S-Space College of Medicine/School of Medicine (의과대학/대학원) Internal Medicine (내과학전공) Journal Papers (저널논문_내과학전공)
Insulin-like growth factor-I receptor blockade reduces the invasiveness of gastrointestinal cancers via blocking production of matrilysin
- Adachi, Yasushi; Li, Rong; Yamamoto, Hiroyuki; Min, Yongfen; Wang, Yu; Li, Hua; Lee, Choon-Taek; Carbone, David P.; Shinomura, Yasuhisa; Imai, Kohzoh; Arimura, Yoshiaki; Imsumran, Arisa; Piao, Wenhua
- Issue Date
- OXFORD UNIV PRESS
- CARCINOGENESIS; Vol.30 8; 1305-1313
- 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.
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