title: Mechanisms of cellular fibrosis associated with cancer regimen-related toxicities.
abstract: Fibrosis is a common, persistent and potentially debilitating complication of chemotherapy and radiation regimens used for the treatment of cancer. The molecular mechanisms underlying fibrosis have been well studied and reveal overall processes that are largely ubiquitous. However, it is important to note that although the processes are similar, they result in cellular phenotypes that are highly tissue specific. These tissue specific differences may present opportunities for therapeutic interventions to prevent or treat this often irreversible condition. Data generated from animal models of cancer therapy-related tissue toxicities have revealed that the signaling pathways involved in fibrosis are the same as those involved in the normal injury response and include the transforming growth factor β superfamily and a range of pro-inflammatory cytokines. The critical difference between normal wound healing and fibrosis development appears to be, that in fibrosis, these signaling pathways escape normal cellular regulation. As a result, an injury state is maintained and processes involved in normal healing are usurped. There are a few, if any, therapeutics that effectively prevent or treat fibrosis in patients. Consequently, cancer survivors may be chronically plagued with a variety of life-altering fibrosis-related symptoms. Uncovering the signaling pathways that drive cellular fibrosis is paramount to the development of specific therapeutics that will mitigate this potentially devastating condition.
authors.affiliation: Biomodels LLC, Watertown MA, USA.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Mancini
authors.affiliation: Biomodels LLC, Watertown MA, USA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Sonis
keywords: TGF-β; chemotherapy toxicity; fibrosis; oral mucositis; proctitis; pulmonary fibrosis; radiation dermatitis; radiation therapy
references.citation: Matrix Biol. 2000 Aug;19(4):325-32
references.pmid: 10963993
references.citation: Oncol Rep. 2011 Aug;26(2):383-8
references.pmid: 21567101
references.citation: Pharmacogenet Genomics. 2009 Feb;19(2):147-52
references.pmid: 19077679
references.citation: Acta Oncol. 2005;44(1):13-22
references.pmid: 15848902
references.citation: Histopathology. 1985 May;9(5):517-34
references.pmid: 4007790
references.citation: Am J Pathol. 2011 Feb;178(2):640-51
references.pmid: 21281796
references.citation: Wound Repair Regen. 2010 Jan-Feb;18(1):50-8
references.pmid: 20082681
references.citation: Am J Gastroenterol. 1988 Oct;83(10):1140-4
references.pmid: 3421224
references.citation: Clin Cancer Res. 2005 Sep 1;11(17):6270-9
references.pmid: 16144931
references.citation: Biochem Biophys Res Commun. 2008 Sep 19;374(2):231-6
references.pmid: 18627765
references.citation: J Support Oncol. 2007 Oct;5(9 Suppl 4):3-11
references.pmid: 18046993
references.citation: Ann Oncol. 2010 Oct;21 Suppl 7:vii252-61
references.pmid: 20943624
references.citation: PLoS One. 2013 Oct 09;8(10):e76964
references.pmid: 24130819
references.citation: Int J Radiat Oncol Biol Phys. 2005 May 1;62(1):273-8
references.pmid: 15850933
references.citation: PLoS One. 2012;7(10):e45870
references.pmid: 23056222
references.citation: Int J Radiat Oncol Biol Phys. 2006 Dec 1;66(5):1281-93
references.pmid: 17126203
references.citation: J Invest Dermatol. 2012 Mar;132(3 Pt 2):985-93
references.pmid: 22217743
references.citation: Int J Radiat Oncol Biol Phys. 2000 May 1;47(2):277-90
references.pmid: 10802350
references.citation: Radiat Res. 2002 Mar;157(3):256-65
references.pmid: 11839087
references.citation: Regen Med. 2007 Sep;2(5):785-94
references.pmid: 17907931
references.citation: Radiat Res. 2012 Nov;178(5):468-80
references.pmid: 23020094
references.citation: Nat Cell Biol. 1999 Sep;1(5):260-6
references.pmid: 10559937
references.citation: Immunol Rev. 2007 Jun;217:141-54
references.pmid: 17498057
references.citation: Front Immunol. 2012 Apr 10;3:71
references.pmid: 22566952
references.citation: Wound Repair Regen. 1995 Apr-Jun;3(2):120-31
references.pmid: 17173641
references.citation: Radiother Oncol. 2012 Dec;105(3):289-95
references.pmid: 23199655
references.citation: Nat Rev Mol Cell Biol. 2012 Oct;13(10):616-30
references.pmid: 22992590
references.citation: Radiother Oncol. 2012 Dec;105(3):350-7
references.pmid: 22954495
references.citation: Stem Cells Transl Med. 2013 Nov;2(11):916-27
references.pmid: 24068742
references.citation: Purinergic Signal. 2009 Sep;5(3):321-6
references.pmid: 19337853
references.citation: J Clin Invest. 2007 Feb;117(2):482-91
references.pmid: 17273560
references.citation: Oncologist. 2007 Jun;12(6):738-47
references.pmid: 17602063
references.citation: Biochim Biophys Acta. 2013 Oct;1833(10):2378-88
references.pmid: 23792174
references.citation: Radiother Oncol. 2007 May;83(2):156-62
references.pmid: 17493699
references.citation: Oral Oncol. 2013 Sep;49(9):932-936
references.pmid: 23891529
references.citation: Am J Surg. 1999 May;177(5):396-8
references.pmid: 10365878
references.citation: J Cell Sci. 2013 May 15;126(Pt 10):2164-75
references.pmid: 23525012
references.citation: Am J Pathol. 2003 Dec;163(6):2247-57
references.pmid: 14633599
references.citation: PLoS One. 2013 Jul 25;8(7):e70479
references.pmid: 23936211
references.citation: Int J Radiat Oncol Biol Phys. 2012 May 1;83(1):228-34
references.pmid: 22000579
references.citation: FASEB J. 2002 Jul;16(9):963-74
references.pmid: 12087057
references.citation: Nature. 1990 Mar 15;344(6263):245-7
references.pmid: 2156165
references.citation: Immunology. 2002 Apr;105(4):375-90
references.pmid: 11985658
references.citation: Histopathology. 2006 Jan;48(1):106-14
references.pmid: 16359542
references.citation: Clin Oncol (R Coll Radiol). 2007 Nov;19(9):724-9
references.pmid: 17728120
references.citation: Int J Radiat Biol. 2008 May;84(5):401-12
references.pmid: 18464069
references.citation: Fibrogenesis Tissue Repair. 2011 Feb 01;4(1):4
references.pmid: 21284856
references.citation: Oral Oncol. 2000 Jul;36(4):373-81
references.pmid: 10899677
references.citation: Am J Pathol. 2005 May;166(5):1321-32
references.pmid: 15855634
references.citation: J Support Oncol. 2007 Feb;5(2 Suppl 1):13-21
references.pmid: 17366929
references.citation: Int J Radiat Oncol Biol Phys. 1998 Aug 1;42(1):169-78
references.pmid: 9747835
references.citation: Int J Radiat Oncol Biol Phys. 2000 Jul 1;47(4):1033-42
references.pmid: 10863076
references.citation: J Med Invest. 2009;56 Suppl:258-9
references.pmid: 20224194
references.citation: J Biol Chem. 2001 Apr 6;276(14):10594-601
references.pmid: 11152469
references.citation: Int J Radiat Oncol Biol Phys. 2013 Jan 1;85(1):e7-13
references.pmid: 23040218
references.citation: PLoS One. 2013;8(1):e53628
references.pmid: 23326473
references.citation: Am J Pathol. 2002 Mar;160(3):1057-68
references.pmid: 11891202
references.citation: J Thorac Cardiovasc Surg. 2003 Aug;126(2):469-75
references.pmid: 12928646
references.citation: Support Care Cancer. 2013 Oct;21(10):2933-48
references.pmid: 23942595
references.citation: Respir Res. 2011 Jun 09;12:76
references.pmid: 21658209
references.citation: Cancer. 2008 Nov 15;113(10):2704-13
references.pmid: 18973181
references.citation: FASEB J. 2004 May;18(7):816-27
references.pmid: 15117886
references.citation: J Korean Med Sci. 2000 Dec;15(6):682-9
references.pmid: 11194195
references.citation: Fibrogenesis Tissue Repair. 2010 Jul 05;3:11
references.pmid: 20602770
references.citation: Life Sci. 2012 Aug 21;91(3-4):89-93
references.pmid: 22727792
references.citation: Int J Radiat Oncol Biol Phys. 2010 Jan 1;76(1):242-50
references.pmid: 20005457
references.citation: Radiother Oncol. 2013 Sep;108(3):469-72
references.pmid: 24094629
references.citation: Int J Radiat Oncol Biol Phys. 1997 Mar 1;37(4):907-11
references.pmid: 9128968
references.citation: Am Soc Clin Oncol Educ Book. 2013;:
references.pmid: 23714511
references.citation: Exp Lung Res. 1998 May-Jun;24(3):321-37
references.pmid: 9635254
references.citation: Int J Radiat Oncol Biol Phys. 2005 Sep 1;63(1):5-24
references.pmid: 15963660
references.citation: J Clin Oncol. 2007 Sep 1;25(25):3991-4008
references.pmid: 17577017
references.citation: Am J Respir Cell Mol Biol. 2001 May;24(5):545-55
references.pmid: 11350823
references.citation: Curr Oncol. 2010 Aug;17(4):94-112
references.pmid: 20697521
references.citation: EMBO J. 2013 Jan 23;32(2):231-44
references.pmid: 23288041
references.citation: J Vasc Surg. 2011 Jan;53(1 Suppl):15S-21S
references.pmid: 20843630
references.citation: J Exp Med. 1984 Aug 1;160(2):600-5
references.pmid: 6206183
references.citation: J Cell Sci. 2005 Oct 1;118(Pt 19):4325-6
references.pmid: 16179603
references.citation: J Biol Chem. 2003 Apr 11;278(15):13008-15
references.pmid: 12571253
references.citation: Exp Lung Res. 1995 Sep-Oct;21(5):791-808
references.pmid: 8556994
references.citation: Int J Radiat Oncol Biol Phys. 2012 Nov 1;84(3):e357-62
references.pmid: 22713836