title: Tumour growth stimulation following partial hepatectomy in mice is associated with increased upregulation of c-Met.
abstract: Hepatic resection is the preferred option for curative treatment of colorectal liver metastasis (CLM). However, this is associated with significant recurrence rates in both hepatic and extrahepatic sites. The upregulation of growth factors required for liver regeneration after resection is thought to stimulate the growth of micrometastases. The current study describes temporal changes in the expression of hepatocyte growth factor receptor (c-Met), epidermal growth factor receptor (EGFR) and insulin growth factor I receptor (IGF-IR) in an orthotopic mouse model of liver resection and tumour induction. Mice underwent 70% hepatectomy and induction of liver metastases through intrasplenic injection of colorectal cancer cells. Control groups included sham-operated mice and 70% hepatectomy alone. The expression levels of liver and tumour c-Met, EGFR and IGF-IR were quantified by quantitative RT-PCR at different time points. 70% liver resection stimulates tumour growth; increases the expression of c-Met within established tumours and surrounding liver parenchyma; downregulates EGFR expression and increases IGF-IR expression within the liver parenchyma. In conclusion, we demonstrate in our mouse model that major hepatectomy stimulates engraftment and growth of CLM and that this effect is probably due to the upregulation of c-Met as a result of the liver regeneration process. Liver IGF-IR may also contribute to this phenomenon through a paracrine effect on tumour growth. This study provides support for the role of c-Met in the stimulation of tumour growth after resection possibly through the promotion of tumour cell proliferation.
authors.affiliation: Department of Surgery, AH/NH Austin Hospital, University of Melbourne, Heidelberg, VIC, 3084, Australia.
authors.forename: Nadia
authors.initials: N
authors.lastname: Harun
authors.forename: Patricia
authors.initials: P
authors.lastname: Costa
authors.forename: C
authors.initials: C
authors.lastname: Christophi
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000096:biosynthesis; D006498:Hepatectomy; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000378:metabolism* / Q000556:secondary* / Q000601:surgery; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D012333:RNA, Messenger; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met
references.citation: PLoS One. 2012;7(4):e34658
references.pmid: 22511956
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4477-82
references.pmid: 15070743
references.citation: Surgery. 1998 Jul;124(1):57-64
references.pmid: 9663252
references.citation: Liver Int. 2010 Nov;30(10):1414-26
references.pmid: 20633100
references.citation: Gene. 2006 Jan 17;366(1):2-16
references.pmid: 16377102
references.citation: Cancer Chemother Pharmacol. 1992;30(1):70-2
references.pmid: 1586983
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10608-13
references.pmid: 15249655
references.citation: Hepatology. 2001 Dec;34(6):1135-48
references.pmid: 11732003
references.citation: Clin Cancer Res. 1995 Feb;1(2):147-54
references.pmid: 9815967
references.citation: HPB (Oxford). 2011 Apr;13(4):246-55
references.pmid: 21418130
references.citation: Mol Cancer Ther. 2012 Mar;11(3):649-59
references.pmid: 22188815
references.citation: Cytokine Growth Factor Rev. 2002 Feb;13(1):41-59
references.pmid: 11750879
references.citation: J Gastroenterol Hepatol. 1996 Jan;11(1):26-32
references.pmid: 8672738
references.citation: Cancer Res. 2002 Feb 15;62(4):1030-5
references.pmid: 11861378
references.citation: Cancer Cell Int. 2010 Jun 28;10:19
references.pmid: 20584290
references.citation: Comp Hepatol. 2004 Jan 14;3 Suppl 1:S52
references.pmid: 14960204
references.citation: Am J Pathol. 2002 Sep;161(3):929-38
references.pmid: 12213721
references.citation: J Invest Surg. 2004 Sep-Oct;17(5):291-4
references.pmid: 15385262
references.citation: Am J Surg. 1964 Dec;108:826-9
references.pmid: 14233766
references.citation: Cancer Res. 2002 Jun 15;62(12):3402-7
references.pmid: 12067982
references.citation: FASEB J. 2006 Apr;20(6):773-5
references.pmid: 16484330
references.citation: J Surg Res. 2007 Apr;138(2):284-90
references.pmid: 17254608
references.citation: Science. 1997 Apr 4;276(5309):60-6
references.pmid: 9082986
references.citation: Cancer Res. 2010 Jan 1;70(1):57-67
references.pmid: 20048072
references.citation: EMBO Mol Med. 2010 Aug;2(8):294-305
references.pmid: 20652897
references.citation: Gastroenterology. 2010 Jun;138(6):2163-76
references.pmid: 20420953
references.citation: Curr Pharm Des. 2012;18(20):2901-13
references.pmid: 22571659
references.citation: Ann Surg. 2009 Sep;250(3):440-8
references.pmid: 19730175
references.citation: Ann Surg. 2007 May;245(5):771-6
references.pmid: 17457170
references.citation: Am J Pathol. 2010 Jan;176(1):2-13
references.pmid: 20019184
references.citation: Cancer Res. 1986 Oct;46(10):5049-53
references.pmid: 3489520
references.citation: Nat Rev Gastroenterol Hepatol. 2013 Aug;10(8):452-62
references.pmid: 23567217
references.citation: Oncogene. 2002 Mar 14;21(12):1791-9
references.pmid: 11896611
references.citation: Ann Surg. 2011 Feb;253(2):336-41
references.pmid: 21217519
references.citation: Clin Exp Metastasis. 2007;24(1):39-48
references.pmid: 17260102
references.citation: PLoS One. 2010 Sep 16;5(9):
references.pmid: 20862286
references.citation: Gastroenterology. 2005 Feb;128(2):503-6
references.pmid: 15685562
references.citation: Med Sci Monit. 2002 Oct;8(10):CR690-6
references.pmid: 12388921
references.citation: J Gastroenterol Hepatol. 2007 Apr;22(4):577-84
references.pmid: 17376054
references.citation: Nature. 1975 Feb 27;253(5494):744-6
references.pmid: 1113868
references.citation: Surg Clin North Am. 1989 Apr;69(2):361-70
references.pmid: 2648618
references.citation: Int Arch Allergy Immunol. 1995 May-Jun;107(1-3):233-5
references.pmid: 7542074
references.citation: Ann Surg Oncol. 2006 Mar;13(3):353-62
references.pmid: 16474912
references.citation: Ther Adv Med Oncol. 2011 Nov;3(1 Suppl):S21-35
references.pmid: 22128285
references.citation: Am J Pathol. 1999 Nov;155(5):1487-98
references.pmid: 10550305
references.citation: J Clin Invest. 1995 Apr;95(4):1789-97
references.pmid: 7535799
references.citation: Mol Cell Endocrinol. 1994 May;101(1-2):85-93
references.pmid: 9397940
references.citation: Clin Exp Metastasis. 2013 Jun;30(5):681-93
references.pmid: 23385555
references.citation: Dig Liver Dis. 2006 Jul;38(7):490-7
references.pmid: 16627020
references.citation: PLoS Med. 2008 Jan 29;5(1):e19
references.pmid: 18232728
references.citation: Clin Cancer Res. 2006 Jun 15;12(12):3657-60
references.pmid: 16778093
references.citation: Anticancer Res. 2009 Nov;29(11):4807-11
references.pmid: 20032439
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17081-6
references.pmid: 17940036
references.citation: Clin Colorectal Cancer. 2010 Oct;9(4):219-23
references.pmid: 20920993
references.citation: Curr Med Chem. 2012;19(33):5735-44
references.pmid: 23033949
references.citation: Jpn J Surg. 1991 Nov;21(6):669-75
references.pmid: 1787614
references.citation: Hepatology. 1996 Aug;24(2):374-9
references.pmid: 8690407
references.citation: Cancer Res. 1999 Aug 15;59(16):3954-60
references.pmid: 10463591
references.citation: J Gastrointest Surg. 2008 May;12(5):966-80
references.pmid: 18181006
references.citation: Surgery. 2013 Feb;153(2):179-88
references.pmid: 22884252
references.citation: Hepatogastroenterology. 2010 Jan-Feb;57(97):76-80
references.pmid: 20422876