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Carcinogenesis Advance Access published online on June 3, 2009
Carcinogenesis, doi:10.1093/carcin/bgp134
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Insulin-like growth factor-I receptor blockade reduces the invasiveness of gastrointestinal cancers via blocking production of matrilysin

Yasushi Adachi1,4,5, Rong Li1,4, Hiroyuki Yamamoto1, Yongfen Min1, Wenhua Piao1, Yu Wang1, Arisa Imsumran1, Hua Li1, Yoshiaki Arimura1, Choon-Taek Lee2, Kohzoh Imai1, David P Carbone3 and Yasuhisa Shinomura1

1 First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan
2 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Lung Institute Seoul National University College of Medicine, Seoul, Korea
3 Vanderbilt-Ingram Cancer Center and Departments of Medicine and Cell Biology, Vanderbilt University, Nashville, TN 37232-6838, USA

5 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 carcinogenicity and proliferation of gastrointestinal cancers. We have previously shown significant therapeutic activity for recombinant adenoviruses expressing dominant negative IGF-IR (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 gastrointestinal carcinomas. We analyzed the role of IGF-IR on invasion in 3 gastrointestinal cancer cell lines, colorectal adenocarcinoma, HT29; pancreatic adenocarcinoma, BxPC3; 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). IGF stimulated secretion of matrilysin and IGF-IR/dn blocked IGF-mediated matrilysin induction in 3 gastrointestinal 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 gastrointestinal carcinomas.

Key Words: gastrointestinal cancers • insulin-like growth factor-I receptor (IGF-IR) • invasion • matrilysin • MMP

4 The first two authors contributed equally to this work.

Received December 30, 2008; revised April 28, 2009; accepted May 20, 2009.


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