Carcinogenesis Advance Access published online on December 20, 2006
Carcinogenesis, 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
1 First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan
2 Department of Surgery, Keiyukai Sapporo Hospital, Sapporo, Japan
3 Vanderbilt -Ingram Cancer Center and Departments of Medicine and Cell Biology, Vanderbilt University, Nashville, TN 37232-6838, USA
4 Correspondence to: Yasushi Adachi MD PhD, First Department of Internal Medicine, Sapporo Medical University, S–1, W–16, Chuo-ku, Sapporo 060–8543, Japan. Phone: 81–11–611–2111 (ext. 3211); Fax: 81–11–611–2282; E-mail: 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 carcinomas (ESCC). In this paper, the association between the expression of IGF-I receptor and IGF-II ligand and prognosis was investigated immunohistochemically in 100 surgically resected ESCC. We then assessed determined 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 up-regulating 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.
Key Words: dominant negative • esophageal squamous cell cancer • insulin like growth factor (IGF) • insulin like growth factor -I receptor (IGF-Ir) • prognosis
3 The first two authors contributed equally to this work.
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