Significance of inflammation-associated regenerative mucosa characterized by Paneth cell metaplasia and beta-catenin accumulation for the onset of colorectal carcinogenesis in rats initiated with 1,2-dimethylhydrazine.
Short-term dextran sodium sulfate (DSS) treatment has been shown to notably accelerate colorectal tumor development in rats initiated with 1,2-dimethylhydrazine (DMH). In the present study, to clarify mechanisms underlying the DSS influence, time-course studies of histopathological and immunohistochemical characteristics and beta-catenin gene mutations in colorectal mucosa in early stages of this model were conducted. F344 males were given three subcutaneous injections of DMH (40 mg/kg body wt) within a week, followed by free access to drinking water containing 1% DSS for a week. At weeks 1, 4, 6 and 8 after the DSS treatment, rats were euthanized and colorectal samples were collected. At week 1, the colorectal mucosa demonstrated extensive erosion along with significant inflammatory cell infiltration and neighboring reactive hyperplasia. By week 4, the mucosal damage was repaired and regenerative mucosa, partly characterized by Paneth cell metaplasia and altered subcellular localization of beta-catenin, was apparent. Areas with Paneth cells/beta-catenin accumulation were significantly more likely to be accompanied by interstitial inflammation and 17 of 24 dysplastic foci were found in regenerative mucosa with Paneth cells. Furthermore, adenomas/carcinomas frequently featured various degrees of Paneth cell differentiation. Point mutations mainly in codons 34 and 41 of beta-catenin gene were detected in 6 of 27 samples of regenerative mucosa with Paneth cells and four of nine dysplastic foci/adenomas/carcinomas. These findings indicate that inflammation-associated regenerative mucosa with Paneth cell metaplasia and alteration in the APC/beta-catenin/Tcf signal transduction pathway are possibly involved in the acceleration of colorectal carcinogenesis in this DMH-DSS rat model.
Imai
Toshio
T
Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-Ku, Tokyo 158-8501, Japan. imai@nihs.go.jp
Fukuta
Katsuhiro
K
Hasumura
Mai
M
Cho
Young-Man
YM
Ota
Yoshio
Y
Takami
Shigeaki
S
Nakagama
Hitoshi
H
Hirose
Masao
M
D019813:1,2-Dimethylhydrazine / Q000009:adverse effects / Q000633:toxicity*; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D015179:Colorectal Neoplasms / Q000139:chemically induced* / Q000473:pathology; D007249:Inflammation / Q000473:pathology*; D007279:Injections, Subcutaneous; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008679:Metaplasia; D019879:Paneth Cells / Q000187:drug effects / Q000473:pathology*; D017354:Point Mutation; D051381:Rats; D012038:Regeneration; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism*
D002273:Carcinogens; D051176:beta Catenin; D019813:1,2-Dimethylhydrazine