM, Yellowhair TR, Resta TC. Contribution of reactive oxygen species to the pathogenesis of pulmonary arterial hypertension. PLoS One 2017; 12:e0180455. [PMID: 28666030 PMCID: PMC5493402 DOI: 10.1371/journal.pone.0180455] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 06/15/2017] [Indexed: 11/19/2022] Open
Abstract
Pulmonary arterial hypertension is associated with a decreased antioxidant capacity. However, neither the contribution of reactive oxygen species to pulmonary vasoconstrictor sensitivity, nor the therapeutic efficacy of antioxidant strategies in this setting are known. We hypothesized that reactive oxygen species play a central role in mediating both vasoconstrictor and arterial remodeling components of severe pulmonary arterial hypertension. We examined the effect of the chemical antioxidant, TEMPOL, on right ventricular systolic pressure, vascular remodeling, and enhanced vasoconstrictor reactivity in both chronic hypoxia and hypoxia/SU5416 rat models of pulmonary hypertension. SU5416 is a vascular endothelial growth factor receptor antagonist and the combination of chronic hypoxia/SU5416 produces a model of severe pulmonary arterial hypertension with vascular plexiform lesions/fibrosis that is not present with chronic hypoxia alone. The major findings from this study are: 1) compared to hypoxia alone, hypoxia/SU5416 exposure caused more severe pulmonary hypertension, right ventricular hypertrophy, adventitial lesion formation, and greater vasoconstrictor sensitivity through a superoxide and Rho kinase-dependent Ca2+ sensitization mechanism. 2) Chronic hypoxia increased medial muscularization and superoxide levels, however there was no effect of SU5416 to augment these responses. 3) Treatment with TEMPOL decreased right ventricular systolic pressure in both hypoxia and hypoxia/SU5416 groups. 4) This effect of TEMPOL was associated with normalization of vasoconstrictor responses, but not arterial remodeling. Rather, medial hypertrophy and adventitial fibrotic lesion formation were more pronounced following chronic TEMPOL treatment in hypoxia/SU5416 rats. Our findings support a major role for reactive oxygen species in mediating enhanced vasoconstrictor reactivity and pulmonary hypertension in both chronic hypoxia and hypoxia/SU5416 rat models, despite a paradoxical effect of antioxidant therapy to exacerbate arterial remodeling in animals with severe pulmonary arterial hypertension in the hypoxia/SU5416 model.
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Affiliation(s)
- Nikki L. Jernigan
- Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America
- * E-mail:
| | - Jay S. Naik
- Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America
| | - Laura Weise-Cross
- Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America
| | - Neil D. Detweiler
- Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America
| | - Lindsay M. Herbert
- Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America
| | - Tracylyn R. Yellowhair
- Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America
| | - Thomas C. Resta
- Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America
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Solitary Fibrous Tumor of the Prostate Which Was Initially Misdiagnosed as Prostate Cancer. Case Rep Urol 2017; 2017:3594914. [PMID: 28337357 PMCID: PMC5346388 DOI: 10.1155/2017/3594914] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Revised: 02/05/2017] [Accepted: 02/13/2017] [Indexed: 12/04/2022] Open
Abstract
Solitary fibrous tumor (SFT) of the prostate is a very rare tumor. We report a case of 65-year-old man with SFT of the prostate which was initially misdiagnosed as prostate cancer. Finally, we performed total prostatectomy and the tumor was histologically diagnosed as SFT of the prostate. The patient's clinical course has progressed favorably with no obvious recurrence 18 months postoperatively.
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12
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Rodríguez-Nieves JA, Patalano SC, Almanza D, Gharaee-Kermani M, Macoska JA. CXCL12/CXCR4 Axis Activation Mediates Prostate Myofibroblast Phenoconversion through Non-Canonical EGFR/MEK/ERK Signaling. PLoS One 2016; 11:e0159490. [PMID: 27434301 PMCID: PMC4951124 DOI: 10.1371/journal.pone.0159490] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 07/04/2016] [Indexed: 11/25/2022] Open
Abstract
Benign prostate hyperplasia (BPH), an enlargement of the prostate common in aging in men, is associated with urinary voiding dysfunction manifest as Lower Urinary Tract Symptoms (LUTS). Although inflammation and abnormal smooth muscle contractions are known to play key roles in the development of LUTS, tissue fibrosis may also be an important and previously unrecognized contributing factor. Tissue fibrosis arises from the unregulated differentiation of fibroblasts or other precursor cell types into myofibroblasts, which is usually accomplished by activation of the TGFβ/TGFβR axis. Previously we reported that the CXC-type chemokines, CXCL5, CXCL8 and CXCL12, which are up-regulated in the aging in the prostate, can drive this differentiation process as well in the absence of TGFβ. Based on this data we sought to elucidate the molecular mechanisms employed by CXCL12, and its receptor CXCR4, during prostate myofibroblast phenoconversion. The results of these studies suggest that CXCL12/CXCR4-mediated signaling events in prostate myofibroblast phenoconversion may proceed through non-canonical pathways that do not depend on TGFβ/TGFβR axis activation or Smad signaling. Here we report that CXCL12/CXCR4 axis activation promotes signaling through the EGFR and downstream MEK/ERK and PI3K/Akt pathways during myofibroblast phenoconversion, but not through TGFβ/TGFβR and downstream Smad signaling, in prostate fibroblasts undergoing myofibroblast phenoconversion. We document that EGFR transactivation is required for CXCL12-mediated signaling and expression of genes associate with myofibroblast phenoconversion (α-SMA, COL1a1). Our study successfully identified TGFβ/TGFβR-independent molecular mechanisms that promote CXCL12/CXCR4-induced myofibroblast phenoconversion. This information may be crucial for the development of novel therapies and potential biomarkers for prostatic fibrosis.
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Affiliation(s)
- José A. Rodríguez-Nieves
- Center for Personalized Cancer Therapy and Department of Biology, University of Massachusetts, Boston, Massachusetts
| | - Susan C. Patalano
- Center for Personalized Cancer Therapy and Department of Biology, University of Massachusetts, Boston, Massachusetts
| | - Diego Almanza
- Center for Personalized Cancer Therapy and Department of Biology, University of Massachusetts, Boston, Massachusetts
| | - Mehrnaz Gharaee-Kermani
- Center for Personalized Cancer Therapy and Department of Biology, University of Massachusetts, Boston, Massachusetts
| | - Jill A. Macoska
- Center for Personalized Cancer Therapy and Department of Biology, University of Massachusetts, Boston, Massachusetts
- * E-mail:
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Nakada S, Minato H, Nojima T. Clinicopathological differences between variants of the NAB2–STAT6 fusion gene in solitary fibrous tumors of the meninges and extra-central nervous system. Brain Tumor Pathol 2016; 33:169-74. [DOI: 10.1007/s10014-016-0264-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Accepted: 05/30/2016] [Indexed: 01/06/2023]
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