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Mesothelioma: HELP
Articles from Burlington
Based on 32 articles published since 2008
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These are the 32 published articles about Mesothelioma that originated from Burlington during 2008-2019.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline Guidelines for Pathologic Diagnosis of Malignant Mesothelioma 2017 Update of the Consensus Statement From the International Mesothelioma Interest Group. 2018

Husain, Aliya Noor / Colby, Thomas V / Ordóñez, Nelson G / Allen, Timothy Craig / Attanoos, Richard Luther / Beasley, Mary Beth / Butnor, Kelly Jo / Chirieac, Lucian R / Churg, Andrew M / Dacic, Sanja / Galateau-Sallé, Françoise / Gibbs, Allen / Gown, Allen M / Krausz, Thomas / Litzky, Leslie Anne / Marchevsky, Alberto / Nicholson, Andrew G / Roggli, Victor Louis / Sharma, Anupama K / Travis, William D / Walts, Ann E / Wick, Mark R. ·From the Department of Pathology, University of Chicago Medical Center, Chicago, Illinois (Drs Husain and Krausz) · the Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona (Dr Colby, emeritus) · the Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston (Dr Ordóñez) · the Department of Pathology, University of Texas Medical Branch, Galveston (Dr Allen) · the Department of Cellular Pathology, University Hospital of Wales and Cardiff University, Cardiff, South Glamorgan, Wales (Dr Attanoos) · the Department of Pathology, Mount Sinai Medical Center, New York, New York (Dr Beasley) · the Department of Pathology, University of Vermont College of Medicine, Burlington (Dr Butnor) · the Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (Dr Chirieac) · the Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada (Dr Churg) · the Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (Dr Dacic) · Centre National Référent MESOPATH Departement de Biopathologie, Lyon Cedex, France (Dr Galateau-Sallé) · the Department of Pathology, University Hospital of Wales, Penarth, South Glamorgan, Wales (Dr Gibbs) · the Department of Pathology, PhenoPath Laboratories, Seattle, Washington (Dr Gown) · the Department of Pathology & Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, (Dr Litzky) · the Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California (Drs Marchevsky and Walts) · the Department of Histopathology, Royal Brompton & Harefield National Health Service Foundation Trust and the National Heart and Lung Institute, Imperial College, Chelsea, London, England (Dr Nicholson) · the Department of Pathology, Duke University Medical Center, Durham, North Carolina (Dr Roggli) · the Department of Pathology, University of Pittsburgh, and the VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania (Dr Sharma) · the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Travis) · and the Department of Pathology, University of Virginia Medical Center, Charlottesville (Dr Wick). ·Arch Pathol Lab Med · Pubmed #28686500.

ABSTRACT: CONTEXT: - Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose. OBJECTIVE: - To provide updated, practical guidelines for the pathologic diagnosis of MM. DATA SOURCES: - Pathologists involved in the International Mesothelioma Interest Group and others with an interest and expertise in the field contributed to this update. Reference material included up-to-date, peer-reviewed publications and textbooks. CONCLUSIONS: - There was discussion and consensus opinion regarding guidelines for (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) recognition of the key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid MM, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels employed is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Depending on the morphology, immunohistochemical panels should contain both positive and negative markers for mesothelial differentiation and for lesions considered in the differential diagnosis. Immunohistochemical markers should have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic and membranous markers). Selected molecular markers are now being used to distinguish benign from malignant mesothelial proliferations. These guidelines are meant to be a practical diagnostic reference for the pathologist; however, some new pathologic predictors of prognosis and response to therapy are also included.

2 Review New insights into understanding the mechanisms, pathogenesis, and management of malignant mesotheliomas. 2013

Mossman, Brooke T / Shukla, Arti / Heintz, Nicholas H / Verschraegen, Claire F / Thomas, Anish / Hassan, Raffit. ·Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont 05405-0068, USA. brooke.mossman@uvm.edu ·Am J Pathol · Pubmed #23395095.

ABSTRACT: Malignant mesothelioma (MM) is a relatively rare but devastating tumor that is increasing worldwide. Yet, because of difficulties in early diagnosis and resistance to conventional therapies, MM remains a challenge for pathologists and clinicians to treat. In recent years, much has been revealed regarding the mechanisms of interactions of pathogenic fibers with mesothelial cells, crucial signaling pathways, and genetic and epigenetic events that may occur during the pathogenesis of these unusual, pleiomorphic tumors. These observations support a scenario whereby mesothelial cells undergo a series of chronic injury, inflammation, and proliferation in the long latency period of MM development that may be perpetuated by durable fibers, the tumor microenvironment, and inflammatory stimuli. One culprit in sustained inflammation is the activated inflammasome, a component of macrophages or mesothelial cells that leads to production of chemotactic, growth-promoting, and angiogenic cytokines. This information has been vital to designing novel therapeutic approaches for patients with MM that focus on immunotherapy, targeting growth factor receptors and pathways, overcoming resistance to apoptosis, and modifying epigenetic changes.

3 Review Epidemiology of mesothelioma and historical background. 2011

Craighead, J E. ·Department of Pathology, University of Vermont, Burlington, VT 05405, USA. john.craighead@theibcinc.com ·Recent Results Cancer Res · Pubmed #21479893.

ABSTRACT: Mesothelioma is a "new" malignant disease strongly associated with exposure to amphibole asbestos exposure (amosite and crocidolite) environmentally and in the work place. Nonetheless, in recent years, we have learned that many cases of mesothelioma are idiopathic, while some are caused by therapeutic irradiation or chronic inflammation in body cavities. This paper reviews the key epidemiological features of the malignancy in the context of the biological and mineralogical factors that influence mesothelioma development. These tumors challenge the diagnostic pathologist's acumen, the epidemiologist's skill in devising meaningful and definitive studies, the industrial hygienist's knowledge of environmental hazards in diverse occupational settings, and the clinician's skill in managing an intrepid and uniformly fatal malignancy.

4 Review Asbestos, lung cancers, and mesotheliomas: from molecular approaches to targeting tumor survival pathways. 2010

Heintz, Nicholas H / Janssen-Heininger, Yvonne M W / Mossman, Brooke T. ·Department of Pathology, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405-0068, USA. ·Am J Respir Cell Mol Biol · Pubmed #20068227.

ABSTRACT: Fifteen years have passed since we published findings in the AJRCMB demonstrating that induction of early response fos/jun proto-oncogenes in rodent tracheal and mesothelial cells correlates with fibrous geometry and pathogenicity of asbestos. Our study was the first to suggest that the aberrant induction of signaling responses by crocidolite asbestos and erionite, a fibrous zeolite mineral associated with the development of malignant mesotheliomas (MMs) in areas of Turkey, led to altered gene expression. New data questioned the widely held belief at that time that the carcinogenic effects of asbestos in the development of lung cancer and MM were due to genotoxic or mutagenic effects. Later studies by our group revealed that proto-oncogene expression and several of the signaling pathways activated by asbestos were redox dependent, explaining why antioxidants and antioxidant enzymes were elevated in lung and pleura after exposure to asbestos and how they alleviated many of the phenotypic and functional effects of asbestos in vitro or after inhalation. Since these original studies, our efforts have expanded to understand the interface between asbestos-induced redox-dependent signal transduction cascades, the relationship between these pathways and cell fate, and the role of asbestos and cell interactions in development of asbestos-associated diseases. Of considerable significance is the fact that the signal transduction pathways activated by asbestos are also important in survival and chemoresistance of MMs and lung cancers. An understanding of the pathogenic features of asbestos fibers and dysregulation of signaling pathways allows strategies for the prevention and therapy of asbestos-related diseases.

5 Review D2-40 immunohistochemistry--so far! 2009

Kalof, Alexandra N / Cooper, Kumarasen. ·Department of Pathology, University of Vermont/Fletcher Allen Health Care, Burlington, VT 05401, USA. alexandra.kalof@vtmednet.org ·Adv Anat Pathol · Pubmed #19098468.

ABSTRACT: D2-40 is a commercially available monoclonal antibody directed against human podoplanin, a transmembrane mucoprotein that is expressed in lymphatic endothelial cells. Since its introduction, D2-40 immunoexpression has been described in a variety of lymphovascular neoplasms including lymphangioma, Kaposi sarcoma, and hemangioendothelioma, as well as nonvascular neoplasms such as epithelioid mesothelioma, seminoma, and hemangioblastoma. More recently, D2-40 immunoexpression has been reported in primary adrenal cortical tumors, schwannomas, and adnexal tumors of the skin. This brief review provides an update on the ever-expanding proposed applications of D2-40 immunohistochemistry in surgical pathology.

6 Article Malignant peritoneal mesothelioma in patients with endometriosis. 2018

Butnor, Kelly J / Rueckert, Justin / Pavlisko, Elizabeth N / Sporn, Thomas A / Roggli, Victor L. ·Department of Pathology and Laboratory Medicine, University of Vermont Medical Center, Burlington, Vermont, USA. · Department of Pathology, Duke University Health System, Durham, North Carolina, USA. ·J Clin Pathol · Pubmed #29794065.

ABSTRACT: AIMS: Florid mesothelial hyperplasia is known to result from endometriosis. Well-differentiated papillary mesothelioma and multiloculated peritoneal inclusion cysts have also been described in women with endometriosis. To our knowledge, peritoneal diffuse malignant mesothelioma (MM) arising in the setting of endometriosis has not been reported. The purpose of this study is to report the clinicopathological characteristics of women with MM and endometriosis. METHODS: The surgical pathology files of a tertiary academic medical centre and the consultation files of one of the study authors were reviewed for cases of MM in females with and without endometriosis. RESULTS: Six women with MM and endometriosis ranging in age from 29 to 55 years (median=45 years) were identified. All had peritoneal MM and endometriosis involving the peritoneum and/or adnexa. Five had epithelioid MM and one had biphasic MM. Two had paraoccupational exposure to asbestos. The median age of women with MM and endometriosis (44.5 years) was significantly less than the median age of cases without endometriosis (58.0 years) (p value=0.01). CONCLUSIONS: To our knowledge, this is the first report of MM in women with endometriosis. Interestingly, MM in the setting of endometriosis has only been observed in the peritoneum and not in other serosal cavities. The findings in the present study suggest that chronic serosal inflammation secondary to endometriosis may be an inducing factor in rare cases of MM of the peritoneum.

7 Article Nuclear grade and necrosis predict prognosis in malignant epithelioid pleural mesothelioma: a multi-institutional study. 2018

Rosen, Lauren E / Karrison, Theodore / Ananthanarayanan, Vijayalakshmi / Gallan, Alexander J / Adusumilli, Prasad S / Alchami, Fouad S / Attanoos, Richard / Brcic, Luka / Butnor, Kelly J / Galateau-Sallé, Françoise / Hiroshima, Kenzo / Kadota, Kyuichi / Klampatsa, Astero / Stang, Nolween Le / Lindenmann, Joerg / Litzky, Leslie A / Marchevsky, Alberto / Medeiros, Filomena / Montero, M Angeles / Moore, David A / Nabeshima, Kazuki / Pavlisko, Elizabeth N / Roggli, Victor L / Sauter, Jennifer L / Sharma, Anupama / Sheaff, Michael / Travis, William D / Vigneswaran, Wickii T / Vrugt, Bart / Walts, Ann E / Tjota, Melissa Y / Krausz, Thomas / Husain, Aliya N. ·Department of Pathology, The University of Chicago Medicine, Chicago, IL, USA. · Department of Public Health Sciences, The University of Chicago, Chicago, IL, USA. · Department of Pathology, Loyola University Medical Center, Chicago, IL, USA. · Department of Thoracic Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Cellular Pathology, University Hospital of Wales, Cardiff, UK. · Department of Cellular Pathology, University Hospital of Wales and Cardiff University, Cardiff, UK. · Medical University of Graz, Institute of Pathology, Graz, Austria. · Department of Pathology, University of Vermont Medical Center, Burlington, VT, USA. · Centre Léon Bérard, BioPathologie, Lyon, France. · Department of Pathology, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan. · Department of Diagnostic Pathology, Kagawa University, Takamatsu, Japan. · Division of Pulmonary, Allergy and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. · Division of Thoracic and Hyperbaric Surgery, Department of Surgery,Medical University of Graz, Graz, Austria. · ,Department of Pathology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. · Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. · Basildon & Thurrock University Hospital, Department of Pathology, Basildon, UK. · Department of Histopathology, Royal Brompton and Harefield Hospitals Imperial College of London, London, UK. · Department of Cancer Studies, University of Leicester, Leicester, UK. · Fukuoka University, Department of Pathology, Fukuoka, Japan. · Department of Pathology, Duke University Medical Center, Durham, NC, USA. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Pathology, University of Pittsburgh Medical Center and VA Pittsburgh Healthcare System, Pittsburgh, PA, USA. · Department of Pathology, Barts Health NHS Trust, London, UK. · Department of Thoracic and Cardiovascular Surgery, Loyola University Medical Center, Chicago, IL, USA. · University Hospital Zurich, Institute for Pathology and Molecular Pathology, Zurich, Switzerland. ·Mod Pathol · Pubmed #29327706.

ABSTRACT: A recently described nuclear grading system predicted survival in patients with epithelioid malignant pleural mesothelioma. The current study was undertaken to validate the grading system and to identify additional prognostic factors. We analyzed cases of epithelioid malignant pleural mesothelioma from 17 institutions across the globe from 1998 to 2014. Nuclear grade was computed combining nuclear atypia and mitotic count into a grade of I-III using the published system. Nuclear grade was assessed by one pathologist for three institutions, the remaining were scored independently. The presence or absence of necrosis and predominant growth pattern were also evaluated. Two additional scoring systems were evaluated, one combining nuclear grade and necrosis and the other mitotic count and necrosis. Median overall survival was the primary endpoint. A total of 776 cases were identified including 301 (39%) nuclear grade I tumors, 354 (45%) grade II tumors and 121 (16%) grade III tumors. The overall survival was 16 months, and correlated independently with age (P=0.006), sex (0.015), necrosis (0.030), mitotic count (0.001), nuclear atypia (0.009), nuclear grade (<0.0001), and mitosis and necrosis score (<0.0001). The addition of necrosis to nuclear grade further stratified overall survival, allowing classification of epithelioid malignant pleural mesothelioma into four distinct prognostic groups: nuclear grade I tumors without necrosis (29 months), nuclear grade I tumors with necrosis and grade II tumors without necrosis (16 months), nuclear grade II tumors with necrosis (10 months) and nuclear grade III tumors (8 months). The mitosis-necrosis score stratified patients by survival, but not as well as the combination of necrosis and nuclear grade. This study confirms that nuclear grade predicts survival in epithelioid malignant pleural mesothelioma, identifies necrosis as factor that further stratifies overall survival, and validates the grading system across multiple institutions and among both biopsy and resection specimens. An alternative scoring system, the mitosis-necrosis score is also proposed.

8 Article Malignant peritoneal mesothelioma and Crohn disease. 2017

Butnor, Kelly J / Pavlisko, Elizabeth N / Sporn, Thomas A / Roggli, Victor L. ·Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA. · Department of Pathology and Laboratory Medicine, University of Vermont Medical Center, Burlington, Vermont, USA. ·J Clin Pathol · Pubmed #27484913.

ABSTRACT: AIMS: Mesothelial reaction simulating peritoneal diffuse malignant mesothelioma (MM) has been reported in the setting of Crohn ileitis. To our knowledge, peritoneal MM arising in patients with inflammatory bowel disease (IBD) has not been reported. The purpose of this study is to report the clinicopathological characteristics of patients with peritoneal MM and IBD. METHODS: A database of approximately 3800 MM was reviewed for cases of MM in patients with IBD. RESULTS: Three patients (0.08%) with peritoneal MM and Crohn disease (CD) were identified, including two women and one man ranging in age from 56 to 65 years. All had a long-standing history of diarrhoea and an established diagnosis of CD of 3 years or greater duration. Two had epithelial MM and one had biphasic MM. Only one had documented asbestos exposure. CONCLUSIONS: Peritoneal MM occurs rarely in patients with IBD, but interestingly, has only been observed in the setting of CD and not in patients with ulcerative colitis. Chronic inflammation has been associated with the development of MM in rare instances and these three cases suggest that CD with transmural inflammation may also be a precursor. The precise role of CD-related transmural inflammation in the carcinogenesis of peritoneal MM remains to be determined.

9 Article Inflammation-Related IL1β/IL1R Signaling Promotes the Development of Asbestos-Induced Malignant Mesothelioma. 2016

Kadariya, Yuwaraj / Menges, Craig W / Talarchek, Jacqueline / Cai, Kathy Q / Klein-Szanto, Andres J / Pietrofesa, Ralph A / Christofidou-Solomidou, Melpo / Cheung, Mitchell / Mossman, Brooke T / Shukla, Arti / Testa, Joseph R. ·Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111. · Histopathology Facility, Fox Chase Cancer Center, Philadelphia, PA 19111. · Department of Medicine, Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. · Department of Pathology, University of Vermont College of Medicine, Burlington, VT, 05405-0068. ·Cancer Prev Res (Phila) · Pubmed #26935421.

ABSTRACT: Exposure to asbestos is causally associated with the development of malignant mesothelioma, a cancer of cells lining the internal body cavities. Malignant mesothelioma is an aggressive cancer resistant to all current therapies. Once inhaled or ingested, asbestos causes inflammation in and around tissues that come in contact with these carcinogenic fibers. Recent studies suggest that inflammation is a major contributing factor in the development of many types of cancer, including malignant mesothelioma. The NALP3/NLRP3 inflammasome, including the component ASC, is thought to be an important mediator of inflammation in cells that sense extracellular insults, such as asbestos, and activate a signaling cascade resulting in release of mature IL1β and recruitment of inflammatory cells. To determine if inflammasome-mediated inflammation contributes to asbestos-induced malignant mesothelioma, we chronically exposed Asc-deficient mice and wild-type littermates to asbestos and evaluated differences in tumor incidence and latency. The Asc-deficient mice showed significantly delayed tumor onset and reduced malignant mesothelioma incidence compared with wild-type animals. We also tested whether inflammation-related release of IL1β contributes to tumor development in an accelerated mouse model of asbestos-induced malignant mesothelioma. Nf2(+/-);Cdkn2a(+/-) mice exposed to asbestos in the presence of anakinra, an IL1 receptor (IL1R) antagonist, showed a marked delay in the median time of malignant mesothelioma onset compared with similarly exposed mice given vehicle control (33.1 weeks vs. 22.6 weeks, respectively). Collectively, these studies provide evidence for a link between inflammation-related IL1β/IL1R signaling and the development of asbestos-induced malignant mesothelioma. Furthermore, these findings provide rationale for chemoprevention strategies targeting IL1β/IL1R signaling in high-risk, asbestos-exposed populations. Cancer Prev Res; 9(5); 406-14. ©2016 AACR.

10 Article Inflammasome Modulation by Chemotherapeutics in Malignant Mesothelioma. 2015

Westbom, Catherine / Thompson, Joyce K / Leggett, Alan / MacPherson, Maximilian / Beuschel, Stacie / Pass, Harvey / Vacek, Pamela / Shukla, Arti. ·Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, United States of America. · Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York, United States of America. · Department of Medical Biostatistics, University of Vermont College of Medicine, Burlington, VT, United States of America. ·PLoS One · Pubmed #26689911.

ABSTRACT: Malignant mesothelioma (MM) is a fatal disease in dire need of therapy. The role of inflammasomes in cancer is not very well studied, however, literature supports both pro-and anti-tumorigenic effects of inflammasomes on cancer depending upon the type of cancer. Asbestos is a causative agent for MM and we have shown before that it causes inflammasome priming and activation in mesothelial cells. MM tumor cells/tissues showed decreased levels of inflammasome components like NLRP3 and caspase-1 as compared to human mesothelial cells or normal tissue counterpart of tumor. Based on our preliminary findings we hypothesized that treatment of MMs with chemotherapeutic drugs may elevate the levels of NLRP3 and caspase-1 resulting in increased cell death by pyroptosis while increasing the levels of IL-1β and other pro-inflammatory molecules. Therefore, a combined strategy of chemotherapeutic drug and IL-1R antagonist may play a beneficial role in MM therapy. To test our hypothesis we used two human MM tumor cell lines (Hmeso, H2373) and two chemotherapeutic drugs (doxorubicin, cisplatin). Through a series of experiments we showed that both chemotherapeutic drugs caused increases in NLRP3 levels, caspase-1 activation, pyroptosis and pro-inflammatory molecules released from MM cells. In vivo studies using SCID mice and Hmeso cells showed that tumors were smaller in combined treatment group of cisplatin and IL-1R antagonist (Anakinra) as compared to cisplatin alone or untreated control groups. Taken together our study suggests that chemotherapeutic drugs in combination with IL-1R antagonist may have a beneficial role in MM treatment.

11 Article Disabling Mitochondrial Peroxide Metabolism via Combinatorial Targeting of Peroxiredoxin 3 as an Effective Therapeutic Approach for Malignant Mesothelioma. 2015

Cunniff, Brian / Newick, Kheng / Nelson, Kimberly J / Wozniak, Alexandra N / Beuschel, Stacie / Leavitt, Bruce / Bhave, Anant / Butnor, Kelly / Koenig, Andreas / Chouchani, Edward T / James, Andrew M / Haynes, Alexina C / Lowther, W Todd / Murphy, Michael P / Shukla, Arti / Heintz, Nicholas H. ·University of Vermont, College of Medicine, Department of Pathology, 149 Beaumont Ave, Burlington, VT, 05405, United States of America. · University of Pennsylvania School of Medicine, Division of Pulmonary, Thoracic Oncology Research Laboratory, Philadelphia, PA, 19147, United States of America. · Wake Forest School of Medicine, Department of Biochemistry, Medical Center Boulevard, Winston-Salem, NC, 27157, United States of America. · University of Vermont, College of Medicine, Department of Surgery, 149 Beaumont Ave, Burlington, VT, 05405, United States of America. · University of Vermont, College of Medicine, Department of Radiology, 149 Beaumont Ave, Burlington, VT, 05405, United States of America. · University of Vermont, Department of Immunology medicine, 149 Beaumont Ave, Burlington, VT, 05405, United States of America. · Medical Research Council, Mitochondrial Biology Unit, Hills Road, Cambridge, CB2 0XY, United Kingdom; Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, United Kingdom. · Medical Research Council, Mitochondrial Biology Unit, Hills Road, Cambridge, CB2 0XY, United Kingdom. ·PLoS One · Pubmed #26011724.

ABSTRACT: Dysregulation of signaling pathways and energy metabolism in cancer cells enhances production of mitochondrial hydrogen peroxide that supports tumorigenesis through multiple mechanisms. To counteract the adverse effects of mitochondrial peroxide many solid tumor types up-regulate the mitochondrial thioredoxin reductase 2--thioredoxin 2 (TRX2)--peroxiredoxin 3 (PRX3) antioxidant network. Using malignant mesothelioma cells as a model, we show that thiostrepton (TS) irreversibly disables PRX3 via covalent crosslinking of peroxidatic and resolving cysteine residues in homodimers, and that targeting the oxidoreductase TRX2 with the triphenylmethane gentian violet (GV) potentiates adduction by increasing levels of disulfide-bonded PRX3 dimers. Due to the fact that activity of the PRX3 catalytic cycle dictates the rate of adduction by TS, immortalized and primary human mesothelial cells are significantly less sensitive to both compounds. Moreover, stable knockdown of PRX3 reduces mesothelioma cell proliferation and sensitivity to TS. Expression of catalase in shPRX3 mesothelioma cells restores defects in cell proliferation but not sensitivity to TS. In a SCID mouse xenograft model of human mesothelioma, administration of TS and GV together reduced tumor burden more effectively than either agent alone. Because increased production of mitochondrial hydrogen peroxide is a common phenotype of malignant cells, and TS and GV are well tolerated in mammals, we propose that targeting PRX3 is a feasible redox-dependent strategy for managing mesothelioma and other intractable human malignancies.

12 Article Differential Susceptibility of Human Pleural and Peritoneal Mesothelial Cells to Asbestos Exposure. 2015

Dragon, Julie / Thompson, Joyce / MacPherson, Maximilian / Shukla, Arti. ·Department of Microbiology and Molecular Genetics, College of Medicine, University of Vermont, Burlington, Vermont, 05405. · Department of Pathology and Laboratory Medicine, College of Medicine, University of Vermont, Burlington, Vermont, 05405. ·J Cell Biochem · Pubmed #25757056.

ABSTRACT: Malignant mesothelioma (MM) is an aggressive cancer of mesothelial cells of pleural and peritoneal cavities. In 85% of cases both pleural and peritoneal MM is caused by asbestos exposure. Although both are asbestos-induced cancers, the incidence of pleural MM is significantly higher (85%) than peritoneal MM (15%). It has been proposed that carcinogenesis is a result of asbestos-induced inflammation but it is not clear what contributes to the differences observed between incidences of these two cancers. We hypothesize that the observed differences in incidences of pleural and peritoneal MM are the result of differences in the direct response of these cell types to asbestos rather than to differences mediated by the in vivo microenvironment. To test this hypothesis we characterized cellular responses to asbestos in a controlled environment. We found significantly greater changes in genome-wide expression in response to asbestos exposure in pleural mesothelial cells as compared to peritoneal mesothelial cells. In particular, a greater response in many common genes (IL-8, ATF3, CXCL2, CXCL3, IL-6, GOS2) was seen in pleural mesothelial cells as compared to peritoneal mesothelial cells. Unique genes expressed in pleural mesothelial cells were mainly pro-inflammatory (G-CSF, IL-1β, IL-1α, GREM1) and have previously been shown to be involved in development of MM. Our results are consistent with the hypothesis that differences in incidences of pleural and peritoneal MM upon exposure to asbestos are the result of differences in mesothelial cell physiology that lead to differences in the inflammatory response, which leads to cancer.

13 Article Antitumor effects of TRAIL-expressing mesenchymal stromal cells in a mouse xenograft model of human mesothelioma. 2015

Lathrop, M J / Sage, E K / Macura, S L / Brooks, E M / Cruz, F / Bonenfant, N R / Sokocevic, D / MacPherson, M B / Beuschel, S L / Dunaway, C W / Shukla, A / Janes, S M / Steele, C / Mossman, B T / Weiss, D J. ·Department of Medicine/Pulmonary, University of Vermont, Burlington, VT, USA. · Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK. · Department of Pathology, University of Vermont, Burlington, VT, USA. · 1] Department of Medicine/Pulmonary, University of Vermont, Burlington, VT, USA [2] Institute of Biophysics Carlos Chagas Filho, Federal, University of Rio de Janeiro, Rio de Janeiro, Brazil. · Department of Medicine, School of Medicine University of Alabama at Birmingham, Birmingham, AL , USA. ·Cancer Gene Ther · Pubmed #25525034.

ABSTRACT: Malignant mesothelioma (MM) remains a highly deadly malignancy with poor treatment option. The MM cells further promote a highly inflammatory microenvironment, which contributes to tumor initiation, development, severity and propagation. We reasoned that the anti-inflammatory actions of mesenchymal stromal cells (MSCs) and further antitumor effects of MSCs engineered to overexpress tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein (MSC-TRAIL) would effectively inhibit mesothelioma growth. Using a mouse xenograft model of intraperitoneal human mesothelioma, native mouse (mMSCs) or human (hMSC) MSCs were administered either systemically (intravenously or intraperitoneally) at various times following tumor inoculation. Both mMSCs and hMSCs localized at the sites of MM tumor growth in vivo and decreased local inflammation. Further, a trend towards decrease in tumor burden was observed. Parallel studies of in vitro exposure of nine primary human mesothelioma cell lines to mMSCs or hMSCs demonstrated reduced tumor cell migration. MSC-TRAIL exposure induced apoptosis of TRAIL-sensitive MM cells in vitro, and both mouse and human MSC-TRAIL significantly reduced the inflammatory tumor environment in vivo. Moreover, human MSC-TRAIL administration significantly reduced peritoneal tumor burden in vivo and increased tumor cell apoptosis. These proof-of-concept studies suggest that TRAIL-expressing MSCs may be useful against malignant mesothelioma.

14 Article Inhibition of mesothelioma cancer stem-like cells with adenovirus-mediated NK4 gene therapy. 2015

Deng, Xu-Bin / Xiao, Li / Wu, Yue / Jin, Fang / Mossman, Brooke / Testa, Joseph R / Xiao, Guang-Hui. ·Cancer Institute, Southern Medical University, Guangzhou, China. · Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA. · Department of Pathology, University of Vermont College of Medicine, Burlington, VT. ·Int J Cancer · Pubmed #25501304.

ABSTRACT: Malignant mesothelioma (MM) is a highly invasive and chemoresistant malignancy induced by asbestos fibers. NK4, a hepatocyte growth factor antagonist and angiogenesis inhibitor, consists of the N-terminal hairpin domain and four kringle domains of the α-chain of hepatocyte growth factor. The therapeutic potential of NK4 has been demonstrated in a variety of tumor types. However, the mechanisms by which NK4 inhibits tumor growth have not been well delineated. In this study, it is shown that the NK4 adenovirus (Ad-NK4) potently inhibits cell viability, invasiveness and tumorigenicity of human MM cells. Significantly, this study demonstrates for the first time that Ad-NK4 inhibits cancer stem-like cell (CSC) properties as assessed by spheroid formation assay, side population analysis and flow cytometric sorting of CD24 cells. In addition to inhibiting phosphorylation of Met and AKT, Ad-NK4 markedly suppressed the active form of β-catenin, a key mediator of both Wnt and AKT pathways. It is further demonstrated that expression of NK4 suppresses β-catenin nuclear localization and transcriptional activity. Intriguingly, the expression levels of Oct4 and Myc, two critical stem cell factors and downstream targets of β-catenin, were also diminished by Ad-NK4. Furthermore, the strong antitumor effect of NK4 was found to be linked to its ability to inhibit CSCs as revealed by immunohistochemical examination of tumor specimens from a mouse xenograft model of human MM. These findings suggest that NK4 acts as a CSC inhibitor by impeding Met/AKT/β-catenin signaling and holds promise for achieving durable therapeutic responses in MM by constraining the CSC component of these aggressive tumors.

15 Article Peroxiredoxin 3 levels regulate a mitochondrial redox setpoint in malignant mesothelioma cells. 2014

Cunniff, Brian / Wozniak, Alexandra N / Sweeney, Patrick / DeCosta, Kendra / Heintz, Nicholas H. ·Department of Biochemistry, University of Utah, Salt Lake City, UT, USA. · Department of Pathology, University of Vermont, College of Medicine, 149 Beaumont Avenue, Burlington, VT 05405, USA. · Department of Pathology, University of Vermont, College of Medicine, 149 Beaumont Avenue, Burlington, VT 05405, USA. Electronic address: Nicholas.Heintz@uvm.edu. ·Redox Biol · Pubmed #25462069.

ABSTRACT: Peroxiredoxin 3 (PRX3), a typical 2-Cys peroxiredoxin located exclusively in the mitochondrial matrix, is the principal peroxidase responsible for metabolizing mitochondrial hydrogen peroxide, a byproduct of cellular respiration originating from the mitochondrial electron transport chain. Mitochondrial oxidants are produced in excess in cancer cells due to oncogenic transformation and metabolic reorganization, and signals through FOXM1 and other redox-responsive factors to support a hyper-proliferative state. Over-expression of PRX3 in cancer cells has been shown to counteract oncogene-induced senescence and support tumor cell growth and survival making PRX3 a credible therapeutic target. Using malignant mesothelioma (MM) cells stably expressing shRNAs to PRX3 we show that decreased expression of PRX3 alters mitochondrial structure, function and cell cycle kinetics. As compared to control cells, knockdown of PRX3 expression increased mitochondrial membrane potential, basal ATP production, oxygen consumption and extracellular acidification rates. shPRX3 MM cells failed to progress through the cell cycle compared to wild type controls, with increased numbers of cells in G2/M phase. Diminished PRX3 expression also induced mitochondrial hyperfusion similar to the DRP1 inhibitor mdivi-1. Cell cycle progression and changes in mitochondrial networking were rescued by transient expression of either catalase or mitochondrial-targeted catalase, indicating high levels of hydrogen peroxide contribute to perturbations in mitochondrial structure and function in shPRX3 MM cells. Our results indicate that PRX3 levels establish a redox set point that permits MM cells to thrive in response to increased levels of mROS, and that perturbing the redox status governed by PRX3 impairs proliferation by altering cell cycle-dependent dynamics between mitochondrial networking and energy metabolism.

16 Article CREB-induced inflammation is important for malignant mesothelioma growth. 2014

Westbom, Catherine M / Shukla, Anurag / MacPherson, Maximilian B / Yasewicz, Elizabeth C / Miller, Jill M / Beuschel, Stacie L / Steele, Chad / Pass, Harvey I / Vacek, Pamela M / Shukla, Arti. ·Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont. · Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama. · Langone Medical Center, NYU School of Medicine, New York, New York. · Department of Medical Biostatistics, College of Medicine, University of Vermont, Burlington, Vermont. · Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont. Electronic address: arti.shukla@uvm.edu. ·Am J Pathol · Pubmed #25111229.

ABSTRACT: Malignant mesothelioma (MM) is an aggressive tumor with no treatment regimen. Previously we have demonstrated that cyclic AMP response element binding protein (CREB) is constitutively activated in MM tumor cells and tissues and plays an important role in MM pathogenesis. To understand the role of CREB in MM tumor growth, we generated CREB-inhibited MM cell lines and performed in vitro and in vivo experiments. In vitro experiments demonstrated that CREB inhibition results in significant attenuation of proliferation and drug resistance of MM cells. CREB-silenced MM cells were then injected into severe combined immunodeficiency mice, and tumor growth in s.c. and i.p. models of MM was followed. We observed significant inhibition in MM tumor growth in both s.c. and i.p. models and the presence of a chemotherapeutic drug, doxorubicin, further inhibited MM tumor growth in the i.p. model. Peritoneal lavage fluids from CREB-inhibited tumor-bearing mice showed a significantly reduced total cell number, differential cell counts, and pro-inflammatory cytokines and chemokines (IL-6, IL-8, regulated on activation normal T cell expressed and secreted, monocyte chemotactic protein-1, and vascular endothelial growth factor). In vitro studies showed that asbestos-induced inflammasome/inflammation activation in mesothelial cells was CREB dependent, further supporting the role of CREB in inflammation-induced MM pathogenesis. In conclusion, our data demonstrate the involvement of CREB in the regulation of MM pathogenesis by regulation of inflammation.

17 Article Extracellular signal-regulated kinase 5 and cyclic AMP response element binding protein are novel pathways inhibited by vandetanib (ZD6474) and doxorubicin in mesotheliomas. 2014

Sayan, Mutlay / Shukla, Arti / MacPherson, Maximilian B / Macura, Sherrill L / Hillegass, Jedd M / Perkins, Timothy N / Thompson, Joyce K / Beuschel, Stacie L / Miller, Jill M / Mossman, Brooke T. ·Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont. ·Am J Respir Cell Mol Biol · Pubmed #24940987.

ABSTRACT: Malignant mesothelioma (MM), lung cancers, and asbestosis are hyperproliferative diseases associated with exposures to asbestos. All have a poor prognosis; thus, the need to develop novel and effective therapies is urgent. Vandetanib (Van) (ZD6474, ZACTIMA) is a tyrosine kinase inhibitor that has shown equivocal results in clinical trials for advanced non-small cell lung cancer. However, tyrosine kinase inhibitors alone have shown no significant clinical activity in phase II trials of patients with unresectable MM. Using epithelioid (HMESO) and sarcomatoid (H2373) human MM lines, the efficacy of tumor cell killing and signaling pathways modulated by Van with and without doxorubicin (Dox) was examined. Van alone reduced total cell numbers in HMESO MM and synergistically increased the toxicity of Dox in HMESO and H2373 cells. Most importantly, we identified two novel cell survival/resistance pathways, ERK5 and cyclic AMP response element binding protein (CREB), that were inhibited by Van and Dox. After silencing of either ERK5 or CREB, significant decreases in cell numbers in the Dox-resistant sarcomatoid H2373 line were observed. Results suggest that a plethora of cell signaling pathways associated with cell survival are induced by Dox but inhibited by the addition of Van in MM. Data from our study support the combined efficacy of Van and Dox as a novel approach in the treatment of MM that is further enhanced by blocking ERK5 or CREB signaling cascades.

18 Article Curcumin: a double hit on malignant mesothelioma. 2014

Miller, Jill M / Thompson, Joyce K / MacPherson, Maximilian B / Beuschel, Stacie L / Westbom, Catherine M / Sayan, Mutlay / Shukla, Arti. ·Department of Pathology, University of Vermont College of Medicine, 89 Beaumont Avenue, HSRF 216, Burlington, VT 05405-0068. arti.shukla@uvm.edu. ·Cancer Prev Res (Phila) · Pubmed #24431405.

ABSTRACT: Inflammation is a key mediator in the development of malignant mesothelioma, which has a dismal prognosis and poor therapeutic strategies. Curcumin, a naturally occurring polyphenol in turmeric, has been shown to possess anticarcinogenic properties through its anti-inflammatory effects. Inflammasomes, a component of inflammation, control the activation of caspase-1 leading to pyroptosis and processing of proinflammatory cytokines, interleukin (IL)-1β and IL-18. In the present study, we investigate the role of curcumin in pyroptotic cell death of malignant mesothelioma cells. Using in vitro models with mouse and human malignant mesothelioma cells, curcumin is shown to induce pyroptosis through activation of caspase-1 and increased release of high-mobility group box 1 (HMGB1) without processing of IL-1β and IL-18. Absence of IL-1β processing in response to curcumin-mediated caspase-1 activation is attributed to blockade of pro-IL-1β priming through inhibition of the NF-κB pathway. Furthermore, curcumin's cytotoxicity in malignant mesothelioma cells is demonstrated to be dependent on pyroptosis as inhibition of caspase-1 resulted in protection against curcumin-induced cell death. We also demonstrate that curcumin-mediated caspase-1 activation is oxidant dependent by using N-acetyl-L-cysteine (NAC) to inhibit pyroptosis. PCR array analysis using the human inflammasome template revealed that curcumin significantly downregulated levels of inflammasome-related gene expression involved in inflammation, e.g., NF-κB, toll-like receptors (TLR), and IL-1β. Our data indicate that curcumin has a double effect on malignant mesothelioma cells through induction of pyroptosis while subsequently protecting against inflammation.

19 Article Malignant mesothelioma: development to therapy. 2014

Thompson, Joyce K / Westbom, Catherine M / Shukla, Arti. ·Pathology Department, University of Vermont, College of Medicine, Burlington, Vermont. ·J Cell Biochem · Pubmed #23959774.

ABSTRACT: Malignant mesothelioma (MM) is an aggressive cancer of the mesothelium caused by asbestos. Asbestos use has been reduced but not completely stopped. In addition, natural or man-made disasters will continue to dislodge asbestos from old buildings into the atmosphere and as long as respirable asbestos is available, MM will continue to be a threat. Due to the long latency period of MM development, it would still take decades to eradicate this disease if asbestos was completely removed from our lives today. Therefore, there is a need for researchers and clinicians to work together to understand this deadly disease and find a solution for early diagnosis and treatment. This article focuses on developmental mechanisms as well as current therapies available for MM.

20 Article Microspheres targeted with a mesothelin antibody and loaded with doxorubicin reduce tumor volume of human mesotheliomas in xenografts. 2013

Macura, Sherrill L / Steinbacher, Jeremy L / Macpherson, Maximilian B / Lathrop, Melissa J / Sayan, Mutlay / Hillegass, Jedd M / Beuschel, Stacie L / Perkins, Timothy N / Spiess, Page C / van der Vliet, Albert / Butnor, Kelly J / Shukla, Arti / Wadsworth, Marilyn / Landry, Christopher C / Mossman, Brooke T. ·Department of Pathology, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405-0068, USA. brooke.mossman@uvm.edu. ·BMC Cancer · Pubmed #24024776.

ABSTRACT: BACKGROUND: Malignant mesotheliomas (MMs) are chemoresistant tumors related to exposure to asbestos fibers. The long latency period of MM (30-40 yrs) and heterogeneity of tumor presentation make MM difficult to diagnose and treat at early stages. Currently approved second-line treatments following surgical resection of MMs include a combination of cisplatin or carboplatin (delivered systemically) and pemetrexed, a folate inhibitor, with or without subsequent radiation. The systemic toxicities of these treatments emphasize the need for more effective, localized treatment regimens. METHODS: Acid-prepared mesoporous silica (APMS) microparticles were loaded with doxorubicin (DOX) and modified externally with a mesothelin (MB) specific antibody before repeated intraperitoneal (IP) injections into a mouse xenograft model of human peritoneal MM. The health/weight of mice, tumor volume/weight, tumor necrosis and cell proliferation were evaluated in tumor-bearing mice receiving saline, DOX high (0.2 mg/kg), DOX low (0.05 mg/kg), APMS-MB, or APMS-MB-DOX (0.05 mg/kg) in saline. RESULTS: Targeted therapy (APMS-MB-DOX at 0.05 mg/kg) was more effective than DOX low (0.05 mg/kg) and less toxic than treatment with DOX high (0.2 mg/kg). It also resulted in the reduction of tumor volume without loss of animal health and weight, and significantly decreased tumor cell proliferation. High pressure liquid chromatography (HPLC) of tumor tissue confirmed that APMS-MB-DOX particles delivered DOX to target tissue. CONCLUSIONS: Data suggest that targeted therapy results in greater chemotherapeutic efficacy with fewer adverse side effects than administration of DOX alone. Targeted microparticles are an attractive option for localized drug delivery.

21 Article Asbestos and erionite prime and activate the NLRP3 inflammasome that stimulates autocrine cytokine release in human mesothelial cells. 2013

Hillegass, Jedd M / Miller, Jill M / MacPherson, Maximilian B / Westbom, Catherine M / Sayan, Mutlay / Thompson, Joyce K / Macura, Sherrill L / Perkins, Timothy N / Beuschel, Stacie L / Alexeeva, Vlada / Pass, Harvey I / Steele, Chad / Mossman, Brooke T / Shukla, Arti. ·Department of Pathology, University of Vermont College of Medicine, Burlington, VT, USA. ·Part Fibre Toxicol · Pubmed #23937860.

ABSTRACT: BACKGROUND: Pleural fibrosis and malignant mesotheliomas (MM) occur after exposures to pathogenic fibers, yet the mechanisms initiating these diseases are unclear. RESULTS: We document priming and activation of the NLRP3 inflammasome in human mesothelial cells by asbestos and erionite that is causally related to release of IL-1β, IL-6, IL-8, and Vascular Endothelial Growth Factor (VEGF). Transcription and release of these proteins are inhibited in vitro using Anakinra, an IL-1 receptor antagonist that reduces these cytokines in a human peritoneal MM mouse xenograft model. CONCLUSIONS: These novel data show that asbestos-induced priming and activation of the NLRP3 inflammasome triggers an autocrine feedback loop modulated via the IL-1 receptor in mesothelial cell type targeted in pleural infection, fibrosis, and carcinogenesis.

22 Article Extracellular signal-regulated kinase 5: a potential therapeutic target for malignant mesotheliomas. 2013

Shukla, Arti / Miller, Jill M / Cason, Christopher / Sayan, Mutlay / MacPherson, Maximilian B / Beuschel, Stacie L / Hillegass, Jedd / Vacek, Pamela M / Pass, Harvey I / Mossman, Brooke T. ·Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont 05405, USA. Arti.Shukla@med.uvm.edu ·Clin Cancer Res · Pubmed #23446998.

ABSTRACT: PURPOSE: Malignant mesothelioma is a devastating disease with a need for new treatment strategies. In the present study, we showed the importance of extracellular signal-regulated kinase 5 (ERK5) in malignant mesothelioma tumor growth and treatment. EXPERIMENTAL DESIGN: ERK5 as a target for malignant mesothelioma therapy was verified using mesothelial and mesothelioma cell lines as well as by xenograft severe combined immunodeficient (SCID) mouse models. RESULTS: We first showed that crocidolite asbestos activated ERK5 in LP9 cells and mesothelioma cell lines exhibit constitutive activation of ERK5. Addition of doxorubicin resulted in further activation of ERK5 in malignant mesothelioma cells. ERK5 silencing increased doxorubicin-induced cell death and doxorubicin retention in malignant mesothelioma cells. In addition, shERK5 malignant mesothelioma lines exhibited both attenuated colony formation on soft agar and invasion of malignant mesothelioma cells in vitro that could be related to modulation of gene expression linked to cell proliferation, apoptosis, migration/invasion, and drug resistance as shown by microarray analysis. Most importantly, injection of shERK5 malignant mesothelioma cell lines into SCID mice showed significant reduction in tumor growth using both subcutaneous and intraperitoneal models. Assessment of selected human cytokine profiles in peritoneal lavage fluid from intraperitoneal shERK5 and control tumor-bearing mice showed that ERK5 was critical in regulation of various proinflammatory (RANTES/CCL5, MCP-1) and angiogenesis-related (interleukin-8, VEGF) cytokines. Finally, use of doxorubicin and cisplatin in combination with ERK5 inhibition showed further reduction in tumor weight and volume in the intraperitoneal model of tumor growth. CONCLUSION: ERK5 inhibition in combination with chemotherapeutic drugs is a beneficial strategy for combination therapy in patients with malignant mesothelioma.

23 Article Mitochondrial-targeted nitroxides disrupt mitochondrial architecture and inhibit expression of peroxiredoxin 3 and FOXM1 in malignant mesothelioma cells. 2013

Cunniff, Brian / Benson, Kira / Stumpff, Jason / Newick, Kheng / Held, Paul / Taatjes, Douglas / Joseph, Joy / Kalyanaraman, Balaraman / Heintz, Nicholas H. ·Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont 05405, USA. ·J Cell Physiol · Pubmed #23018647.

ABSTRACT: Malignant mesothelioma (MM) is an intractable tumor of the peritoneal and pleural cavities primarily linked to exposure to asbestos. Recently, we described an interplay between mitochondrial-derived oxidants and expression of FOXM1, a redox-responsive transcription factor that has emerged as a promising therapeutic target in solid malignancies. Here we have investigated the effects of nitroxides targeted to mitochondria via triphenylphosphonium (TPP) moieties on mitochondrial oxidant production, expression of FOXM1 and peroxiredoxin 3 (PRX3), and cell viability in MM cells in culture. Both Mito-carboxy-proxyl (MCP) and Mito-TEMPOL (MT) caused dose-dependent increases in mitochondrial oxidant production that was accompanied by inhibition of expression of FOXM1 and PRX3 and loss of cell viability. At equivalent concentrations TPP, CP, and TEMPOL had no effect on these endpoints. Live cell ratiometric imaging with a redox-responsive green fluorescent protein targeted to mitochondria (mito-roGFP) showed that MCP and MT, but not CP, TEMPOL, or TPP, rapidly induced mitochondrial fragmentation and swelling, morphological transitions that were associated with diminished ATP levels and increased production of mitochondrial oxidants. Mdivi-1, an inhibitor of mitochondrial fission, did not rescue mitochondria from fragmentation by MCP. Immunofluorescence microscopy experiments indicate a fraction of FOXM1 coexists in the cytoplasm with mitochondrial PRX3. Our results indicate that MCP and MT inhibit FOXM1 expression and MM tumor cell viability via perturbations in redox homeostasis caused by marked disruption of mitochondrial architecture, and suggest that both compounds, either alone or in combination with thiostrepton or other agents, may provide credible therapeutic options for the management of MM.

24 Article Peroxiredoxin 3 is a redox-dependent target of thiostrepton in malignant mesothelioma cells. 2012

Newick, Kheng / Cunniff, Brian / Preston, Kelsey / Held, Paul / Arbiser, Jack / Pass, Harvey / Mossman, Brooke / Shukla, Arti / Heintz, Nicholas. ·Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont, United States of America. ·PLoS One · Pubmed #22761781.

ABSTRACT: Thiostrepton (TS) is a thiazole antibiotic that inhibits expression of FOXM1, an oncogenic transcription factor required for cell cycle progression and resistance to oncogene-induced oxidative stress. The mechanism of action of TS is unclear and strategies that enhance TS activity will improve its therapeutic potential. Analysis of human tumor specimens showed FOXM1 is broadly expressed in malignant mesothelioma (MM), an intractable tumor associated with asbestos exposure. The mechanism of action of TS was investigated in a cell culture model of human MM. As for other tumor cell types, TS inhibited expression of FOXM1 in MM cells in a dose-dependent manner. Suppression of FOXM1 expression and coincidental activation of ERK1/2 by TS were abrogated by pre-incubation of cells with the antioxidant N-acetyl-L-cysteine (NAC), indicating its mechanism of action in MM cells is redox-dependent. Examination of the mitochondrial thioredoxin reductase 2 (TR2)-thioredoxin 2 (TRX2)-peroxiredoxin 3 (PRX3) antioxidant network revealed that TS modifies the electrophoretic mobility of PRX3. Incubation of recombinant human PRX3 with TS in vitro also resulted in PRX3 with altered electrophoretic mobility. The cellular and recombinant species of modified PRX3 were resistant to dithiothreitol and SDS and suppressed by NAC, indicating that TS covalently adducts cysteine residues in PRX3. Reduction of endogenous mitochondrial TRX2 levels by the cationic triphenylmethane gentian violet (GV) promoted modification of PRX3 by TS and significantly enhanced its cytotoxic activity. Our results indicate TS covalently adducts PRX3, thereby disabling a major mitochondrial antioxidant network that counters chronic mitochondrial oxidative stress. Redox-active compounds like GV that modify the TR2/TRX2 network may significantly enhance the efficacy of TS, thereby providing a combinatorial approach for exploiting redox-dependent perturbations in mitochondrial function as a therapeutic approach in mesothelioma.

25 Article A multifunctional mesothelin antibody-tagged microparticle targets human mesotheliomas. 2012

Macura, Sherrill L / Hillegass, Jedd M / Steinbacher, Jeremy L / MacPherson, Maximilian B / Shukla, Arti / Beuschel, Stacie L / Perkins, Timothy N / Butnor, Kelly J / Lathrop, Melissa J / Sayan, Mutlay / Hekmatyar, Khan / Taatjes, Douglas J / Kauppinen, Risto A / Landry, Christopher C / Mossman, Brooke T. ·Department of Pathology, University of Vermont College of Medicine, Burlington, VT 05405, USA. ·J Histochem Cytochem · Pubmed #22723527.

ABSTRACT: Pleural and peritoneal mesotheliomas (MMs) are chemoresistant tumors with no effective therapeutic strategies. The authors first injected multifunctional, acid-prepared mesoporous spheres (APMS), microparticles functionalized with tetraethylene glycol oligomers, intraperitoneally into rodents. Biodistribution of APMS was observed in major organs, peritoneal lavage fluid (PLF), and urine of normal mice and rats. After verification of increased mesothelin in human mesotheliomas injected into severe combined immunodeficient (SCID) mice, APMS were then functionalized with an antibody to mesothelin (APMS-MB) or bovine serum albumin (BSA), a nonspecific protein control, and tumor targeting was evaluated by inductively coupled plasma mass spectrometry and multifluorescence confocal microscopy. Some APMS were initially cleared via the urine over a 24 hr period, and small amounts were observed in liver, spleen, and kidneys at 24 hr and 6 days. Targeting with APMS-MB increased APMS uptake in mesenteric tumors at 6 days. Approximately 10% to 12% of the initially injected amount was observed in both spheroid and mesenteric MM at this time point. The data suggest that localized delivery of APMS-MB into the peritoneal cavity after encapsulation of drugs, DNA, or macromolecules is a novel therapeutic approach for MM and other tumors (ovarian and pancreatic) that overexpress mesothelin.

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