Targeting Mechanisms of Asbestos and Erionite Carcinogenesis in Mesothelioma

Published OnlineFirst November 7, 2011; DOI: 10.1158/1078-0432.CCR-11-2259

Clinical Cancer Molecular Pathways Research

Molecular Pathways: Targeting Mechanisms of Asbestos and Erionite Carcinogenesis in Mesothelioma

Michele Carbone1,2 and Haining Yang1,2

Abstract Malignant mesothelioma is an aggressive malignancy related to asbestos and erionite exposure. AP-1 transcriptional activity and the NF-kB signaling pathway have been linked to mesothelial cell transformation and tumor progression. HGF and c-Met are highly expressed in mesotheliomas. Phosphoi- nositide 3-kinase, AKT, and the downstream mTOR are involved in cell growth and survival, and they are often found to be activated in mesothelioma. p16INK4a and p14ARF are frequently inactivated in human mesothelioma, and 50% of mesotheliomas contain the NF2 mutation. Molecular therapies aimed at interfering with these pathways have not improved the dismal prognosis of mesothelioma, except possibly for a small subset of patients who benefit from certain therapies. Recent studies have shown the importance of asbestos-induced inflammation in the initiation and growth of mesothelioma, and HMGB1 and Nalp3 inflammasome have been identified as key initiators of this process. Asbestos induces cell necrosis, causing the release of HMGB1,whichinturnmayactivateNalp3inflammasome,a process that is enhanced by asbestos-induced production of reactive oxygen species. HMGB1 and Nalp3 induce proinflammatory responses and lead to interleukin-1b and TNF-a secretion and NF-kBactivity, thereby promoting cell survival and tumor growth. Novel strategies that interfere with asbestos- and erionite-mediated inflammation might prevent or delay the onset of mesothelioma in high-risk cohorts, including genetically predisposed individuals, and/or inhibit tumor growth. The very recent discovery that germline BAP1 mutations cause a new cancer syndrome characterized by mesothelioma, uveal melanoma, and melanocytic tumors provides researchers with a novel target for prevention and early detection. Clin Cancer Res; 18(3); 598–604. 2011 AACR.

Background extend along the c-axis. Amphiboles are distinguished from each other by the number of the cations (calcium, iron, "Asbestos" is a nonspecific term that refers to 6 fibrous magnesium, and sodium) they contain (1). Thus, "asbes- silicate minerals that are used commercially and are divided tos" is a commercial rather than a scientific term. Approx- into 2 groups, serpentine and amphibole, based on their imately 396 fibrous minerals are found in nature; 390 of chemical composition and crystalline structures (1). these minerals are not called asbestos, and they are not Among the serpentine minerals, only chrysotile is used subject to restrictive regulations because they had not been commercially. Chrysotile is a hydrated magnesium silicate, used commercially at the time regulations to control the use and its stoichiometric chemical composition may be given of some mineral fibers were implemented. An unintended as Mg3Si2O5(OH)4. Worldwide, more than 95% of the consequence of this very confusing nomenclature is that it is asbestos used commercially is chrysotile (1). The chemical often erroneously assumed that only asbestos, and not composition of asbestos minerals in the amphibole group other mineral fibers, causes cancer. One such naturally can vary widely. The commercially used asbestiform amphi- occurring fibrous mineral is erionite. Although exposure boles are actinolite, tremolite, anthophyllite, amosite, and to erionite is less widespread, it is more potent than asbestos crocidolite. These minerals are all hydrated silicates and in causing mesothelioma (2, 3). have double tetrahedral chains of Si8O22 composition that Exposure to asbestos and other fibrous minerals contributes to asbestosis and some lung cancers, and it is the main cause of mesothelioma, a highly aggressive cancer that arises Authors' Affiliations: 1University of Hawaii Cancer Center and 2Depart- ment of Pathology, John A. Burns School of Medicine, University of Hawaii, from mesothelial cells of the pleura, peritoneum, and Honolulu, Hawaii pericardium, with a median survival of 1 year from diag- Corresponding Author: Haining Yang, 651 Ilalo Street, BSB Rm. 231, nosis (1). Currently, mesothelioma causes approximately Honolulu, HI 96813. Phone: 808-440-4588; Fax: 808-587-0790; E-mail: 3,000 deaths each year in the United States and an addi- [email protected] tional 5,000 deaths each year in western Europe (1). Despite doi: 10.1158/1078-0432.CCR-11-2259 asbestos abatement efforts, mesothelioma rates have not 2011 American Association for Cancer Research. significantly changed in the United States since 1994, and

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they are estimated to increase by 5% to 10% per year in most colleagues (11) and confirmed by genetic testing. In addi- European countries over the next 25 years (1). The contin- tion to familial cases, BAP1 somatic mutations have been ued use of asbestos in some commercial products within the identified in 25% of sporadic mesotheliomas (10, 12) and United States and the difficulty of removing asbestos that is 84% of metastasizing uveal melanomas (13), but they already in place present additional risks for mesothelioma appear to be relatively rare in other cancers (14, 15). BAP1 and lung cancer that will persist into the foreseeable future. is a deubiquitinating enzyme that has tumor-suppressor We can anticipate a dramatic increase in the incidence of activity (14, 15). BAP1 seems to regulate deubiquitination mesothelioma and other asbestos-associated malignancies during the DNA damage response and the cell cycle, thus in the third world, particularly in India, where the use of influencing S-phase progression, cell necrosis, and apopto- asbestos continues to increase exponentially and few, if any, sis (14, 15). Mutations that abolish the deubiquitinating precautions are taken (4). activity of BAP1 and/or its nuclear localization abolish Moreover, increased urban development may disturb BAP1 tumor-suppressor activity (15). The exact target of outcrops of asbestos, erionite, or soil containing other types BAP1 remains unclear. Ventii and colleagues (15) proposed of carcinogenic mineral fibers, leading to more instances of that expression of BAP1 induces early exit out of G1, causing exposure (1, 2, 5–9). Recent investigations uncovered expo- an accumulation of DNA damage and cell death. Along sure to erionite in North Dakota, where more than 300 these lines, we hypothesize that by influencing DNA dam- miles of roads, playgrounds, and driveways have been age repair, BAP1 may help prevent environmental carcino- paved, mostly during the past 2 decades, with gravel con- genesis caused by asbestos/erionite or UV light. This would taining erionite. More erionite exposure is suspected in explain the very high incidence of mesothelioma, uveal nearby states. The air concentrations of erionite in cars and melanoma, and melanocytic tumors (rather than other not school buses transiting on North Dakota roads were found environmentally related cancer types) among BAP1 germ- to be equal to or greater than those recorded in some line mutant carriers. Turkish villages that experienced a 6.5% mortality from DNA damage may be caused directly by mechanical mesothelioma (9). A similar problem occurred in New interference of asbestos fibers with chromosome segrega- Caledonia, where exposure to antigorite, a type of serpen- tion during mitosis (16) or, more likely, indirectly by tine mineral fiber that was used as road gravel, led to a asbestos-related induction of mesothelial cells and macro- mesothelioma epidemic (6). phages to generate mutagenic reactive oxygen species (ROS) Because the interval between initial asbestos or erionite and inducible nitric oxide synthase (iNOS), both of which exposure and diagnosis ranges from 25 to 71 years are mutagenic in vitro (17, 18). The generation of oxidants (1, 9), there would be time to implement preventative by macrophages as they attempt to digest asbestos fibers therapies within exposed cohorts, such as in North Dako- may trigger the activation of several signaling pathways. ta (where most roads were paved with erionite-containing Two such pathways, mitogen-activated protein kinase gravel in the recent past), if we could identify the precise (MAPK) signaling and the resulting activator protein 1 mechanisms of asbestos carcinogenesis and develop bio- (AP-1) transcriptional activity, have been linked to meso- markers of exposure and mesothelioma to monitor the thelial cell transformation (19). Other minerals, such as population at risk. crystalline silica, also elicit ROS and iNOS production from lung macrophages but do not cause mesothelioma (20). Pathogenesis of mesothelioma and mechanisms of Thus, the capacity of asbestos to induce ROS and iNOS is asbestos carcinogenesis only one of multiple factors that contribute to asbestos The observation that only a fraction (5%) of workers carcinogenesis. exposed to high doses of asbestos for prolonged periods of In addition to triggering MAPK signaling, asbestos may time developed mesothelioma and the identification of directly initiate AP-1 activity through EGFR and down- clusters of mesothelioma cases within certain families sug- stream pathways (19). Similar to EGFR signaling, activation gest that genetics influences mineral fiber carcinogenesis of hepatocyte growth/scatter factor (HGF) and its receptor (1). Studies of an epidemic of mesothelioma in Cappado- tyrosine kinase (RTK) c-Met leads to cell proliferation and cia, Turkey and the United States showed that the risk of motility. Both HGF and c-Met are highly expressed in most developing mesothelioma is transmitted with an autoso- mesotheliomas, especially those that are SV40-positive mal-dominant pattern in certain high-risk families (2). (21). HGF activation is mediated through the phosphati- Germline mutations of the BAP1 gene have now been linked dylinositol-3-kinase (PI3K)/MEK5/Fos-related antigen 1 to a high incidence of malignant mesothelioma in some (Fra-1) feedback pathway (19). PI3K, AKT, and the down- U.S. families (10). Individuals with heterozygous BAP1 stream mTOR are involved in cell growth and survival, and germline mutations are affected by a novel cancer syndrome they are often found to be activated in mesothelioma (22). characterized by a very high risk of developing mesotheli- P16INK4a and p14ARF are frequently inactivated in meso- oma, uveal melanoma, and possibly additional cancers thelioma (23–25), and 50% of mesotheliomas contain (10). Mesothelioma may become dominant in these fam- missense or nonsense mutations in the neurofibromatosis ilies upon exposure to asbestos or erionite (10). The iden- type 2 (NF2) gene (26, 27). It was shown that mice that were tification of BAP1 mutant carriers may be facilitated by the homozygous null for the ARF tumor suppressor rapidly detection of melanocytic nevi, as described by Wiesner and developed mesothelioma upon exposure to asbestos and

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that mice that were heterozygous for ARF were also suscep- activation of Nalp3 inflammasome and subsequent IL-1b tible to mesothelioma and consistently exhibited biallelic secretion, a process that is enhanced by asbestos-induced inactivation of ARF (28, 29). production of ROS (38, 39). In one study, Nalp3-deficient mice exhibited decreased pulmonary pathology in response Chronic inflammation and mesothelioma to silica and asbestos exposure compared with wild-type Inflammation is the hallmark of asbestos deposition in controls (38). tissue and contributes to asbestos carcinogenesis (1, 30, 31). In addition, upon asbestos exposure, HMGB1 is released The inflammatory infiltrate into tissue areas containing by reactive macrophages and other inflammatory cells, asbestos deposits consists largely of phagocytic macro- as well as by human mesothelial cells (HMC; 36). HMGB1 phages that internalize asbestos and release numerous is a critical regulator in the initiation of asbestos-mediated cytokines and mutagenic ROS (32). Two such cytokines, inflammation leading to the release of TNF-a and subse- TNF-a and interleukin (IL)-1b, have been convincingly quent NF-kB signaling (36). TNF-a is a central mediator linked to asbestos-related carcinogenesis (31, 33). Both in asbestos-, silica- and bleomycin-induced models of IL-1b and TNF-a were shown to enhance erionite fiber- pulmonary fibrogenesis (40). In one study, asbestos- induced transformation of the immortalized nontumori- exposed TNF-a receptor knockout mice did not develop genic human mesothelial cell line MeT-5A (33). Caspase-1 the fibroproliferative lesions found in asbestos-exposed activation promotes the secretion of IL-1b and requires the wild-type mice (41). TNF-a–induced NF-kB signaling was assembly of high-molecular-weight complexes known as shown to be the critical link between inflammation and inflammasomes (34). The Nalp3 inflammasome, the best carcinogenesis in multiple cancer models, including meso- characterized of these complexes, is activated by a wide thelioma (31). Asbestos-mediated TNF-a signaling induces variety of stimuli, including exogenous pathogen-associat- the activation of NF-kB–dependent mechanisms, thus pro- ed molecular patterns (PAMP) and endogenous damage- moting the survival of HMCs after asbestos exposure (31). associated molecular patterns [DAMP (34, 35)]. Asbestos This allows HMCs with accumulated asbestos-induced induces cell necrosis, causing the release of high-mobility genetic damage to survive, divide, and propagate genetic group protein B1 [HMGB1 (36)], a typical DAMP and a key aberrations in premalignant cells that can give rise to a mediator of inflammation (37). This, in turn, can trigger malignant clone.

Necrosis

Asbestos

HMC HMGB1 Figure 1. Working hypothesis for mesothelioma carcinogenesis. Nalp3 Asbestos causes necrotic HMC death, inflammasome Caspase-1 β Macrophages leading to the release of HMGB1 into Pro-IL-1β IL-1 the extracellular space. As a typical DAMP and a key mediator of inflammation, HMGB can induce activation of Nalp3 inflammasome and subsequent IL-1b secretion, as well as TNF-α Inflammation eliciting macrophage accumulation and triggering the inflammatory response and TNF-a secretion, which increases the survival of asbestos- damaged HMCs. This allows key genetic alterations to accumulate within HMCs that sustain asbestos- induced DNA damage, leading to the initiation of mesothelioma.

Asbestos HMC

HMC survival and transformation

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In healthy cells, HMGB1 is found primarily in the nucle- ecule RTK inhibitors, including erlotinib and imatinib us, where it stabilizes chromatin and plays multiple roles in (Fig. 2). However, the results of such studies to date have DNA transcription, replication, and recombination. During not been promising (45, 46). The accumulation of cyto- programmed necrosis, HMGB1 translocates from the nucle- plasmic b-catenin, a downstream component of the Wnt us to the cytosol and the extracellular space, where it binds signaling pathway, in the majority of human mesothelio- several proinflammatory molecules and triggers the inflam- mas indicates that Wnt signaling is abnormally activated matory responses that distinguish this type of cell death (47). Moreover, the dishevelled proteins (also downstream from apoptosis. These findings provide mechanistic links of Wnt) are often overexpressed in mesothelioma, and between asbestos-induced cell death, chronic inflamma- siRNA knockdown of dishevelled proteins was shown to tion, and mesothelioma. Secreted HMGB1 stimulates suppress mesothelioma growth (48). These data suggest RAGE, TLR2, and TLR4 (the 3 main HMGB1 receptors) that agents that target components of the Wnt signaling expressed on neighboring inflammatory cells such as pathway could benefit mesothelioma patients. The inverse macrophages and induces the release of several inflamma- correlation between VEGF serum levels and mesothelioma tory cytokines, including TNF-a and IL-1b. In addition, patient survival (49) suggests that VEGF signaling contri- HMGB1 enhances the activity of NF-kB, which promotes butes to mesothelioma. However, a phase II clinical trial of tumor formation, progression, and metastasis (42). An the humanized anti-VEGF monoclonal antibody bevacizu- investigation into the targeting of extracellular HMGB1 as mab plus erlotinib (Fig. 2) in mesothelioma patients a novel strategy for mesothelioma prevention and/or ther- yielded no clinical benefits (50). PI3K, AKT, and the down- apy is currently underway (43). As illustrated in Fig. 1, we stream mTOR are often found to be activated in mesothe- hypothesize that HMGB1 functions as a master switch that lioma, and inhibition of mTOR using rapamycin enhances initiates a series of inflammatory responses leading to the apoptosis of mesothelioma cells in vitro (22), which malignant transformation of asbestos- or erionite-damaged suggests that mTOR may serve as a target for mesothelioma HMCs. therapies (Fig. 2). The NF-kB signaling pathway is critical for the pathogenesis of mesothelioma. Therapies aimed at Clinical–Translational Advances inhibiting NF-kB activity, such as ranpirnase and bortezomib, may benefit a small subset (10%) of patients (51–53). Molecular therapies Molecular therapies that target aspects of tumor immunity Although increased expression of EGFR has been noted in may also have a significant impact on the course of meso- human mesothelioma, a phase II clinical trial of the EGFR thelioma because the altered microenvironment will affect signaling inhibitor gefitinib yielded disappointing results the ability of the immune system to mount antitumor (44). Because RTKs are frequently activated in mesothelio- responses. Sterman and colleagues (54) led several clinical ma, investigators tested the possible benefits of small-mol- trials examining the effects of intrapleural delivery of type I

HMG BoxA, anti-HMGB1 Glyburide Anti-RAGE, anti-TLR-2, 4 Glycyrrhizin Nalp3 inflammasome Ethyl pyruvate Anakinra Bevacizumab

IL-1 Gefitinib VEGF HMGB1 Figure 2. Potential targets and strategies for EGFR TNF-α mesothelioma therapy that have been proposed Erlotinib based on recent studies. PDGFR, platelet- derived growth factor receptor. PI3K VEGF HMGB1 Etanercept AKT Infliximab NF-kB

Rapamycin mTOR

Bortezomib PDGFR-β Imatinib Ranpirnase c-KIT

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IFN-encoded adenoviruses. These trials showed that high Infliximab, a chimeric human–mouse anti-TNF-a, and eta- local concentrations of IFN-a or IFN-b were well tolerated nercept, a soluble TNF receptor fusion protein, have both and induced strong cellular and humoral antitumor immune been used to treat patients with rheumatoid arthritis and responses, leading to tumor cell death. Some patients with other diseases, including plaque psoriasis and ankylosing mesothelioma experienced prolonged survival. spondylitis. Glyburide, the most widely used sulfonylurea In summary, molecular therapies have not affected the drug for type 2 diabetes in the United States, inhibits the average survival of mesothelioma patients, although in Nalp3 inflammasome (60). Specific molecules that target several trials 5% to 10% of the patients responded and the activity of HMGB1 are anti-HMGB1 and anti-RAGE experienced prolonged survival. Investigators in clinical antibodies, recombinant HMG Box A, and ethyl pyruvate, trials normally look at averages, and therefore no significant an inhibitor of HMGB1 secretion (ref. 42; Fig. 2). benefit can be detected for any therapy when the benefit Early detection of mesothelioma is associated with occurs in only a small fraction of patients. Thus, the chal- improved clinical outcomes (1). The finding of signifi- lenge ahead of us is to identify the subset of patients who cantly higher serum levels of HMGB1 in asbestos-exposed will respond to a given type of therapy. individuals compared with cohorts of smokers with his- tologically proved bronchial inflammation and dysplasia Targeting asbestos-induced inflammation to prevent (36) suggests that HMGB1 may be a potential marker of or treat mesothelioma exposure to carcinogenic mineral fibers. Moreover, solu- Chronic inflammation has been associated with an ble mesothelin-related peptide (SMRP) and osteopontin increased risk of developing numerous types of cancer. In were proposed to be candidate markers for the early this regard, daily treatment with aspirin for 5 years was detection of mesothelioma (i.e., before the appearance shown to reduce tumor burden in several common malig- of clinical symptoms). nancies (55), and results from animal experiments support a beneficial role for anti-inflammatory therapies in mesothelioma (56). Thus, we hypothesize that prolonged aspirin Conclusions treatment may help reduce the incidence of mesothelioma and other asbestos-related malignancies among high-risk Because the latency period from initial asbestos or erio- cohorts with either a lengthy history of exposure and/or nite exposure to disease progression is often decades long genetic predisposition. (1), novel therapies that prevent or delay carcinogenesis in On the basis of recent findings, it is tempting to speculate exposed individuals could lead to a substantial decrease in that HMGB1 and the Nalp3 inflammasome act as critical mesothelioma mortality. In light of our recent increased initiators of chronic inflammation in asbestos- and erionite- understanding that asbestos carcinogenesis is linked to exposed individuals, with the secretion of IL-1b and TNF-a chronic inflammation, we can design multiple strategies to acting as the key downstream driving force. Therefore, target inflammation in asbestos- and erionite-exposed indi- HMGB1, Nalp3, TNF-a, and IL-1b can all serve as potential viduals. Clinical and translational research focusing on such targets for inhibitors of asbestos-induced inflammation strategies has the potential to reduce the impact of the leading to mesothelioma. Indeed, Hamada and colleagues carcinogenic effect of asbestos and erionite exposure. More- BAP1 (57) showed that bronchoalveolar lavage fluid from over, genetic testing for mutations in exposed cohorts patients with idiopathic pulmonary fibrosis exhibited ele- should help us identify genetically susceptible individuals vated levels of HMGB1 and that treatment with an anti- who have the highest risk of developing mesothelioma HMGB1 antibody prevented bleomycin-induced lung (10). These individuals could be targeted for early detection, fibrosis in mice. In addition to mesothelioma, several solid for example, by monitoring HMGB1, SMRP, or other bio- tumors, including melanoma, prostate, pancreatic, breast, markers. Strategies that seek to prevent carcinogenesis in and gastrointestinal cancers (42), display elevated levels of asbestos/erionite-exposed, high-risk individuals would HMGB1; therefore, therapies that seek to block HMGB1 have the most wide-reaching impact on the incidence of signaling would likely prove effective in other cancer types this deadly cancer. as well as in mesothelioma. Treatment with an IL-1 receptor antagonist can protect Disclosure of Potential Conflicts of Interest mice from developing fibrosis upon exposure to bleomycin or silica (58). In a murine model of bleomycin- or silica- No potential conflicts of interest were disclosed. induced pulmonary fibrosis, infusion with the human recombinant soluble TNF receptor rsTNFR-b was effective Grant Support not only in preventing the development of pulmonary fibrosis but also in the treatment of established fibrosis National Cancer Institute (RO1CA160715-01 to H. Yang, and PO1CA- (40). Similar results were observed with the use of anti-TNF- 114047 to M. Carbone), University of Hawaii Foundation (M. Carbone), Mesothelioma Applied Research Foundation (H. Yang), Hawaii Community a antibodies (59). Specific U.S. Food and Drug Adminis- Foundation (H. Yang), and Riviera United-4 a CURE (H. Yang). tration–approved reagents that inhibit these molecules are available. Anakinra, an IL-1 receptor antagonist, is used in Received September 15, 2011; revised October 18, 2011; accepted October therapies for patients with autoimmune diseases and gout. 20, 2011; published OnlineFirst November 7, 2011.

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604 Clin Cancer Res; 18(3) February 1, 2012 Clinical Cancer Research

Molecular Pathways: Targeting Mechanisms of Asbestos and Erionite Carcinogenesis in Mesothelioma

Michele Carbone and Haining Yang

Clin Cancer Res 2012;18:598-604. Published OnlineFirst November 7, 2011.

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