IGFBP-2 overexpression reduces the appearance of dysplastic aberrant crypt foci and inhibits growth of adenomas in chemically induced colorectal carcinogenesis.
Colon cancer patients frequently show increased levels of serum insulin-like growth factor-binding protein-2 (IGFBP-2), however, the pathogenetic relevance of this phenomenon for colorectal cancer is unclear. Therefore, we have used IGFBP-2 transgenic animals which overexpress IGFBP-2 systemically and locally in the intestine to study its role in chemically induced colorectal carcinogenesis. Mice received intraperitoneal injections of 1,2-dimethylhydrazine (DMH) (40 mg/kg body weight) once a week for 6 weeks to selectively induce aberrant crypt foci (ACF) and tumors in the colon. While tumor incidence was comparable in transgenic and control mice, the volume of adenomas in IGFBP-2 transgenic mice was reduced more than 2-fold. Furthermore, serum IGFBP-2 levels negatively correlated with tumor volume in the IGFBP-2 transgenic group. Histological examination showed that IGFBP-2 transgenic mice developed significantly less dysplastic ACF with a high potential to progress to advanced stages. The reduced tumor volume in IGFBP-2 transgenic animals was due to significantly reduced proliferative capacity, evidenced by a lower proportion of cells positive for Ki67. Our results demonstrate for the first time in an experimental model that IGFBP-2 overabundance prior to the onset and during colorectal carcinogenesis reduces tumor growth by inhibition of cell proliferation.
Diehl
Daniela
D
Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany.
Hessel
Esther
E
Oesterle
Doris
D
Renner-Müller
Ingrid
I
Elmlinger
Martin
M
Langhammer
Martina
M
Göttlicher
Martin
M
Wolf
Eckhard
E
Lahm
Harald
H
Hoeflich
Andreas
A
D019813:1,2-Dimethylhydrazine / Q000633:toxicity; D000236:Adenoma / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D000818:Animals; D001835:Body Weight; D002273:Carcinogens / Q000633:toxicity; D049109:Cell Proliferation; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002273:Carcinogens; D018971:Insulin-Like Growth Factor Binding Protein 2; D012333:RNA, Messenger; D019813:1,2-Dimethylhydrazine