Sequential observations on the occurrence of preneoplastic and neoplastic lesions in mouse colon treated with azoxymethane and dextran sodium sulfate

Suzuki, Rikako; Kohno, Hiroyuki; Sugie, Shigeyuki; Tanaka, Takuji

doi:10.1111/j.1349-7006.2004.tb03252.x

Cited by 107 publications

(123 citation statements)

References 40 publications

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“…Our recent work suggest involvement of oxidative/ nitrosative stress in tumor-promoting effect of DSS on AOMinduced colon carcinogenesis in mice. (51) In conclusion, the results in the current study indicate that a single dose of DMH followed by DSS resulted in a high incidence of colonic epithelial malignancies with β-catenin mutations within 20 weeks. Furthermore, half of the β-catenin mutations, detected in adenocarcinomas, were at codon 37 and 41, and strong β-catenin expression was seen in their nucleus and cytoplasm.…”

Section: Proteinmentioning

confidence: 63%

β‐Catenin mutations in a mouse model of inflammation‐related colon carcinogenesis induced by 1,2‐dimethylhydrazine and dextran sodium sulfate

et al. 2005

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In a previous study, we developed a novel mouse model for colitisrelated carcinogenesis, utilizing a single dose of azoxymethane (AOM) followed by dextran sodium sulfate (DSS) in drinking water. In the present study, we investigated whether colonic neoplasms can be developed in mice initiated with a single injection of another genotoxic colonic carcinogen 1,2-dimethylhydrazine (DMH), instead of AOM and followed by exposure of DSS in drinking water. Male crj: CD-1 (ICR) mice were given a single intraperitoneal administration (10, 20 or 40 mg/kg body weight) of DMH and 1-week oral exposure (2% in drinking water) of a non-genotoxic carcinogen, DSS. All animals were killed at week 20, histological alterations and immunohistochemical expression of β β β β-catenin, cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS) were examined in induced colonic epithelial lesions (colonic dysplasias and neoplasms). Also, the β β β β-catenin gene mutations in paraffin-embedded colonic adenocarcinomas were analyzed by the single strand conformation polymorphism method, restriction enzyme fragment length polymorphism and direct sequencing. The incidences of colonic neoplasms with dysplastic lesions developed were 100% with 2.29 ± ± ± ± 0.95 multiplicity, and 100% with 10.38 ± ± ± ± 4.00 multiplicity in mice given DMH at doses of 10 mg/kg or 20 mg/kg and 2%DSS, respectively. Although approximately half of the mice given DMH at a dose of 40 mg/kg bodyweight were dead after 2-3 days after the injection, mice who received DMH 40 mg/kg and 2%DSS had 100% incidence of colonic neoplasms with 9.75 ± ± ± ± 6.29 multiplicity. Immunohistochemical investigation revealed that adnocarcinomas, induced by DMH at all doses and 2%DSS, showed positive reactivities against β β β β-catenin, COX-2 and iNOS. In DMH/ DSS-induced adenocarcinomas, 10 of 11 (90.9%) adenocacrcinomas had β β β β-catenin gene mutations. Half of the mutations were detected at codon 37 or 41, encoding serine and threonine that are direct targets for phosphorylation by glycogen synthase kinase-3β β β β. The present results suggests that, as in the previously reported model (AOM/DSS) our experimental protocol, DMH initiation followed by DSS, may provide a novel and useful mouse model for investigating inflammation-related colon carcinogenesis and for identifying xenobiotics with modifying effects. (Cancer Sci 2005; 96: 69-76) C olorectal cancer (CRC) is one of the most common nonsmoking related cancers. The risk for CRC is associated with extent and duration of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease.(1,2) The etiopathogenesis of IBD remains uncertain, although it is generally assumed that chronic inflammation is the primary driving force.(3) To understand the pathogenesis of IBD and IBD-related CRC, several animal models were reported. The chemically induced and genetic models of colonic inflammation do not completely mimic the disease situation found in UC patients, (4) although they are more readily available, reproduci...

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Section: Proteinmentioning

confidence: 63%

β‐Catenin mutations in a mouse model of inflammation‐related colon carcinogenesis induced by 1,2‐dimethylhydrazine and dextran sodium sulfate

et al. 2005

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“…Colitis and colonic neoplasia were induced using previously established methods (27,28). Colitis was induced by 2% DSS in drinking water for 7 days.…”

Section: Methodsmentioning

confidence: 99%

SPINK1 Status in Colorectal Cancer, Impact on Proliferation, and Role in Colitis-Associated Cancer

Ida

Ozaki

Araki

et al. 2015

Molecular Cancer Research

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Colorectal cancer is a major cause of deaths due to cancer; therefore, research into its etiology is urgently needed. Although it is clear that chronic inflammation is a risk factor for colorectal cancer, the details remain uncertain. Serine protease inhibitor, Kazal type 1 (SPINK1) is mainly produced in pancreatic acinar cells. However, SPINK1 is expressed in various cancers and in inflammatory states, such as colon cancer and inflammatory bowel disease. There are structural similarities between SPINK1 and epidermal growth factor (EGF). Hence, it was hypothesized that SPINK1 functions as a growth factor for tissue repair in inflammatory states, and if prolonged, acts as a promoter for cell proliferation in cancerous tissues. Here, immunohistochemical staining for SPINK1 was observed in a high percentage of colorectal cancer patient specimens and SPINK1 induced proliferation of human colon cancer cell lines. To clarify its role in colon cancer in vivo, a mouse model exposed to the colon carcinogen azoxymethane and nongenotoxic carcinogen dextran sodium sulfate revealed that Spink3 (mouse homolog of SPINK1) is overexpressed in cancerous tissues. In Spink3 heterozygous mice, tumor multiplicity and tumor volume were significantly decreased compared with wild-type mice. These results suggest that SPINK1/Spink3 stimulates the proliferation of colon cancer cells and is involved in colorectal cancer progression.Implications: Evidence suggests that SPINK1 is an important growth factor that connects chronic inflammation and cancer.

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“…13 Although it has been reported that DSS promotes dysplasia after a subcarcinogenic dose of AOM 14,15 and that combined treatment of a carcinogenic dose of AOM and DSS induces MDF in rats, 16 it still remains to be demonstrated whether a subcarcinogenic AOM dose followed by DSS induces MDF. Therefore, we evaluated the presence of MDF, ACF and tumours induced by a subcarcinogenic dosage of AOM followed by DSS.…”

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confidence: 99%

Mucin‐depleted foci show strong activation of inflammatory markers in 1,2‐dimethylhydrazine‐induced carcinogenesis and are promoted by the inflammatory agent sodium dextran sulfate

Femia

Dolara

Luceri

et al. 2009

Intl Journal of Cancer

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Mucin‐depleted foci (MDF), formed by dysplastic crypts devoid of mucins, have been identified in the colon of carcinogen‐treated rodents and in humans at high risk for colon cancer. The lack of the protective layer of mucus may cause inflammation which has been linked to colon carcinogenesis, therefore, the expression of markers such as cyclooxygenase‐2 (COX‐2), inducible nitric oxide synthase (i‐NOS) and macrophage infiltration was studied with immunohistochemistry (IH) in MDF harvested from F344 rats treated with the colon carcinogen 1,2‐dimethylhydrazine (DMH). The same determinations were performed in aberrant crypt foci (ACF) and, at a later time point, in tumours. A dramatic increase in COX‐2, i‐NOS and macrophage infiltration was observed in MDF but ACF showed a moderate increase compared with the paired normal mucosa. Tumours were positive for all the markers. RT‐PCR experiments demonstrated that i‐NOS RNA expression was increased in a set of MDF confirming the results obtained with immunohistochemistry. In an inflammation‐cancer experimental model [mice treated with azoxymethane (AOM) and dextran sodium sulphate (DSS)], we observed that DSS‐induced inflammation promoted MDF in a dose‐dependent manner, whereas ACF were not affected. In conclusion, we report here for the first time a strong activation of the inflammatory process in MDF, which may contribute to the further progression of MDF to tumours. © 2009 UICC

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Sequential observations on the occurrence of preneoplastic and neoplastic lesions in mouse colon treated with azoxymethane and dextran sodium sulfate

Cited by 107 publications

References 40 publications

β‐Catenin mutations in a mouse model of inflammation‐related colon carcinogenesis induced by 1,2‐dimethylhydrazine and dextran sodium sulfate

β‐Catenin mutations in a mouse model of inflammation‐related colon carcinogenesis induced by 1,2‐dimethylhydrazine and dextran sodium sulfate

SPINK1 Status in Colorectal Cancer, Impact on Proliferation, and Role in Colitis-Associated Cancer

Mucin‐depleted foci show strong activation of inflammatory markers in 1,2‐dimethylhydrazine‐induced carcinogenesis and are promoted by the inflammatory agent sodium dextran sulfate

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