title: The effect of IGF-I receptor blockade for human esophageal squamous cell carcinoma and adenocarcinoma.
abstract: Insulin-like growth factor-I receptor (IGF-IR) signaling is required for carcinogenicity and tumor development, and this pathway has not been well studied in human esophageal carcinomas. Esophageal cancer is one of the human cancers with the worst prognosis and has two main histologies: squamous cell carcinomas (ESCC) and adenocarcinoma (EAC). Previously, we have reported that detection of the IGF axis may be useful for the prediction of recurrence and poor prognosis of ESCC. We have also shown the successful therapy for several gastrointestinal cancers using recombinant adenoviruses expressing dominant negative IGF-IR (ad-IGF-IR/dn). The aim of this study is to develop potential targeted therapeutics to IGF-IR and to assess the effect of IGF-IR blockade in both of these types of esophageal cancer. We determined immunohistochemical expression of IGF-IR in a tissue microarray. We then assessed the effect of IGF-IR blockade on signal transduction, proliferation, apoptosis, and motility. Ad-IGF-IR/dn, a tyrosine kinase inhibitor, BMS-536924, and adenovirus expressing shRNA for IGF-IR were used. IGF-IR expression was common in both tumor types but not in normal tissues. IGF-IR was detected in metastatic sites at similar levels compared to the primary site. IGF-IR inhibition suppressed proliferation and colony formation in both cancers. IGF-IR blockades up-regulated both stress- and chemotherapy-induced apoptosis and reduced migration. Although IGF-IR/dn blocked ligand-induced activation of Akt-1 mainly, BMS-536924 effectively blocked both activation of Akt and MAPK. The IGF axis might play a key role in tumor progression of esophageal carcinomas. The IGF-IR targeting strategies might thus be useful anticancer therapeutics for human esophageal malignancies.
authors.affiliation: First Department of Internal Medicine, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan, yadachi@sapmed.ac.jp.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Adachi
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Ohashi
authors.forename: Arisa
authors.initials: A
authors.lastname: Imsumran
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Matsunaga
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Taniguchi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nosho
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Arimura
authors.forename: David P
authors.initials: DP
authors.lastname: Carbone
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D000256:Adenoviridae; D063646:Carcinogenesis; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D000077277:Esophageal Squamous Cell Carcinoma; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D058990:Molecular Targeted Therapy; D011379:Prognosis; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1
references.citation: J Gastroenterol. 2010 Feb;45(2):159-70
references.pmid: 19902140
references.citation: Clin Cancer Res. 2005 Mar 1;11(5):2063-73
references.pmid: 15756033
references.citation: Carcinogenesis. 2007 May;28(5):947-56
references.pmid: 17183068
references.citation: Gastroenterology. 2002 Oct;123(4):1191-204
references.pmid: 12360481
references.citation: Cancer Cell. 2004 Mar;5(3):231-9
references.pmid: 15050915
references.citation: Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11217-21
references.pmid: 8248231
references.citation: N Engl J Med. 2003 Dec 4;349(23):2241-52
references.pmid: 14657432
references.citation: Oncogene. 2003 Sep 29;22(42):6589-97
references.pmid: 14528284
references.citation: Clin Cancer Res. 2008 Jul 15;14(14):4631-9
references.pmid: 18628478
references.citation: Clin Cancer Res. 2011 Aug 1;17(15):5048-59
references.pmid: 21642381
references.citation: Int J Cancer. 2010 Oct 15;127(8):1931-40
references.pmid: 20104520
references.citation: Int J Cancer. 1996 Nov 15;68(4):441-6
references.pmid: 8945613
references.citation: J Natl Cancer Inst. 1999 Apr 7;91(7):620-5
references.pmid: 10203281
references.citation: Clin Cancer Res. 2005 Apr 15;11(8):3065-74
references.pmid: 15837762
references.citation: J Clin Endocrinol Metab. 1988 May;66(5):1014-8
references.pmid: 3360895
references.citation: Anticancer Res. 2012 Jul;32(7):2827-34
references.pmid: 22753744
references.citation: Science. 1998 Jan 23;279(5350):563-6
references.pmid: 9438850
references.citation: Cancer Gene Ther. 2003 Jan;10(1):57-63
references.pmid: 12489029
references.citation: Mol Cancer Ther. 2008 Jun;7(6):1483-93
references.pmid: 18566219
references.citation: Cancer Res. 1996 Sep 1;56(17):4013-20
references.pmid: 8752172
references.citation: Am J Physiol. 1994 Jul;267(1 Pt 1):G105-14
references.pmid: 8048522
references.citation: Gut. 1994 Jul;35(7):941-5
references.pmid: 7794305
references.citation: J Surg Res. 1997 May;69(2):354-8
references.pmid: 9224406
references.citation: Br J Surg. 2012 Mar;99(3):387-96
references.pmid: 22241325
references.citation: Cancer Res. 2002 Nov 15;62(22):6529-37
references.pmid: 12438247
references.citation: Cell. 1994 Dec 16;79(6):927-30
references.pmid: 8001140
references.citation: Cell. 1993 Oct 8;75(1):59-72
references.pmid: 8402901
references.citation: Cancer Cell. 2004 Mar;5(3):221-30
references.pmid: 15050914
references.citation: Mol Cancer Ther. 2009 Dec;8(12):3341-9
references.pmid: 19996272
references.citation: Hum Pathol. 2003 Aug;34(8):803-8
references.pmid: 14506643
references.citation: Am J Gastroenterol. 2012 Feb;107(2):196-204
references.pmid: 22146489
references.citation: Cancer Sci. 2012 Feb;103(2):252-61
references.pmid: 22044563
references.citation: Cancer Res. 1991 Apr 1;51(7):1898-903
references.pmid: 2004373
references.citation: Lung Cancer. 2007 Mar;55(3):279-86
references.pmid: 17134788
references.citation: Cancer Res. 2004 Nov 1;64(21):7711-23
references.pmid: 15520175
references.citation: Cancer Res. 2003 Oct 1;63(19):6432-41
references.pmid: 14559833
references.citation: EMBO J. 1986 Oct;5(10):2503-12
references.pmid: 2877871
references.citation: Gut. 2005 May;54(5):591-600
references.pmid: 15831900
references.citation: Apoptosis. 2011 Feb;16(2):174-83
references.pmid: 21082354
references.citation: Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2181-5
references.pmid: 8134369
references.citation: Endocrinology. 1994 Dec;135(6):2511-6
references.pmid: 7527333
references.citation: J Lab Clin Med. 1998 Aug;132(2):134-41
references.pmid: 9708574
references.citation: Gut. 2012 Jan;61(1):33-42
references.pmid: 21813472
references.citation: Acta Pharmacol Sin. 2007 May;28(5):721-30
references.pmid: 17439729
references.citation: Int J Cancer. 1992 Dec 2;52(6):910-7
references.pmid: 1281142
references.citation: J Natl Cancer Inst. 2000 Sep 20;92(18):1472-89
references.pmid: 10995803
references.citation: J Biomed Sci. 2002 Nov-Dec;9(6 Pt 2):665-74
references.pmid: 12432233
references.citation: Cancer Res. 2006 Feb 15;66(4):1940-8
references.pmid: 16488992
references.citation: J Med Chem. 2005 Sep 8;48(18):5639-43
references.pmid: 16134929
references.citation: J Biol Chem. 1996 May 10;271(19):11477-83
references.pmid: 8626706