Published on March 13, 2014
MECHANISMS OF ASBESTOS-RELATED DISEASES: IMPLICATIONS FOR EARLY DIAGNOSIS AND THERAPY Agnes B. Kane, MD, PhD Department of Pathology and Laboratory Medicine Brown University 1 1. Asbestos-Related Cancers 1. Classical and Emerging Hallmarks and Enabling Characteristics of Cancer 1. Tumor-Promoting Inflammation 1. Genomic Instability and Mutation 1. Avoiding Immune Destruction – Implications for Therapy Biomarkers for Early Diagnosis
2 History of Asbestos-Related Diseases Becklake, Am. Rev. Resp. Dis. 114:187-227, 1976 IOM (2006); IARC (2009) ASBESTOS-RELATED CANCERS
CLASSICAL HALLMARKS OF CANCER ENABLING CHARACTERISTICS Hanahan and Weinberg, Cell (2011) 3 Differential Gene Expression in Malignant Pleural Mesothelioma Røe et al. PLOS ONE (2009) Hanahan and Weinberg, Cell (2000) Sustained proliferation Resistance to apoptosis Inflammatory cytokines
INFLAMMATION IN THE TUMOR MICROENVIRONMENT “Tumors behave like wounds that fail to heal.” Harold F. Dvorak, 2007 Liguori et al. Cancers (2011) 4 Healing Wound Tumor
ASBESTOS FIBERS CAUSE PERSISTENT INFLAMMATION IN THE LUNGS AND PLEURA: NLRP3 INFLAMMASOME ACTIVATION Mossman et al. Am J Pathol (2013) 5 Incomplete or Frustrated Phagocytosis of Asbestos Fibers by Macrophages
6 ASBESTOS FIBERS AND CHRONIC INFLAMMATION Murine Models of Asbestosis Fiber Penetration into Alveolar Walls Walls J. Brain, Harvard School of Public Health Signaling Networks Linking Inflammation and Fibrosis Sabo-Attwood et al. Am J Pathol (2011)
PATHWAYS LINKING CHRONIC INFLAMMATION AND CANCER Colotta et al. (2009), Multhoff et al. (2012), Kundu and Surh, (2012) 7
TUMOR ASSOCIATED MACROPHAGES (TAM): MASTER REGULATORS OF THE TUMOR MICROENVIRONMENT Human malignant mesothelioma mesothelioma cells: cytokeratin + (pink) macrophages: CD68+ (brown) Kim et al. Am J Respir Cell Mol Biol (2005) Rogers and Holen, J Translational Medicine (2011) 8 TAMs contribute to cancer hallmarks: sustained tumor growth angiogenesis invasion and metastasis
TUMOR MICROENVIRONMENT OF MURINE MESOTHELIOMA Miselis et al. Cancer Microenvironment (2011) Tumor-Associated Macrophages (F4/80) MDSCs (CB11b & GR-1) Regulatory T cells (CD4 & CD25) Cytotoxic T cells (CD3 & CD8) 9 MDSC: myeloid-derived suppressor cell Overall, the tumor microenvironment is immunosuppressive – an emerging hallmark of cancer
GENE EXPRESSION PROFILES OF MURINE AND HUMAN MESOTHELIOMAS ↑CCL2 (MCP-1) chemokine expression – inflammatory mediator ↑soluble mesothelin-related peptide (SMRP) ↓galectin-3 (LGALS3) expression Mohr et al. Biochim Biophys Acta (2004) Miselis et al. Cancer Microenvironment (2011) 10 Pleural Fluid Biomarkers for Early Diagnosis SMRP –membrane-anchored glycoprotein soluble serum protein biomarker limited sensitivity for diagnosis of mesothelioma Gueugnon et al. Am J Pathol (2011) Blanquart et al. J. Thorac Oncology (2012) Mesothelin expression in malignant pleural mesothelioma
TUMOR-ASSOCIATED INFLAMMATION AS A THERAPEUTIC TARGET Coussens et al. Science (2013) 1. Deplete or reprogram tumor-associated macrophages Miselis et al. Mol Cancer Ther (2008); Rogers and Holen (2011) 11 Antiviral, antibacterial M1 polarization Tumor resistance Immunosuppressive M2 polarization Tumor promotion Macrophage Depletion Reduces Murine Mesothelioma Tumor Burden Liposome-encapsulated clodronateLiposome-encapsulated PBS Tumor Burden
2. Inhibit or sequester inflammatory mediators arachidonic acid metabolites (COX-2 inhibitors) inhibit inflammasome – IL1-RA (Anakinra), IL-18BP cytokine blockade – IL-6 antibody, TNF-α blockers, CCL2 antagonists inhibit signaling pathways – NF-ΚB, STAT3, JAK2 inhibitors TUMOR-ASSOCIATED INFLAMMATION AS A THERAPEUTIC TARGET Coussens et al. Science (2013) 3. Harness host cytotoxic T Cells Cornelissen et al. Clin Dev Immunol (2012) 12
INFLAMMATION, DNA DAMAGE, AND GENOMIC INSTABILITY Colotta et al. Carcinogenesis (2009), Grivennikov et al. Cell (2010), Aivaliotis et al. J Biomed Biotechnol (2012), Dizdaroglu, Cancer Letts (2012) 13 RONS – reactive oxygen and nitrogen species
14 DNA DAMAGE AND GENOMIC INSTABILITY McKinnon, Nature Rev Neuro (2009) DNA strand breaks, oxidized bases dysregulated DNA repair mutations defective cell cycle checkpoints, dysregulated homologous recombination chromosomal instability
ASBESTOS FIBERS AND DNA DAMAGE Nagai and Toyokuni, Arch Biochem Biophys (2010) 15 multipolar mitoses multinucleated cells Human lung epithelial cells exposed to asbestos in vitro: induction of aneuploidy
16 GLOBAL SEQUENCING OF MESOTHELIOMA GENOME REVEALS ANEUPLOIDY AND COMPLEX CHROMOSOMAL REARRANGEMENTS Bueno et al. PLOS One (2010) LOH/homozygous deletion 9p21.3 p16/CDKN2A Copy number alterations 9q33.1 DBC1 deletion Allelic imbalance 19p13 KEAP1 loss LOH 3p14 FHIT loss MOLECULAR ALTERATIONS IN ASBESTOS-RELATED LUNG CANCER Andujar et al. (2010) Nymark et al. (2009) Ruosaari et al. (2008) Pylkkänen et al. (2002) Normal Lung DNA
OXIDATIVE DNA DAMAGE AND EPIGENETIC CHANGES 17 O’Hagan et al. Cancer Cell (2011) ROS DNA breaks oxidized guanine recruitment of gene silencing complex to sites of oxidative damage: DNA damage proteins (γ-H2AX, SIRT1) DNA methylating enzymes (DNMT1, DNMT3B) methylation of CpG promoter islands epigenetic gene silencing “epigenetic therapy” – DNA demethylating agents
18 METHYLATION PROFILES OF PLEURAL MESOTHELIOMA Christensen et al. Cancer Res (2009) Methylation profiles discriminate between mesothelioma and nontumor pleura Methylation classes are associated with lung tissue asbestos body burden Pleural mesothelioma and lung adenocarcinomas have distinct methylation profiles
PLEURAL FLUID CYTOLOGICAL MARKERS FOR MESOTHELIOMA Matsumoto et al. Cancer Cytopathol (2013) Homozygous Deletion of 9p21 Gene Locus: p16/CDKN2A tumor suppressor gene FISH Cytology arrows – 9p21 deletion in mesothelioma cells arrowheads – normal lymphocytes (red signal) cell-in-cell engulfment multinucleation multicellular clusters 19
GENOMIC INSTABILITY AND CANCER PROGRESSION 20 Kidane et al. Crit Rev Biochem Mol Biol (2014) NF-ΚB activation at the crossroads of inflammation and DNA repair miR – 21 IL10 expression (anti-inflammatory) miR – 210 inhibits RAD52 miR – 155 inhibits mismatch repair NF-ΚB is a master regulator of inflammation: increased expression of cytokines NF-ΚB is also induced by ROS and DNA damage increased expression of microRNAs inhibits expression of DNA repair proteins
MicroRNA (miRNA) Expression Profiles in Asbestos-Related Lung Cancer Nymark et al. Genes, Chromosomes & Cancer (2011) 21 Downregulated Target Genes GADD45A DNA repair TXNRD1 oxidative stress KDM4B histone demethylation Upregulated Target Genes PTGS2 (COX2) inflammation Differential expression of miRNAs in asbestos-related lung cancers Increased expression of miRNAs downregulates target genes and inhibits protein expression
22 SUMMARY 1. Asbestos fibers trigger chronic inflammation that enables tumor development 2. Asbestos fibers directly and indirectly generate ROS leading to genomic instability and mutation 3. The tumor microenvironment is immunosuppressive allowing evasion of host immune attack 4. Combination therapies that target chronic inflammation and harness the host immune response, in addition to cytotoxic agents, may be more effective against asbestos-related cancers Research funding provided by the National Institute of Environmental Health Sciences Additional information – Broaddus VC, Everitt JI, Black B, Kane AB: Non-neoplastic and neoplastic pleural endpoints following fiber exposure. J Toxicol Environ Health, Part B 14: 153-178 (2011) Hanahan and Weinberg Cell (2011)
23 FUTURE DIRECTIONS FOR EARLY DIAGNOSIS AND THERAPY 1. MicroRNA profiles in peripheral blood cells or plasma 2. Proteomics for identification of new serum protein biomarkers 3. Multifunctional diagnostic and therapeutic probes: THERANOSTIC NANOPARTICLES Nanoparticle Drug Applications gold doxorubicin diagnosis, PTT iron oxide doxorubicin, targeting, docetaxel MRI, therapy silica doxorubicin imaging, PTT quantum doxorubicin, imaging, dots methotrexate therapyAhmed et al. Drug Discovery Today (2012) PTT = laser photothermal therapy
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Chair. Agnes B. Kane, MD, PhD, Chair of Pathology and Laboratory Medicine, Professor of Medical Science Agnes_Kane@Brown.Edu Box: Box G-E5 Phone: 401-863-1110