Carcinogenesis Advance Access originally published online on December 20, 2006
Carcinogenesis 2007 28(5):947-956; doi:10.1093/carcin/bgl247
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Insulin-like growth factor-I receptor as a marker for prognosis and a therapeutic target in human esophageal squamous cell carcinoma
First Department of Internal Medicine, Sapporo Medical University, South-1, West-16, Chuo-ku, Sapporo 060–8543, Japan
1 Department of Surgery, Keiyukai Sapporo Hospital, Sapporo 003-0027, Japan
2 Vanderbilt-Ingram Cancer Center and Departments of Medicine and Cell Biology, Vanderbilt University, Nashville, TN 37232-6838, USA
* To whom correspondence should be addressed. Tel: +81 11 611 2111; Fax: +81 11 611 2282; Email: yadachi{at}sapmed.ac.jp
Insulin-like growth factor (IGF)-I receptor (IGF-Ir) signaling is required for tumorigenicity and progression of many tumors but this pathway has not been well studied as a prognostic factor or potential therapeutic target in esophageal squamous cell carcinoma (ESCC). In this paper, the association between the expression of IGF-Ir and IGF-II ligand and prognosis was investigated immunohistochemically in 100 surgically resected ESCC. We then assessed the therapeutic effect of blocking IGF receptor signaling using dominant negative IGF-Ir (IGF-Ir/dn) in ESCC in vitro. Expression of IGF-Ir and IGF-II were detected in 60 and 50% of tumors, respectively, and were associated with invasion depth, metastasis, advanced tumor stage and recurrence. Patients with tumors expressing both IGF-Ir and IGF-II had a significantly shorter survival than those expressing either alone or neither in both single and multivariate analysis. IGF-Ir/dn suppressed proliferation and motility as well as upregulating chemotherapy-induced apoptosis through blocking ligand-induced Akt activation. We propose that detection of IGF-Ir/IGF-II in ESCC may be useful for the prediction of recurrence and poor prognosis and for selecting patients for IGF-Ir-targeted therapy. Therapeutic blockade of IGF-Ir may be a useful anticancer therapeutic for ESCC.
Abbreviations: Ad-IGF-Ir/482st, adenoviruses expressing IGF-Ir/482st; Ad-IGF-Ir/950st, adenoviruses expressing IGF-Ir/950st; des(1-3)IGF-I, NH2-terminally truncated IGF-I; dn, dominant negative; ELISA, enzyme-linked immunosorbent assay; IGF, insulin-like growth factor; IGFBP, IGF-binding protein; IGF-Ir, IGF-I receptor; IGF-Ir/dn, dominant negative form of IGF-Ir; IGF-Ir/482st, truncated IGF-Ir of 482 amino acid long; IGF-Ir/950st, truncated IGF-Ir of 950 amino acid long; IR, insulin receptor; MAPK, mitogen-activated protein kinase; moi, multiplicity of infection; PBS, phosphate-buffered saline; TNM, tumor node metastasis; UV, ultraviolet
These authors contributed equally to this work. Received April 18, 2006; revised November 24, 2006; accepted December 10, 2006.
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