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.
Abbreviations
- ad-IGF-IR/482st:
-
Adenovirus expressing IGF-IR /482st
- ad-IGF-IR/950st:
-
Adenovirus expressing IGF-IR/950st
- ad-shIG F-IR:
-
Adenovirus expressing short-hairpin IGF-IR
- des(1–3)IGF-I:
-
NH2 terminally truncated IGF-I
- dn:
-
Dominant negative
- EAC:
-
Esophageal adenocarcinoma
- ESCC:
-
Esophageal squamous cell carcinoma
- ERK:
-
Extracellular signal-regulated kinase
- IGF:
-
Insulin-like growth factor
- IGFBP:
-
IGF binding protein
- IGF-IR:
-
IGF-I receptor
- IGF-IR/482st:
-
Truncated IGF-IR of 482 amino acid long
- IGF-IR/950st:
-
Truncated IGF-IR of 950 amino acid long
- IGF-IR/dn:
-
Dominant negative form of IGF-IR
- InsR:
-
Insulin receptor
- mAb:
-
Monoclonal antibody
- PI3-K:
-
Phosphatidylinositide 3-kinase
- TKI:
-
Tyrosine kinase inhibitor
References
Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med. 2003;349:2241–52.
Sagar PM, Gauperaa T, Sue-Ling H, McMahon MJ, Johnston D. An audit of the treatment of cancer of the oesophagus. Gut. 1994;35:941–5.
Baserga R. Oncogenes and the strategy of growth factors. Cell. 1994;79:927–30.
Sell C, Rubini M, Rubin R, Liu JP, Efstratiadis A, Baserga R. Simian virus 40 large tumor antigen is unable to transform mouse embryonic fibroblasts lacking type 1 insulin-like growth factor receptor. Proc Natl Acad Sci U S A. 1993;90:11217–21.
Ullrich A, Gray A, Tam AW, Yang-Feng T, Tsubokawa M, Collins C, et al. Insulin-like growth factor i receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity. Embo J. 1986;5:2503–12.
Yu H, Rohan T. Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst. 2000;92:1472–89.
Remacle-Bonnet M, Garrouste F, el Atiq F, Roccabianca M, Marvaldi J, Pommier G. Des-(1–3)-igf-i, an insulin-like growth factor analog used to mimic a potential igf-ii autocrine loop, promotes the differentiation of human colon-carcinoma cells. Int J Cancer. 1992;52:910–7.
Ma J, Pollak MN, Giovannucci E, Chan JM, Tao Y, Hennekens CH, et al. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (igf)-i and igf-binding protein-3. J Natl Cancer Inst. 1999;91:620–5.
Harper J, Burns JL, Foulstone EJ, Pignatelli M, Zaina S, Hassan AB. Soluble igf2 receptor rescues apc(min/+) intestinal adenoma progresion induced by igf2 loss of imprinting. Cancer Res. 2006;66:1940–8.
Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, et al. Plasma insulin-like growth factor-i and prostate cancer risk: a prospective study. Science. 1998;279:563–6.
Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor i (igf-1) and type 1 igf receptor (igf1r). Cell. 1993;75:59–72.
Vinayek R, Pichney LS, Tantry U, Dutta SK, Resau J, Vengurlekar S. Characterization of insulin-like growth factor i receptors in human esophageal epithelial cells. Am J Physiol. 1994;267:G105–14.
Qureshi FG, Tchorzewski MT, Duncan MD, Harmon JW. Egf and igf-i synergistically stimulate proliferation of human esophageal epithelial cells. J Surg Res. 1997;69:354–8.
Tchorzewski MT, Qureshi FG, Duncan MD, Duncan KL, Saini N, Harmon JW. Role of insulin-like growth factor-i in esophageal mucosal healing processes. J Lab Clin Med. 1998;132:134–41.
Costigan DC, Guyda HJ, Posner BI. Free insulin-like growth factor i (igf-i) and igf-ii in human saliva. J Clin Endocrinol Metab. 1988;66:1014–8.
Mori M, Inoue H, Shiraishi T, Mimori K, Shibuta K, Nakashima H, et al. Relaxation of insulin-like growth factor 2 gene imprinting in esophageal cancer. Int J Cancer. 1996;68:441–6.
Liu YC, Leu CM, Wong FH, Fong WS, Chen SC, Chang C, et al. Autocrine stimulation by insulin-like growth factor i is involved in the growth, tumorigenicity and chemoresistance of human esophageal carcinoma cells. J Biomed Sci. 2002;9:665–74.
Ouban A, Muraca P, Yeatman T, Coppola D. Expression and distribution of insulin-like growth factor-1 receptor in human carcinomas. Hum Pathol. 2003;34:803–8.
Chen SC, Chou CK, Wong FH, Chang CM, Hu CP. Overexpression of epidermal growth factor and insulin-like growth factor-i receptors and autocrine stimulation in human esophageal carcinoma cells. Cancer Res. 1991;51:1898–903.
Takaoka M, Harada H, Andl CD, Oyama K, Naomoto Y, Dempsey KL, et al. Epidermal growth factor receptor regulates aberrant expression of insulin-like growth factor-binding protein 3. Cancer Res. 2004;64:7711–23.
Imsumran A, Adachi Y, Yamamoto H, Li R, Wang Y, Min Y, et al. Insulin-like growth factor-i receptor as a marker for prognosis and a therapeutic target in human esophageal squamous cell carcinoma. Carcinogenesis. 2007;28:947–56.
Doyle SL, Donohoe CL, Finn SP, Howard JM, Lithander FE, Reynolds JV, et al. Igf-1 and its receptor in esophageal cancer: association with adenocarcinoma and visceral obesity. Am J Gastroenterol. 2012;107:196–204.
Donohoe CL, Doyle SL, McGarrigle S, Cathcart MC, Daly E, O’Grady A, et al. Role of the insulin-like growth factor 1 axis and visceral adiposity in oesophageal adenocarcinoma. Br J Surg. 2012;99:387–96.
Surmacz E. Growth factor receptors as therapeutic targets: strategies to inhibit the insulin-like growth factor i receptor. Oncogene. 2003;22:6589–97.
Wu JD, Odman A, Higgins LM, Haugk K, Vessella R, Ludwig DL, et al. In vivo effects of the human type i insulin-like growth factor receptor antibody a12 on androgen-dependent and androgen-independent xenograft human prostate tumors. Clin Cancer Res. 2005;11:3065–74.
Cohen BD, Baker DA, Soderstrom C, Tkalcevic G, Rossi AM, Miller PE, et al. Combination therapy enhances the inhibition of tumor growth with the fully human anti-type 1 insulin-like growth factor receptor monoclonal antibody cp-751,871. Clin Cancer Res. 2005;11:2063–73.
Garcia-Echeverria C, Pearson MA, Marti A, Meyer T, Mestan J, Zimmermann J, et al. In vivo antitumor activity of nvp-aew541-a novel, potent, and selective inhibitor of the igf-ir kinase. Cancer Cell. 2004;5:231–9.
Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Akiyama M, et al. Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell. 2004;5:221–30.
Prager D, Li HL, Asa S, Melmed S. Dominant negative inhibition of tumorigenesis in vivo by human insulin- like growth factor i receptor mutant. Proc Natl Acad Sci U S A. 1994;91:2181–5.
D’Ambrosio C, Ferber A, Resnicoff M, Baserga R. A soluble insulin-like growth factor i receptor that induces apoptosis of tumor cells in vivo and inhibits tumorigenesis. Cancer Res. 1996;56:4013–20.
Adachi Y, Lee CT, Coffee K, Yamagata N, Ohm JE, Park KH, et al. Effects of genetic blockade of the insulin-like growth factor receptor in human colon cancer cell lines. Gastroenterology. 2002;123:1191–204.
Min Y, Adachi Y, Yamamoto H, Ito H, Itoh F, Lee CT, et al. Genetic blockade of the insulin-like growth factor-i receptor: a promising strategy for human pancreatic cancer. Cancer Res. 2003;63:6432–41.
Lee CT, Park KH, Adachi Y, Seol JY, Yoo CG, Kim YW, et al. Recombinant adenoviruses expressing dominant negative insulin-like growth factor-i receptor demonstrate antitumor effects on lung cancer. Cancer Gene Ther. 2003;10:57–63.
Min Y, Adachi Y, Yamamoto H, Imsumran A, Arimura Y, Endo T, et al. Insulin-like growth factor i receptor blockade enhances chemotherapy and radiation responses and inhibits tumour growth in human gastric cancer xenografts. Gut. 2005;54:591–600.
Ohashi H, Adachi Y, Yamamoto H, Taniguchi H, Nosho K, Suzuki H, et al. Insulin-like growth factor receptor expression is associated with aggressive phenotypes and has therapeutic activity in biliary tract cancers. Cancer Sci. 2012;103:252–61.
Wang Y, Adachi Y, Imsumran A, Yamamoto H, Piao W, Li H, et al. Targeting for insulin-like growth factor-i receptor with short hairpin RNA for human digestive/gastrointestinal cancers. J Gastroenterol. 2010;45:159–70.
Wittman M, Carboni J, Attar R, Balasubramanian B, Balimane P, Brassil P, et al. Discovery of a (1h-benzoimidazol-2-yl)-1h-pyridin-2-one (bms-536924) inhibitor of insulin-like growth factor i receptor kinase with in vivo antitumor activity. J Med Chem. 2005;48:5639–43.
Lee YJ, Imsumran A, Park MY, Kwon SY, Yoon HI, Lee JH, et al. Adenovirus expressing shRNA to igf-1r enhances the chemosensitivity of lung cancer cell lines by blocking igf-1 pathway. Lung Cancer. 2007;55:279–86.
Hana V, Murphy LJ. Expression of insulin-like growth factors and their binding proteins in the estrogen responsive Ishikawa human endometrial cancer cell line. Endocrinology. 1994;135:2511–6.
Quinn KA, Treston AM, Unsworth EJ, Miller MJ, Vos M, Grimley C, et al. Insulin-like growth factor expression in human cancer cell lines. J Biol Chem. 1996;271:11477–83.
Pennisi PA, Barr V, Nunez NP, Stannard B, Le Roith D. Reduced expression of insulin-like growth factor i receptors in mcf-7 breast cancer cells leads to a more metastatic phenotype. Cancer Res. 2002;62:6529–37.
Kalinina T, Bockhorn M, Kaifi JT, Thieltges S, Gungor C, Effenberger KE, et al. Insulin-like growth factor-1 receptor as a novel prognostic marker and its implication as a cotarget in the treatment of human adenocarcinoma of the esophagus. Int J Cancer. 2010;127:1931–40.
Kong KL, Kwong DL, Chan TH, Law SY, Chen L, Li Y, et al. Microrna-375 inhibits tumour growth and metastasis in oesophageal squamous cell carcinoma through repressing insulin-like growth factor 1 receptor. Gut. 2012;61:33–42.
Juan HC, Tsai HT, Chang PH, Huang CY, Hu CP, Wong FH. Insulin-like growth factor 1 mediates 5-fluorouracil chemoresistance in esophageal carcinoma cells through increasing survivin stability. Apoptosis. 2011;16:174–83.
Zou K, Ju JH, Xie H. Pretreatment with insulin enhances anticancer functions of 5-fluorouracil in human esophageal and colonic cancer cells. Acta Pharmacol Sin. 2007;28:721–30.
Carboni JM, Wittman M, Yang Z, Lee F, Greer A, Hurlburt W, et al. Bms-754807, a small molecule inhibitor of insulin-like growth factor-1r/ir. Mol Cancer Ther. 2009;8:3341–9.
Bao XH, Takaoka M, Hao HF, Wang ZG, Fukazawa T, Yamatsuji T, et al. Esophageal cancer exhibits resistance to a novel igf-1r inhibitor nvp-aew541 with maintained ras-MAPK activity. Anticancer Res. 2012;32:2827–34.
Piao W, Wang Y, Adachi Y, Yamamoto H, Li R, Imsumran A, et al. Insulin-like growth factor-i receptor blockade by a specific tyrosine kinase inhibitor for human gastrointestinal carcinomas. Mol Cancer Ther. 2008;7:1483–93.
Ii M, Li H, Adachi Y, Yamamoto H, Ohashi H, Taniguchi H, et al. The efficacy of igf-i receptor monoclonal antibody against human gastrointestinal carcinomas is independent of k-ras mutation status. Clin Cancer Res. 2011;17:5048–59.
Watanabe N, Takaoka M, Sakurama K, Tomono Y, Hatakeyama S, Ohmori O, et al. Dual tyrosine kinase inhibitor for focal adhesion kinase and insulin-like growth factor-i receptor exhibits anticancer effect in esophageal adenocarcinoma in vitro and in vivo. Clin Cancer Res. 2008;14:4631–9.
Acknowledgments
This work was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology and from the Ministry of Health, Labor and Welfare, Japan. This work was also supported by a grant from the Japanese Society of Strategies for Cancer Research and Therapy.
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Yasushi Adachi, Hirokazu Ohashi, and Arisa Imsumran contributed equally to this work.
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Adachi, Y., Ohashi, H., Imsumran, A. et al. The effect of IGF-I receptor blockade for human esophageal squamous cell carcinoma and adenocarcinoma. Tumor Biol. 35, 973–985 (2014). https://doi.org/10.1007/s13277-013-1131-2
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DOI: https://doi.org/10.1007/s13277-013-1131-2