Carcinogenesis Advance Access originally published online on June 3, 2009
Carcinogenesis 2009 30(8):1305-1313; doi:10.1093/carcin/bgp134
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Insulin-like growth factor-I receptor blockade reduces the invasiveness of gastrointestinal cancers via blocking production of matrilysin
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First Department of Internal Medicine, Sapporo Medical University, South-1, West-16, Chuo-ku, Sapporo 060–8543, Japan
1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Lung Institute, Seoul National University College of Medicine, Seoul 110-774, Korea
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 ext. 3211; Fax: +81 11 611 2282; Email: yadachi{at}sapmed.ac.jp
Insulin-like growth factor-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of gastrointestinal (GI) cancers. We have previously shown significant therapeutic activity for recombinant adenoviruses expressing dominant-negative insulin-like growth factor-I receptor (IGF-IR/dn), including suppression of tumor invasion. In this study, we sought to evaluate the mechanism of inhibition of invasion and the relationship between IGF-IR and matrix metalloproteinase (MMP) activity in GI carcinomas. We analyzed the role of IGF-IR on invasion in three GI cancer cell lines, colorectal adenocarcinoma, HT29; pancreatic adenocarcinoma, BxPC3 and gastric adenocarcinoma, MKN45, using a modified Boyden chamber method and subcutaneous xenografts in nude mice. The impact of IGF-IR signaling on the expression of MMPs and the effects of blockade of matrilysin or IGF-IR on invasiveness were assessed using recombinant adenoviruses, a tyrosine kinase inhibitor NVP-AEW541 and antisense matrilysin. Invasive subcutaneous tumors expressed several MMPs. IGF-IR/dn reduced the expression of these MMPs but especially matrilysin (MMP-7). Insulin-like growth factor (IGF) stimulated secretion of matrilysin and IGF-IR/dn blocked IGF-mediated matrilysin induction in three GI cancers. Both IGF-IR/dn and inhibition of matrilysin reduced in vitro invasion to the same degree. NVP-AEW541 also reduced cancer cell invasion both in vitro and in murine xenograft tumors via suppression of matrilysin. Thus, blockade of IGF-IR is involved in the suppression of cancer cell invasion through downregulation of matrilysin. Strategies of targeting IGF-IR may have significant therapeutic utility to prevent invasion and progression of human GI carcinomas.
Abbreviations: GI, gastrointestinal; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor-binding protein; IGF-IR, insulin-like growth factor-I receptor; IGF-IR/dn, dominant-negative insulin-like growth factor-I receptor; MMP, matrix metalloproteinase; PI3-K, phosphatidylinositide 3-kinase; TIMP, tissue inhibitor of metalloproteinase; TKI, tyrosine kinase inhibitor
These authors contributed equally to this work. Received December 30, 2008; revised April 28, 2009; accepted May 20, 2009.