Molecular Pathways: Targeting Mechanisms of Asbestos and ... · cytokines and mutagenic ROS (32)....

Molecular Pathways

Molecular Pathways: Targeting Mechanisms of Asbestosand Erionite Carcinogenesis in Mesothelioma

Michele Carbone1,2 and Haining Yang1,2

AbstractMalignant 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 trans-

formation and tumor progression. HGF and c-Met are highly expressed in mesotheliomas. Phosphoi-

nositide 3-kinase, AKT, and the downstreammTOR 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, which in turn may activate Nalp3 inflammasome, 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-kB activity,

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

"Asbestos" is a nonspecific term that refers to 6 fibroussilicateminerals that are used commercially and are dividedinto 2 groups, serpentine and amphibole, based on theirchemical composition and crystalline structures (1).Among the serpentine minerals, only chrysotile is usedcommercially. Chrysotile is a hydrated magnesium silicate,and its stoichiometric chemical composition may be givenas Mg3Si2O5(OH)4. Worldwide, more than 95% of theasbestos used commercially is chrysotile (1). The chemicalcomposition of asbestos minerals in the amphibole groupcan varywidely. The commercially used asbestiform amphi-boles are actinolite, tremolite, anthophyllite, amosite, andcrocidolite. These minerals are all hydrated silicates andhave double tetrahedral chains of Si8O22 composition that

extend along the c-axis. Amphiboles are distinguished fromeach other by the number of the cations (calcium, iron,magnesium, and sodium) they contain (1). Thus, "asbes-tos" is a commercial rather than a scientific term. Approx-imately 396 fibrous minerals are found in nature; 390 ofthese minerals are not called asbestos, and they are notsubject to restrictive regulations because they had not beenused commercially at the time regulations to control the useof some mineral fibers were implemented. An unintendedconsequence of this very confusing nomenclature is that it isoften erroneously assumed that only asbestos, and notother mineral fibers, causes cancer. One such naturallyoccurring fibrous mineral is erionite. Although exposureto erionite is lesswidespread, it ismore potent than asbestosin causing mesothelioma (2, 3).

Exposure to asbestos and other fibrous minerals contri-butes to asbestosis and some lung cancers, and it is themaincause ofmesothelioma, ahighly aggressive cancer that arisesfrom mesothelial cells of the pleura, peritoneum, andpericardium, with a median survival of 1 year from diag-nosis (1). Currently, mesothelioma causes approximately3,000 deaths each year in the United States and an addi-tional 5,000deaths each year inwestern Europe (1).Despiteasbestos abatement efforts, mesothelioma rates have notsignificantly changed in the United States since 1994, and

Authors' Affiliations: 1University of Hawaii Cancer Center and 2Depart-ment of Pathology, John A. Burns School ofMedicine, University of Hawaii,Honolulu, Hawaii

Corresponding Author: Haining Yang, 651 Ilalo Street, BSB Rm. 231,Honolulu, HI 96813. Phone: 808-440-4588; Fax: 808-587-0790; E-mail:[email protected]

doi: 10.1158/1078-0432.CCR-11-2259

�2011 American Association for Cancer Research.

ClinicalCancer

Research

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they are estimated to increase by 5% to 10%per year inmostEuropean countries over the next 25 years (1). The contin-ueduse of asbestos in some commercial productswithin theUnited States and the difficulty of removing asbestos that isalready in place present additional risks for mesotheliomaand lung cancer that will persist into the foreseeable future.We can anticipate a dramatic increase in the incidence ofmesothelioma and other asbestos-associated malignanciesin the third world, particularly in India, where the use ofasbestos continues to increase exponentially and few, if any,precautions are taken (4).Moreover, increased urban development may disturb

outcrops of asbestos, erionite, or soil containing other typesof carcinogenic mineral fibers, leading to more instances ofexposure (1, 2, 5–9). Recent investigations uncovered expo-sure to erionite in North Dakota, where more than 300miles of roads, playgrounds, and driveways have beenpaved, mostly during the past 2 decades, with gravel con-taining erionite. More erionite exposure is suspected innearby states. The air concentrations of erionite in cars andschool buses transiting on North Dakota roads were foundto be equal to or greater than those recorded in someTurkish villages that experienced a 6.5% mortality frommesothelioma (9). A similar problem occurred in NewCaledonia, where exposure to antigorite, a type of serpen-tine mineral fiber that was used as road gravel, led to amesothelioma epidemic (6).Because the interval between initial asbestos or erionite

exposure and diagnosis ranges from �25 to 71 years(1, 9), there would be time to implement preventativetherapies within exposed cohorts, such as in North Dako-ta (where most roads were paved with erionite-containinggravel in the recent past), if we could identify the precisemechanisms of asbestos carcinogenesis and develop bio-markers of exposure and mesothelioma to monitor thepopulation at risk.

Pathogenesis of mesothelioma and mechanisms ofasbestos carcinogenesisThe observation that only a fraction (�5%) of workers

exposed to high doses of asbestos for prolonged periods oftime developed mesothelioma and the identification ofclusters of mesothelioma cases within certain families sug-gest that genetics influences mineral fiber carcinogenesis(1). Studies of an epidemic of mesothelioma in Cappado-cia, Turkey and the United States showed that the risk ofdeveloping mesothelioma is transmitted with an autoso-mal-dominant pattern in certain high-risk families (2).Germlinemutations of theBAP1 genehavenowbeen linkedto a high incidence of malignant mesothelioma in someU.S. families (10). Individuals with heterozygous BAP1germlinemutations are affected by anovel cancer syndromecharacterized by a very high risk of developing mesotheli-oma, uveal melanoma, and possibly additional cancers(10). Mesothelioma may become dominant in these fam-ilies upon exposure to asbestos or erionite (10). The iden-tification of BAP1 mutant carriers may be facilitated by thedetection of melanocytic nevi, as described by Wiesner and

colleagues (11) and confirmed by genetic testing. In addi-tion to familial cases, BAP1 somatic mutations have beenidentified in 25% of sporadic mesotheliomas (10, 12) and84% of metastasizing uveal melanomas (13), but theyappear to be relatively rare in other cancers (14, 15). BAP1is a deubiquitinating enzyme that has tumor-suppressoractivity (14, 15). BAP1 seems to regulate deubiquitinationduring the DNA damage response and the cell cycle, thusinfluencing S-phase progression, cell necrosis, and apopto-sis (14, 15). Mutations that abolish the deubiquitinatingactivity of BAP1 and/or its nuclear localization abolishBAP1 tumor-suppressor activity (15). The exact target ofBAP1 remains unclear. Ventii and colleagues (15) proposedthat expression of BAP1 induces early exit out of G1, causingan accumulation of DNA damage and cell death. Alongthese lines, we hypothesize that by influencing DNA dam-age repair, BAP1 may help prevent environmental carcino-genesis caused by asbestos/erionite or UV light. This wouldexplain the very high incidence of mesothelioma, uvealmelanoma, and melanocytic tumors (rather than other notenvironmentally related cancer types) among BAP1 germ-line mutant carriers.

DNA damage may be caused directly by mechanicalinterference of asbestos fibers with chromosome segrega-tion during mitosis (16) or, more likely, indirectly byasbestos-related induction of mesothelial cells and macro-phages to generatemutagenic reactive oxygen species (ROS)and inducible nitric oxide synthase (iNOS), both of whichare mutagenic in vitro (17, 18). The generation of oxidantsby macrophages as they attempt to digest asbestos fibersmay trigger the activation of several signaling pathways.Two such pathways, mitogen-activated protein kinase(MAPK) signaling and the resulting activator protein 1(AP-1) transcriptional activity, have been linked to meso-thelial cell transformation (19). Other minerals, such ascrystalline silica, also elicit ROS and iNOS production fromlung macrophages but do not cause mesothelioma (20).Thus, the capacity of asbestos to induce ROS and iNOS isonly one of multiple factors that contribute to asbestoscarcinogenesis.

In addition to triggering MAPK signaling, asbestos maydirectly initiate AP-1 activity through EGFR and down-stream pathways (19). Similar to EGFR signaling, activationof hepatocyte growth/scatter factor (HGF) and its receptortyrosine kinase (RTK) c-Met leads to cell proliferation andmotility. Both HGF and c-Met are highly expressed in mostmesotheliomas, especially those that are SV40-positive(21). HGF activation is mediated through the phosphati-dylinositol-3-kinase (PI3K)/MEK5/Fos-related antigen 1(Fra-1) feedback pathway (19). PI3K, AKT, and the down-stream mTOR are involved in cell growth and survival, andthey are often found to be activated in mesothelioma (22).

P16INK4a and p14ARF are frequently inactivated in meso-thelioma (23–25), and �50% of mesotheliomas containmissense or nonsense mutations in the neurofibromatosistype 2 (NF2) gene (26, 27). It was shown thatmice thatwerehomozygous null for the ARF tumor suppressor rapidlydeveloped mesothelioma upon exposure to asbestos and

Targeting Mechanisms of Asbestos Carcinogenesis

www.aacrjournals.org Clin Cancer Res; 18(3) February 1, 2012 599




that mice that were heterozygous for ARF were also suscep-tible to mesothelioma and consistently exhibited biallelicinactivation of ARF (28, 29).

Chronic inflammation and mesotheliomaInflammation is the hallmark of asbestos deposition in

tissue and contributes to asbestos carcinogenesis (1, 30, 31).The inflammatory infiltrate into tissue areas containingasbestos deposits consists largely of phagocytic macro-phages that internalize asbestos and release numerouscytokines and mutagenic ROS (32). Two such cytokines,TNF-a and interleukin (IL)-1b, have been convincinglylinked to asbestos-related carcinogenesis (31, 33). BothIL-1b and TNF-a were shown to enhance erionite fiber-induced transformation of the immortalized nontumori-genic human mesothelial cell line MeT-5A (33). Caspase-1activation promotes the secretion of IL-1b and requires theassembly of high-molecular-weight complexes known asinflammasomes (34). The Nalp3 inflammasome, the bestcharacterized of these complexes, is activated by a widevariety of stimuli, including exogenous pathogen-associat-ed molecular patterns (PAMP) and endogenous damage-associated molecular patterns [DAMP (34, 35)]. Asbestosinduces cell necrosis, causing the release of high-mobilitygroup protein B1 [HMGB1 (36)], a typical DAMP and a keymediator of inflammation (37). This, in turn, can trigger

activation of Nalp3 inflammasome and subsequent IL-1bsecretion, a process that is enhanced by asbestos-inducedproduction of ROS (38, 39). In one study, Nalp3-deficientmice exhibited decreased pulmonary pathology in responseto silica and asbestos exposure compared with wild-typecontrols (38).

In addition, upon asbestos exposure, HMGB1 is releasedby reactive macrophages and other inflammatory cells,as well as by human mesothelial cells (HMC; 36). HMGB1is a critical regulator in the initiation of asbestos-mediatedinflammation leading to the release of TNF-a and subse-quent NF-kB signaling (36). TNF-a is a central mediatorin asbestos-, silica- and bleomycin-induced models ofpulmonary fibrogenesis (40). In one study, asbestos-exposed TNF-a receptor knockout mice did not developthe fibroproliferative lesions found in asbestos-exposedwild-type mice (41). TNF-a–induced NF-kB signaling wasshown to be the critical link between inflammation andcarcinogenesis in multiple cancer models, including meso-thelioma (31). Asbestos-mediated TNF-a signaling inducesthe activation of NF-kB–dependent mechanisms, thus pro-moting the survival of HMCs after asbestos exposure (31).This allows HMCs with accumulated asbestos-inducedgenetic damage to survive, divide, and propagate geneticaberrations in premalignant cells that can give rise to amalignant clone.

© 2011 American Association for Cancer Research

Asbestos

HMC HMGB1

Necrosis

Macrophages

Inflammation

HMC survival

and transformation

HMCAsbestos

Nalp3

inflammasomeIL-1β

Pro-IL-1β

TNF-α

Caspase-1

Figure 1. Working hypothesis formesothelioma carcinogenesis.Asbestos causes necrotic HMC death,leading to the release of HMGB1 intothe extracellular space. As a typicalDAMP and a key mediator ofinflammation, HMGB can induceactivation of Nalp3 inflammasome andsubsequent IL-1b secretion, as well aseliciting macrophage accumulationand triggering the inflammatoryresponse and TNF-a secretion, whichincreases the survival of asbestos-damaged HMCs. This allows keygenetic alterations to accumulatewithin HMCs that sustain asbestos-induced DNA damage, leading to theinitiation of mesothelioma.

Carbone and Yang

Clin Cancer Res; 18(3) February 1, 2012 Clinical Cancer Research600




In healthy cells, HMGB1 is found primarily in the nucle-us, where it stabilizes chromatin and plays multiple roles inDNA transcription, replication, and recombination.Duringprogrammednecrosis, HMGB1 translocates from the nucle-us to the cytosol and the extracellular space, where it bindsseveral proinflammatory molecules and triggers the inflam-matory responses that distinguish this type of cell deathfrom apoptosis. These findings provide mechanistic linksbetween asbestos-induced cell death, chronic inflamma-tion, and mesothelioma. Secreted HMGB1 stimulatesRAGE, TLR2, and TLR4 (the 3 main HMGB1 receptors)expressed on neighboring inflammatory cells such asmacrophages and induces the release of several inflamma-tory cytokines, including TNF-a and IL-1b. In addition,HMGB1 enhances the activity of NF-kB, which promotestumor formation, progression, and metastasis (42). Aninvestigation into the targeting of extracellular HMGB1 asa novel strategy for mesothelioma prevention and/or ther-apy is currently underway (43). As illustrated in Fig. 1, wehypothesize that HMGB1 functions as a master switch thatinitiates a series of inflammatory responses leading tomalignant transformation of asbestos- or erionite-damagedHMCs.

Clinical–Translational Advances

Molecular therapiesAlthough increased expression of EGFRhas beennoted in

human mesothelioma, a phase II clinical trial of the EGFRsignaling inhibitor gefitinib yielded disappointing results(44). Because RTKs are frequently activated in mesothelio-ma, investigators tested the possible benefits of small-mol-

ecule RTK inhibitors, including erlotinib and imatinib(Fig. 2). However, the results of such studies to date havenot been promising (45, 46). The accumulation of cyto-plasmic b-catenin, a downstream component of the Wntsignaling pathway, in the majority of human mesothelio-mas indicates that Wnt signaling is abnormally activated(47). Moreover, the dishevelled proteins (also downstreamof Wnt) are often overexpressed in mesothelioma, andsiRNA knockdown of dishevelled proteins was shown tosuppress mesothelioma growth (48). These data suggestthat agents that target components of the Wnt signalingpathway could benefit mesothelioma patients. The inversecorrelation between VEGF serum levels and mesotheliomapatient survival (49) suggests that VEGF signaling contri-butes to mesothelioma. However, a phase II clinical trial ofthe humanized anti-VEGF monoclonal antibody bevacizu-mab plus erlotinib (Fig. 2) in mesothelioma patientsyielded no clinical benefits (50). PI3K, AKT, and the down-stream mTOR are often found to be activated in mesothe-lioma, and inhibition of mTOR using rapamycin enhancesthe apoptosis of mesothelioma cells in vitro (22), whichsuggests that mTORmay serve as a target for mesotheliomatherapies (Fig. 2). TheNF-kB signaling pathway is critical forthe pathogenesis of mesothelioma. Therapies aimed atinhibiting NF-kB activity, such as ranpirnase and bortezo-mib, may benefit a small subset (10%) of patients (51–53).

Molecular therapies that target aspects of tumor immunitymay also have a significant impact on the course of meso-thelioma because the altered microenvironment will affectthe ability of the immune system to mount antitumorresponses. Sterman and colleagues (54) led several clinicaltrials examining the effects of intrapleural delivery of type I

Figure 2. Potential targets and strategies formesothelioma therapy that havebeenproposedbased on recent studies. PDGFR, platelet-derived growth factor receptor.

© 2011 American Association for Cancer Research

Bevacizumab

VEGFEGFR

PI3K

AKT

mTOR

VEGF

NF-kB

PDGFR-βc-KIT

HMGB1

Infliximab

Etanercept

IL-1

Anakinra

HMG BoxA, anti-HMGB1

Anti-RAGE, anti-TLR-2, 4

Ethyl pyruvate

HMGB1

Glycyrrhizin Nalp3 inflammasome

Glyburide

TNF-αGefitinib

Rapamycin

ImatinibBortezomib

Ranpirnase

Erlotinib






IFN-encoded adenoviruses. These trials showed that highlocal concentrations of IFN-a or IFN-b were well toleratedand induced strong cellular andhumoral antitumor immuneresponses, leading to tumor cell death. Some patients withmesothelioma experienced prolonged survival.

In summary, molecular therapies have not affected theaverage survival of mesothelioma patients, although inseveral trials 5% to 10% of the patients responded andexperienced prolonged survival. Investigators in clinicaltrials normally look at averages, and therefore no significantbenefit can be detected for any therapy when the benefitoccurs in only a small fraction of patients. Thus, the chal-lenge ahead of us is to identify the subset of patients whowill respond to a given type of therapy.

Targeting asbestos-induced inflammation to preventor treat mesothelioma

Chronic inflammation has been associated with anincreased risk of developing numerous types of cancer. Inthis regard, daily treatment with aspirin for �5 years wasshown to reduce tumor burden in several common malig-nancies (55), and results from animal experiments supporta beneficial role for anti-inflammatory therapies in meso-thelioma (56). Thus, we hypothesize that prolonged aspirintreatment may help reduce the incidence of mesotheliomaand other asbestos-related malignancies among high-riskcohorts with either a lengthy history of exposure and/orgenetic predisposition.

On the basis of recent findings, it is tempting to speculatethat HMGB1 and the Nalp3 inflammasome act as criticalinitiators of chronic inflammation in asbestos- and erionite-exposed individuals, with the secretion of IL-1b and TNF-aacting as the key downstream driving force. Therefore,HMGB1, Nalp3, TNF-a, and IL-1b can all serve as potentialtargets for inhibitors of asbestos-induced inflammationleading to mesothelioma. Indeed, Hamada and colleagues(57) showed that bronchoalveolar lavage fluid frompatients with idiopathic pulmonary fibrosis exhibited ele-vated levels of HMGB1 and that treatment with an anti-HMGB1 antibody prevented bleomycin-induced lungfibrosis in mice. In addition to mesothelioma, several solidtumors, including melanoma, prostate, pancreatic, breast,and gastrointestinal cancers (42), display elevated levels ofHMGB1; therefore, therapies that seek to block HMGB1signaling would likely prove effective in other cancer typesas well as in mesothelioma.

Treatment with an IL-1 receptor antagonist can protectmice from developing fibrosis upon exposure to bleomycinor silica (58). In a murine model of bleomycin- or silica-induced pulmonary fibrosis, infusion with the humanrecombinant soluble TNF receptor rsTNFR-b was effectivenot only in preventing the development of pulmonaryfibrosis but also in the treatment of established fibrosis(40). Similar results were observedwith the use of anti-TNF-a antibodies (59). Specific U.S. Food and Drug Adminis-tration–approved reagents that inhibit these molecules areavailable. Anakinra, an IL-1 receptor antagonist, is used intherapies for patients with autoimmune diseases and gout.

Infliximab, a chimeric human–mouse anti-TNF-a, and eta-nercept, a soluble TNF receptor fusion protein, have bothbeen used to treat patients with rheumatoid arthritis andother diseases, including plaque psoriasis and ankylosingspondylitis. Glyburide, the most widely used sulfonylureadrug for type 2 diabetes in the United States, inhibits theNalp3 inflammasome (60). Specific molecules that targetthe activity of HMGB1 are anti-HMGB1 and anti-RAGEantibodies, recombinant HMG Box A, and ethyl pyruvate,an inhibitor of HMGB1 secretion (ref. 42; Fig. 2).

Early detection of mesothelioma is associated withimproved clinical outcomes (1). The finding of signifi-cantly higher serum levels of HMGB1 in asbestos-exposedindividuals compared with cohorts of smokers with his-tologically proved bronchial inflammation and dysplasia(36) suggests that HMGB1 may be a potential marker ofexposure to carcinogenic mineral fibers. Moreover, solu-ble mesothelin-related peptide (SMRP) and osteopontinwere proposed to be candidate markers for the earlydetection of mesothelioma (i.e., before the appearanceof clinical symptoms).

Conclusions

Because the latency period from initial asbestos or erio-nite exposure to disease progression is often decades long(1), novel therapies that prevent or delay carcinogenesis inexposed individuals could lead to a substantial decrease inmesothelioma mortality. In light of our recent increasedunderstanding that asbestos carcinogenesis is linked tochronic inflammation, we can design multiple strategies totarget inflammation in asbestos- and erionite-exposed indi-viduals. Clinical and translational research focusingon suchstrategies has the potential to reduce the impact of thecarcinogenic effect of asbestos and erionite exposure. More-over, genetic testing for BAP1mutations in exposed cohortsshould help us identify genetically susceptible individualswho have the highest risk of developing mesothelioma(10). These individuals couldbe targeted for early detection,for example, by monitoring HMGB1, SMRP, or other bio-markers. Strategies that seek to prevent carcinogenesis inasbestos/erionite-exposed, high-risk individuals wouldhave the most wide-reaching impact on the incidence ofthis deadly cancer.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Grant Support

National Cancer Institute (RO1CA160715-01 to H. Yang, and PO1CA-114047 to M. Carbone), University of Hawaii Foundation (M. Carbone),Mesothelioma Applied Research Foundation (H. Yang), Hawaii CommunityFoundation (H. Yang), and Riviera United-4 a CURE (H. Yang).

Received September 15, 2011; revisedOctober 18, 2011; acceptedOctober20, 2011; published OnlineFirst November 7, 2011.

Carbone and Yang





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2012;18:598-604. Published OnlineFirst November 7, 2011.Clin Cancer Res Michele Carbone and Haining Yang Erionite Carcinogenesis in MesotheliomaMolecular Pathways: Targeting Mechanisms of Asbestos and

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