title: New insights into understanding the mechanisms, pathogenesis, and management of malignant mesotheliomas.
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.
authors: Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont 05405-0068, USA. brooke.mossman@uvm.edu
authors: Brooke T
authors: BT
authors: Mossman
authors: Arti
authors: A
authors: Shukla
authors: Nicholas H
authors: NH
authors: Heintz
authors: Claire F
authors: CF
authors: Verschraegen
authors: Anish
authors: A
authors: Thomas
authors: Raffit
authors: R
authors: Hassan
mesh_terms: D001194:Asbestos / Q000009:adverse effects; D044127:Epigenesis, Genetic; D006801:Humans; D007167:Immunotherapy; D007249:Inflammation / Q000473:pathology; D008654:Mesothelioma / Q000175:diagnosis / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D008954:Models, Biological
chemical_list: D001194:Asbestos
references: Clin Cancer Res. 2012 Sep 1;18(17):4485-90
references: 22825583
references: J Clin Gastroenterol. 2013 Jan;47(1):e7-11
references: 22460164
references: Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16626-30
references: 18922767
references: Mol Cancer. 2006 Oct 26;5(1):50
references: 17067392
references: J Thorac Oncol. 2008 Jul;3(7):756-63
references: 18594322
references: Mol Cancer. 2009 Oct 24;8:91
references: 19852844
references: J Clin Oncol. 2007 Jun 10;25(17):2406-13
references: 17557954
references: Clin Cancer Res. 2010 Dec 1;16(23):5805-13
references: 20956618
references: J Natl Compr Canc Netw. 2012 Jan;10(1):26-41
references: 22223867
references: Am J Pathol. 2005 Jun;166(6):1827-40
references: 15920167
references: Cancer Sci. 2007 Mar;98(3):438-46
references: 17270034
references: PLoS One. 2011 Apr 19;6(4):e18828
references: 21526190
references: J Clin Oncol. 2009 Mar 20;27(9):1413-8
references: 19224855
references: J Thorac Cardiovasc Surg. 2008 Mar;135(3):620-6, 626.e1-3
references: 18329481
references: Mol Cancer. 2007 Dec 21;6:81
references: 18096084
references: Int J Cancer. 2010 Dec 15;127(12):2859-69
references: 21351265
references: Int J Radiat Oncol Biol Phys. 1999 Feb 1;43(3):511-6
references: 10078630
references: Int J Clin Exp Pathol. 2012;5(5):472-8
references: 22808303
references: Cancer Sci. 2010 Jan;101(1):1-6
references: 19793348
references: Exp Mol Pathol. 2012 Aug;93(1):154-61
references: 22504106
references: Cancer Res. 1998 Jan 15;58(2):189-94
references: 9443389
references: Ann N Y Acad Sci. 2010 Aug;1203:7-14
references: 20716277
references: Eur J Cardiothorac Surg. 2008 Mar;33(3):502-6
references: 18248818
references: Curr Treat Options Oncol. 2011 Jun;12(2):201-16
references: 21465419
references: Cancer Treat Res. 2007;134:1-19
references: 17633044
references: Cancer Res. 2009 Jan 1;69(1):227-34
references: 19118007
references: Thorax. 2000 Sep;55(9):731-5
references: 10950889
references: J Clin Oncol. 2005 Jun 10;23(17):3923-31
references: 15897550
references: Lab Invest. 2008 May;88(5):504-14
references: 18332875
references: Am J Respir Crit Care Med. 2010 Jun 15;181(12):1383-90
references: 20167848
references: Br J Ind Med. 1989 Apr;46(4):271-6
references: 2540793
references: Am J Pathol. 1998 Feb;152(2):333-40
references: 9466557
references: Clin Cancer Res. 2004 Jun 15;10(12 Pt 1):3937-42
references: 15217923
references: J Clin Oncol. 2003 Jul 15;21(14):2636-44
references: 12860938
references: J Clin Oncol. 2005 Oct 1;23(28):6881-9
references: 16192580
references: Lancet Oncol. 2011 Aug;12(8):763-72
references: 21723781
references: Clin Cancer Res. 2007 Sep 1;13(17):5144-9
references: 17785569
references: Am J Physiol Lung Cell Mol Physiol. 2003 Nov;285(5):L1018-25
references: 12909582
references: J Leukoc Biol. 2009 Nov;86(5):1065-73
references: 19741157
references: Leukemia. 2005 Aug;19(8):1318-23
references: 15920488
references: Mutat Res. 2011 Aug 16;723(2):171-6
references: 21570478
references: Clin Cancer Res. 2006 Aug 1;12(15):4695-701
references: 16899620
references: Lung Cancer. 2006 Feb;51(2):207-15
references: 16384623
references: Am J Respir Cell Mol Biol. 2009 Jul;41(1):114-23
references: 19097984
references: Arch Pathol Lab Med. 2012 Mar;136(3):262-7
references: 22372902
references: Am J Respir Cell Mol Biol. 2010 Feb;42(2):133-9
references: 20068227
references: Oncogene. 2012 Dec 6;31(49):5117-22
references: 22286761
references: Cancer Treat Rev. 2011 Nov;37(7):533-42
references: 21183281
references: PLoS One. 2012;7(6):e39404
references: 22761781
references: Mol Cancer Ther. 2005 May;4(5):835-42
references: 15897248
references: Clin Cancer Res. 2011 May 15;17(10):3431-42
references: 21220472
references: Lung Cancer. 2001 Feb-Mar;31(2-3):303-10
references: 11165411
references: J Toxicol Environ Health B Crit Rev. 2011;14(1-4):246-66
references: 21534090
references: Ann Surg Oncol. 1997 Dec;4(8):628-33
references: 9416409
references: Nat Genet. 2011 Aug 28;43(10):1022-5
references: 21874000
references: Cancer Res. 2005 Sep 15;65(18):8090-5
references: 16166281
references: Cell. 2012 May 11;149(4):780-94
references: 22579283
references: Am J Respir Cell Mol Biol. 1997 Sep;17(3):265-71
references: 9308911
references: Ann Oncol. 2009 May;20 Suppl 4:73-5
references: 19454470
references: J Thorac Oncol. 2009 Jan;4(1):97-101
references: 19096314
references: Trends Immunol. 2012 Mar;33(3):119-26
references: 22277903
references: Oncogene. 2005 Sep 8;24(40):6080-9
references: 15897870
references: Cancer Immunol Immunother. 2010 Oct;59(10):1467-79
references: 20532500
references: Mol Cell Biol. 2005 Mar;25(6):2384-94
references: 15743831
references: Hepatology. 2011 Mar;53(3):983-95
references: 21294146
references: J Thorac Oncol. 2011 Aug;6(8):1304-12
references: 21847060
references: Am J Respir Cell Mol Biol. 2000 Sep;23(3):371-8
references: 10970829
references: Lung Cancer. 2005 May;48(2):291-6
references: 15829331
references: J Thorac Oncol. 2012 Mar;7(3):587-94
references: 22307011
references: Occup Environ Med. 2000 Aug;57(8):563-7
references: 10896964
references: J Toxicol Environ Health B Crit Rev. 2011;14(1-4):179-245
references: 21534089
references: Curr Opin Pulm Med. 2007 Jul;13(4):339-443
references: 17534183
references: Ann Oncol. 2007 Jul;18(7):1196-202
references: 17429100
references: Jpn J Cancer Res. 1995 Dec;86(12):1150-8
references: 8636003
references: J Thorac Oncol. 2011 Jun;6(6):1132-41
references: 21532502
references: Oncogene. 2003 Nov 20;22(52):8524-8
references: 14627993
references: J Toxicol Environ Health B Crit Rev. 2011;14(1-4):76-121
references: 21534086
references: Ann Thorac Surg. 2007 Nov;84(5):1685-92; discussion 1692-3
references: 17954086
references: Clin Cancer Res. 2010 Dec 15;16(24):6132-8
references: 21037025
references: Int J Cancer. 2011 Sep 1;129(5):1075-86
references: 21710492
references: J Thorac Oncol. 2011 Nov;6(11):1950-4
references: 22005473
references: Clin Cancer Res. 2011 Jun 1;17(11):3697-705
references: 21521777
references: Eur Respir J. 1997 Jan;10(1):219-25
references: 9032518
references: Cancer Res. 2010 Mar 1;70(5):1916-24
references: 20160038
references: Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):10854-8
references: 7479897
references: Environ Health Perspect. 2010 Dec;118(12):1707-13
references: 20705543
references: J Thorac Cardiovasc Surg. 1999 Jan;117(1):54-63; discussion 63-5
references: 9869758
references: Am J Respir Cell Mol Biol. 2008 Nov;39(5):576-83
references: 18511708
references: Cancer Res. 1996 Dec 1;56(23):5334-8
references: 8968079
references: AJR Am J Roentgenol. 1993 Sep;161(3):533-7
references: 8394641
references: J Thorac Oncol. 2010 Oct;5(10):1692-703
references: 20802345
references: J Thorac Oncol. 2010 Feb;5(2):275-9
references: 20035240
references: J Natl Compr Canc Netw. 2012 Jan;10(1):42-7
references: 22223868
references: Cancer Res. 2009 Dec 1;69(23):9073-82
references: 19887624
references: J Clin Oncol. 2012 Jul 10;30(20):2509-15
references: 22665541
references: Int J Oncol. 2001 Feb;18(2):425-33
references: 11172613
references: Free Radic Biol Med. 2006 Sep 15;41(6):874-85
references: 16934670
references: Int J Oncol. 2010 Aug;37(2):437-44
references: 20596671
references: Part Fibre Toxicol. 2010 Mar 22;7:5
references: 20307263
references: Mol Cancer. 2010 Dec 15;9:314
references: 21159167
references: Eur Respir J. 2011 Jan;37(1):129-35
references: 20530048
references: Neoplasia. 2011 Jan;13(1):12-22
references: 21245936
references: Science. 1980 Jan 18;207(4428):311-3
references: 7350661
references: Clin Cancer Res. 2007 Dec 1;13(23):7166-71
references: 18056197
references: Br J Cancer. 2008 Jan 29;98(2):256-62
references: 17971776
references: Clin Cancer Res. 2005 Mar 15;11(6):2300-4
references: 15788680
references: Clin Cancer Res. 2011 Sep 15;17(18):5926-34
references: 21813632
references: Science. 2008 May 2;320(5876):674-7
references: 18403674
references: J Toxicol Environ Health A. 2010;73(5):423-36
references: 20155583
references: Crit Rev Toxicol. 2008;38 Suppl 1:49-73
references: 18686078
references: Mutat Res. 2000 Jun 22;468(1):87-92
references: 10863160
references: J Thorac Cardiovasc Surg. 2009 Aug;138(2):405-11
references: 19619785
references: Expert Opin Investig Drugs. 2012 Jun;21(6):833-44
references: 22519641
references: Cancer Res. 2004 Sep 15;64(18):6530-6
references: 15374964
references: Curr Opin Pulm Med. 2012 Mar;18(2):161-7
references: 22139761
references: PLoS One. 2011;6(10):e25391
references: 21984916
references: Am J Pathol. 1987 Sep;128(3):426-45
references: 2820232
references: Oncology. 2011;81(5-6):330-5
references: 22237142
references: Int J Artif Organs. 2007 Jun;30(6):527-40
references: 17628854
references: Cancer Res. 2002 Nov 1;62(21):6065-9
references: 12414630
references: J Biol Chem. 2005 Jul 8;280(27):25369-76
references: 15878867
references: Cancer Res. 1995 May 15;55(10):2085-9
references: 7743507