Carcinogenesis. 2009 Aug;30(8):1305-13. Epub 2009 Jun 3.
growth factor-I receptor blockade reduces the invasiveness of
gastrointestinal cancers via blocking production of matrilysin.
Adachi Y, Li R, Yamamoto H, Min Y, Piao W, Wang Y, Imsumran A, Li H, Arimura Y, Lee CT, Imai K, Carbone DP, Shinomura Y.
Department of Internal Medicine, Sapporo Medical University, South-1,
West-16, Chuo-ku, Sapporo 060-8543, Japan.
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.