GASTRIC CANCER

Insulin-like growth factor I receptor blockade enhances chemotherapy and radiation responses and inhibits tumour growth in human gastric cancer xenografts

Y Min^1,*, Y Adachi^1,*, H Yamamoto¹, A Imsumran¹, Y Arimura¹, T Endo¹, Y Hinoda², C-T Lee³, S Nadaf³, D P Carbone³, K Imai¹

¹ First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan
² Department of Clinical Laboratory Science, Yamaguchi University School of Medicine, Ube, Japan
³ Vanderbilt-Ingram Cancer Center and Departments of Medicine and Cell Biology, Vanderbilt University, Nashville, Tennessee 37232-6838, USA

Correspondence to:
Correspondence to:
Dr Y Adachi
First Department of Internal Medicine, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo 060–8543, Japan; yadachi{at}sapmed.ac.jp

Background and aims: Insulin-like growth factor (IGF) I receptor (IGF-Ir) signalling is required for carcinogenicity and proliferation of many tumours but this pathway has not been studied in detail in gastric cancer. We have previously shown successful therapy for colorectal, pancreatic, and lung cancer using recombinant adenoviruses expressing dominant negative (dn) IGF-Ir. In this study, we sought to better dissect the role of IGF-Ir on progression of gastric cancer and determine whether IGF-Ir targeted adenoviruses represent potentially effective therapeutics for human gastric cancer.

Methods: We assessed the effect of IGF-Ir ligands on proliferation and survival in gastric cancer cells in culture. Then, recombinant adenoviruses expressing truncated IGF-Ir (482 and 950 amino acids long, IGF-Ir/dn) that function as dn inhibitors were studied in the treatment of human gastric cancer xenografts. We characterised the effects of IGF-Ir/dn on signalling blockade, growth, apoptosis induction, and in vivo therapeutic efficacy.

Results: IGF-Ir signalling promoted tumour growth and survival in gastric cancer. IGF-Ir/dn expression suppressed tumorigenicity both in vitro and in vivo and upregulated stressor induced apoptosis. IGF-Ir/dn blocked Akt-1 activation induced by IGF-I, IGF-II, and des(1-3)IGF-I, but not by insulin. IGF-Ir/dn expression increased radiation and chemotherapy induced apoptosis and the combination of IGF-Ir/dn and chemotherapy was very effective against tumours in mice. In an intraperitoneal model, IGF-Ir/dn therapy also suppressed peritoneal dissemination.

Conclusions: IGF-Ir is involved in the regulation of survival and cell growth in human gastric cancer and may be a good molecular therapeutic target. Adenovirus-IGF-Ir/dn may thus have therapeutic use in gastric cancer.

Abbreviations: IGF, insulin-like growth factor; IGF-Ir, insulin-like growth factor I receptor; IGFBP, insulin-like growth factor binding protein; IGF-2r, insulin-like growth factor receptor 2; dn, dominant negative; IGF-Ir/dn, dominant negative form of IGF-Ir; IGF-Ir/482st, truncated IGF-Ir of 482 amino acids long; IGF-Ir/950st, truncated IGF-Ir of 950 amino acids long; 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; MAPK, mitogen activated protein kinase; ERK, extracellular signal regulated kinase; PI3-K, phosphatidylinositide 3-kinase; moi, multiplicity of infection; 5-FU, 5-fluorouracil; RT-PCR, reverse transcription-polymerase chain reaction; SDS-PAGE, sodium dodecyl sulphate-polyacrylamide gel electrophoresis; Ad-LacZ, adenovirus expressing ß-galactosidase

Keywords: adenovirus; akt-1; dominant negative; insulin-like growth factor; gastric cancer; xenografts

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