Carcinogenesis Advance Access published online on January 16, 2004
Carcinogenesis, doi:10.1093/carcin/bgh059
© 2004 by Oxford University Press
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CARCINOGENESIS
1 Department of Tumor Pathology, Gifu University School of Medicine, 40 Tsukasamachi, Gifu 500-8705, Japan
* Corresponding author. E-mail: yhirose{at}cc.gifu-u.ac.jp.
Received 23 July 2003
; revised 9 December 2003
; accepted 12 December 2003
Epidemiological studies have shown that obesity and diabetes mellitus may be risk factors for colon cancer. However, the underlying mechanisms of how those chronic diseases promote colon carcinogenesis remain unknown. C57BL/KsJ-db/db mice have obese and diabetic phenotypes because of disruption of leptin receptor. The present study was designed to investigate whether development of azoxymethane (AOM)-induced dysplastic and early neoplastic (premalignant) lesions of colon is modulated in db/db mice. Homozygous db/db mice, heterozygous db/+ mice, and littermate controls (+/+) were injected AOM under food restriction (approximately 10.8 kcal/mouse/day) and sacrificed 5 wk after the carcinogen treatment. Their colons were assessed for the premalignant lesions induced by AOM. We found a significant increase in the multiplicity of the total premalignant lesions in db/db mice when compared to db/+ or +/+ mice. Phenotypically, serum leptin and insulin levels in db/db mice were significantly higher than those in db/+ or +/+ mice, whereas the body weights and glucose levels in blood of db/db, db/+, and +/+ mice were comparable. In addition, immunostaining of leptin receptor and insulin-like growth factor-I receptor showed upregulation of those protein levels specifically in the lesions. Our data indicate that development of AOM-induced premalignant lesions are enhanced in db/db mice with hyperleptinemia and hyperinsulinemia. The results have important implications for further exploration of the possible underlying events that affect the positive association between colon cancer and chronic diseases (obesity and diabetes).
Enhancement of development of azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db mice
2 Department of Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan
3 Institute for Cancer Prevention, 1 Dana Road, Valhalla, NY 10595, USA
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