ID
68
Cancer Name
Pleural Mesothelioma – Lifestyle/Metabolic Focus
Main Grouping
Respiratory
Organ System
Pleura (lung lining)
Cell Origin
Mesothelial cells
Pathways Affected
Malignant pleural mesothelioma involves a pathway landscape defined by the loss of tumor suppressor function rather than oncogene activation: the Hippo/NF2/LATS1/LATS2/YAP1/TAZ tumor suppressor pathway (NF2 loss ~25-40%), the BAP1/H2Aub1/PRC2 epigenetic pathway (BAP1 loss ~40-60%), the CDKN2A/p16/CDK4/RB1 cell cycle pathway (CDKN2A deletion ~30-60%), chronic NF-kB-driven inflammation from asbestos fiber-induced NLRP3 inflammasome activation, PI3K/AKT/mTOR pathway activation, and TGF-beta/SMAD-driven fibrotic mesothelial-to-mesenchymal transition.
The NF2/Hippo/LATS1/2/YAP1/TAZ pathway is the defining tumor suppressor pathway inactivated in approximately 25 to 40 percent of MPM: NF2 encodes Merlin — a FERM-domain protein that activates the Hippo kinase cascade (MST1/2 → LATS1/2 → YAP1/TAZ phosphorylation); loss of Merlin/NF2 inactivates LATS1/2 kinases — creating nuclear accumulation of unphosphorylated YAP1 and TAZ that bind TEAD transcription factors driving expression of CTGF, CYR61, Survivin, cyclin D1, and other pro-proliferative target genes; LATS2 mutations (found in approximately 8% of MPM) directly inactivate the LATS kinase that phosphorylates YAP1 providing additional Hippo pathway loss; YAP1 nuclear accumulation in MPM correlates with poor prognosis; quercetin inhibits YAP1 in cancer cell models — relevant to the NF2/Hippo pathway inactivation defining approximately 25-40% of MPM; curcumin inhibits YAP1 transcriptional activity in cancer cell models; resveratrol activates Hippo/LATS in cancer cell models.
The BAP1/H2Aub1/PRC2/chromatin remodeling pathway is the most commonly altered pathway in MPM with BAP1 loss-of-function in approximately 40 to 60 percent of cases: BAP1 (BRCA1-associated protein 1) is the catalytic component of the Polycomb Repressive DUB (PR-DUB) complex; BAP1 removes monoubiquitin from histone H2A at lysine 119 (H2Aub1) — a chromatin mark placed by PRC1 (Polycomb Repressive Complex 1) that promotes transcriptional silencing of target genes; BAP1 loss results in global H2Aub1 hypermethylation creating aberrant Polycomb-mediated silencing of tumor suppressor genes including CDKN1A (p21), CDKN1B (p27), and DNA repair genes; BAP1 loss also impairs homologous recombination DNA repair through disruption of the BRCA1 complex interactions; BAP1 loss creates a synthetic lethality opportunity with PARP and EZH2 inhibitors; the methionine/SAM cycle is critical for BAP1-loss MPM because PRC2/EZH2 requires SAM for H3K27me3 trimethylation — EZH2 activity is relatively unopposed in BAP1-loss MPM creating increased H3K27me3 silencing; curcumin inhibits EZH2 in cancer cell models targeting the PRC2/H3K27me3 pathway derepressed by BAP1 loss; quercetin inhibits HDAC in cancer cell models.
The asbestos/NLRP3 inflammasome/NF-kB/chronic inflammation pathway is the central mechanism of asbestos fiber-induced mesothelioma carcinogenesis: asbestos fibers (both chrysotile/serpentine and amphibole/crocidolite/amosite) are phagocytosed by pleural mesothelial cells and pleural macrophages; frustrated phagocytosis of long biopersistent fibers activates the NLRP3 inflammasome complex in macrophages — releasing mature IL-1beta and IL-18 creating local pleuritis and chronic inflammation; sustained NF-kB activation in mesothelial cells exposed to asbestos-fiber-induced ROS and IL-1beta/TNF-alpha creates constitutive anti-apoptotic gene expression (Bcl-2, Bcl-XL, Survivin, XIAP) and pro-inflammatory cytokine production (IL-6, IL-8, VEGF, TGF-beta) driving progressive mesothelial transformation; the reactive oxygen species (ROS) generated by frustrated phagocytosis and iron-catalyzed Fenton reactions from asbestos-bound iron directly damage DNA creating the somatic mutations defining MPM; curcumin inhibits NF-kB through IKK-beta suppression confirmed — directly targeting the asbestos-induced NF-kB constitutive activation driving MPM survival; quercetin inhibits NF-kB and NLRP3 inflammasome in cell models targeting chronic asbestos fiber-induced inflammatory signaling; EGCG inhibits NF-kB in mesothelioma cell models.
The Nrf2/ARE antioxidant response pathway is directly relevant to MPM through asbestos-induced oxidative stress: quercetin was confirmed to upregulate Nrf2 at mRNA and protein levels in MSTO-211H and H2452 human mesothelioma cells, with nuclear Nrf2 translocation confirmed, ARE-binding activity confirmed, Nrf2 promoter-luc assay confirmed, and HO-1 (heme oxygenase-1) upregulation confirmed by RT-PCR (PMC4443283) — demonstrating that quercetin simultaneously induces apoptosis in MPM cells while activating the Nrf2/ARE antioxidant defense pathway; sulforaphane activates Nrf2/ARE in MSTO-211H human mesothelioma cells confirmed — upregulating NQO1, HO-1, and glutathione biosynthesis enzymes (confirmed in published sulforaphane mesothelioma research); cysteine/glutathione antioxidant defense addresses the chronic oxidative stress from asbestos fiber iron-catalyzed ROS generation driving MPM DNA damage.
The PI3K/AKT/mTOR pathway is active in a subset of MPM: PTEN loss, PI3K activation, and mTOR hyperactivation are documented in MPM; PI3K inhibition demonstrated preclinical anti-MPM activity; curcumin was confirmed to suppress MPM cell growth in H2373, H2452, H2461, H226 cell lines partly by stimulating apoptosis (PMC3809898) and inhibits PI3K/AKT/mTOR in mesothelioma cell models; quercetin inhibits PI3K/AKT in cancer cell models targeting PI3K activation in MPM; curcumin also demonstrated antitumor effects in vivo in the AB12 murine MPM model confirmed (PMC3809898).
Description
Malignant pleural mesothelioma (MPM) is a rare but highly aggressive primary cancer arising from the mesothelial cells lining the pleural cavities of the lungs. It represents one of the most aggressive solid tumors with a median overall survival of approximately 12 to 18 months from diagnosis for all comers, and approximately 18 to 24 months for epithelioid subtype treated with first-line therapy. In the United States, approximately 2,500 to 3,000 new cases of MPM are diagnosed annually. Globally, approximately 30,000 to 40,000 new MPM cases are diagnosed per year with increasing numbers in regions where asbestos use continues.
Asbestos fiber exposure is the dominant established etiological factor for MPM, accounting for approximately 80 percent of cases. The latency period between initial asbestos exposure and MPM diagnosis is typically 20 to 50 years — one of the longest carcinogenic latencies documented for any human cancer. Occupational exposures historically affected workers in shipbuilding, construction, mining, insulation installation, and manufacturing industries. Erionite (a naturally occurring mineral fiber), radiation exposure, and germline BAP1 mutations contribute to non-asbestos MPM cases. Male-to-female ratio is approximately 4:1 to 5:1 reflecting historical occupational exposure patterns.
The diagnosis of MPM requires histological confirmation with immunohistochemistry using multiple mesothelial markers (calretinin, WT1, CK5/6, D2-40, mesothelin) and exclusion of adenocarcinoma (CEA-, TTF-1-, claudin-4-). The 2018 IASLC/ITMIG staging system (also adopted in modified form as AJCC 8th edition for pleural mesothelioma) uses TNM classification; pleural effusion is classified as T1; invasion of ipsilateral lung, pericardium, and chest wall as T2-T3; mediastinal organ invasion as T4. Stage IV 5-year OS approaches 0 percent; stage I/II 5-year OS approximately 40 to 50 percent but less than 5 percent of patients are diagnosed at stage I.
The molecular biology of MPM is defined by tumor suppressor gene inactivation: BAP1 loss (~40-60%), NF2/Merlin loss (~25-40%), CDKN2A/p16 homozygous deletion (~30-60%), MTAP co-deletion (~70% of CDKN2A-deleted tumors), and SETD2 mutations (~10-15%). These alterations collectively inactivate the Hippo/YAP1/TAZ pathway (NF2 loss), epigenetic regulatory machinery (BAP1 loss creating H2Aub1 accumulation and PRC2 de-repression), cell cycle checkpoints (CDKN2A/p16 loss), and DNA repair pathways (BAP1 loss impairing HR). The lifestyle/metabolic focus of this template addresses the documented modifiable biochemical pathways — NF-kB chronic inflammation, oxidative stress, Nrf2 antioxidant response, PI3K/AKT/mTOR, Hippo/YAP1, and TCA cycle/TGF-beta fibrotic signaling — that contribute to mesothelial cell transformation, MPM progression, and disease trajectory modification.
Published laboratory research documents quercetin from onions inhibiting growth of malignant mesothelioma MSTO-211H and H2452 cells, inducing apoptosis, and activating Nrf2/ARE antioxidant response confirmed by MTT assay, Nrf2 mRNA and protein upregulation, nuclear Nrf2 translocation, ARE-binding assay, Nrf2 promoter-luc assay, and RT-PCR of HO-1 (PMC4443283); and curcumin from turmeric suppressing mesothelioma cell growth in H2373, H2452, H2461, and H226 MPM cell lines confirmed by MTT assay with apoptosis induction confirmed (PMC3809898).
Plant-Based Description
Whole-food plant-based dietary patterns provide phytochemicals with directly confirmed activity in human malignant pleural mesothelioma cell lines. Quercetin from onions, kale, and apples was confirmed to inhibit growth of MSTO-211H and H2452 human malignant mesothelioma cells (MTT assay), induce apoptosis, and activate Nrf2/ARE antioxidant response pathway — upregulating Nrf2 mRNA and protein, confirming nuclear Nrf2 translocation, ARE-binding activity, Nrf2 promoter activity, and HO-1 expression by RT-PCR (PMC4443283) — directly targeting Nrf2/ARE antioxidant defense against asbestos-induced ROS in MPM cells and inducing apoptosis via p53 upregulation and caspase-3/7 activation; curcumin from turmeric was confirmed to suppress growth of H2373, H2452, H2461, and H226 MPM cell lines by MTT assay with apoptosis confirmed (PMC3809898) and inhibits NF-kB, PI3K/AKT, YAP1, and EZH2 targeting multiple dominant pathways in MPM; quercetin additionally induced p53 expression and caspase-3/PARP cleavage in MSTO-211H mesothelioma cells confirmed; sulforaphane activated Nrf2/ARE in MSTO-211H human mesothelioma cells confirmed in published research; EGCG inhibits NF-kB, PI3K/AKT, and STAT3 in mesothelioma cell models; resveratrol inhibits NF-kB and activates Hippo/LATS targeting YAP1 nuclear accumulation from NF2 loss.
Plant Chemistry Detail
Quercetin from onions, kale, and apples has confirmed anti-malignant mesothelioma activity in a published study (PMC4443283) using MSTO-211H and H2452 human malignant mesothelioma cell lines. In this confirmed study: quercetin treatment inhibited cell growth in MSTO-211H and H2452 mesothelioma cells confirmed by MTT assay in a dose-dependent manner; quercetin induced apoptosis in MSTO-211H and H2452 mesothelioma cells confirmed; quercetin upregulated Nrf2 (NF-E2-related factor 2) at both mRNA and protein levels confirmed by RT-PCR and Western blot in MSTO-211H and H2452 cells; quercetin did not alter Nrf2 ubiquitination but extended the half-life of the Nrf2 protein confirmed; nuclear Nrf2 translocation confirmed by subcellular fractionation assay; Nrf2 ARE-binding activity confirmed by electrophoretic mobility shift assay (EMSA/ARE-binding assay); Nrf2 promoter-driven luciferase reporter activity confirmed; HO-1 (heme oxygenase-1 — a key Nrf2 target gene) upregulation confirmed by RT-PCR — demonstrating that quercetin activates the full Nrf2/ARE transcriptional program in MPM cells; Nrf2 siRNA knockdown experiment confirmed that Nrf2-independent apoptosis pathways also contribute to quercetin's anti-MPM activity. In a separate published study (PubMed22842769), quercetin reduced MSTO-211H mesothelioma cell viability with IC50 of 58 μM, increased sub-G1 cell population (apoptosis), suppressed Sp1 transcription factor expression at mRNA and protein levels confirmed, downregulated Sp1 target genes cyclin D1, Mcl-1, and survivin confirmed, and activated apoptotic signaling cascades through cleavage of Bid, caspase-3, and PARP and downregulation of Bcl-xL and upregulation of Bax confirmed by Western blot.
Curcumin from turmeric was confirmed to suppress growth of H2373, H2452, H2461, and H226 human MPM cell lines and AB12 murine MPM cells in vitro by MTT assay in a dose-dependent manner; curcumin induced apoptosis in MPM cell lines confirmed; curcumin demonstrated antitumor effects in the AB12 murine MPM in vivo model confirmed (PMC3809898) — providing in vivo validation of anti-MPM activity; curcumin inhibited NF-kB in mesothelioma cell models — targeting the constitutive NF-kB survival signaling driven by asbestos-induced inflammatory pathway activation; curcumin inhibits EZH2 in cancer cell models targeting PRC2/H3K27me3 pathway derepressed by BAP1 loss in approximately 40-60% of MPM; curcumin inhibits YAP1 transcriptional activity targeting the Hippo/YAP1 pathway deregulated by NF2 loss in approximately 25-40% of MPM. Sulforaphane activates Nrf2/ARE in MSTO-211H human mesothelioma cells confirmed — upregulating NQO1, HO-1, and increasing glutathione biosynthesis in MPM cells targeting the chronic oxidative stress from asbestos-fiber iron-catalyzed ROS.
Nutritional Focus
Nutritional focus in pleural mesothelioma metabolic/lifestyle research is led by quercetin from onions and kale with directly confirmed activity in human MPM cell lines: quercetin inhibiting MSTO-211H and H2452 human malignant mesothelioma cell growth confirmed by MTT assay; inducing apoptosis confirmed; activating Nrf2/ARE antioxidant response in MPM cells confirmed by Nrf2 mRNA/protein upregulation, nuclear Nrf2 translocation, ARE-binding assay, Nrf2 promoter-luc assay, and HO-1 RT-PCR (PMC4443283) — targeting asbestos-induced chronic oxidative stress that drives BAP1/NF2/CDKN2A somatic mutations in MPM; quercetin additionally inducing p53 upregulation and caspase-3/PARP cleavage in MSTO-211H mesothelioma cells (PubMed22842769); curcumin from turmeric confirmed to suppress H2373, H2452, H2461, and H226 MPM cell growth by MTT assay with apoptosis induction confirmed and in vivo anti-MPM activity confirmed in AB12 murine MPM model (PMC3809898) — targeting NF-kB constitutive activation from asbestos-induced chronic inflammation (~80% of MPM cases), EZH2/PRC2 pathway derepressed by BAP1 loss (~40-60%), and YAP1 transcriptional program from NF2/Hippo loss (~25-40%); sulforaphane from cruciferous vegetables activating Nrf2/ARE in MSTO-211H mesothelioma cells confirmed — upregulating NQO1 and HO-1 and providing cysteine-dependent glutathione defense against asbestos fiber ROS; EGCG from green tea inhibiting NF-kB, PI3K/AKT, and STAT3 in mesothelioma cell models; resveratrol inhibiting NF-kB and activating Hippo/LATS1/2 targeting YAP1 nuclear accumulation from NF2 loss; quercetin and curcumin both inhibiting IDO1 in cancer cell models targeting tryptophan-kynurenine immunosuppression in the MPM tumor microenvironment; methionine SAM-cycle providing SAM substrate for EZH2/SETD2 histone methylation reactions that are dysregulated by BAP1 and SETD2 mutations in MPM; and dietary fiber producing butyrate/SCFAs that inhibit HDAC targeting the epigenetic dysregulation from BAP1/H2Aub1/PRC2 pathway disruption in MPM.
Research Notes
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Key Foods
Turmeric,Broccoli,Kale,Spinach,Brussels Sprouts,Cauliflower,Garlic,Yellow Onion,Carrot,Tomato,Beetroot,Cabbage,Blueberry,Pomegranate,Grape,Raspberry,Strawberry,Apple,Orange,Lemon,Soybeans,Edamame,Green Lentils,Black Beans,Chickpeas,Brown Rice,Quinoa,Oats,Wild Rice,Black Rice,Walnut,Almond,Brazil Nut,Flaxseed,Pumpkin Seeds,Chia Seeds,Sesame Seeds,Hemp Seeds,Shiitake,Maitake,Lions Mane,Cremini,Portobello,Green Tea,Ginger,Black Pepper,Garlic Powder,Parsley,Rosemary,Oregano,Sweet Potato, Celery, Leek,Avocado,Artichoke,Radish,Tangerine, Red Onion
Linked Nutrients
vitamin-c,vitamin-e,vitamin-a,vitamin-b9,vitamin-b6,selenium,zinc,magnesium,calcium,potassium,iron,quercetin,curcumin,sulforaphane,egcg,resveratrol,beta-carotene,anthocyanins,beta-glucans,dietary-fiber,l-theanine
