Insulin-like growth factor-I receptor blockade reduces the invasiveness of gastrointestinal cancers via blocking production of matrilysin.
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.
Adachi
Yasushi
Y
First Department of Internal Medicine, Sapporo Medical University, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan. yadachi@sapmed.ac.jp
Li
Rong
R
Yamamoto
Hiroyuki
H
Min
Yongfen
Y
Piao
Wenhua
W
Wang
Yu
Y
Imsumran
Arisa
A
Li
Hua
H
Arimura
Yoshiaki
Y
Lee
Choon-Taek
CT
Imai
Kohzoh
K
Carbone
David P
DP
Shinomura
Yasuhisa
Y
D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology* / Q000517:prevention & control; D000818:Animals; D015153:Blotting, Western; D005260:Female; D005455:Fluorescent Antibody Technique; D005770:Gastrointestinal Neoplasms / Q000201:enzymology / Q000473:pathology* / Q000517:prevention & control; D005799:Genes, Dominant; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D055104:Infusions, Subcutaneous; D020783:Matrix Metalloproteinase 7 / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013002:Somatomedins / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D061965:Matrix Metalloproteinase Inhibitors; C501177:NVP-AEW541; D011743:Pyrimidines; D011758:Pyrroles; D012333:RNA, Messenger; D013002:Somatomedins; D017526:Receptor, IGF Type 1; D020783:Matrix Metalloproteinase 7