Journal
LABORATORY INVESTIGATION
Volume 85, Issue 3, Pages 388-396Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/labinvest.3700232
Keywords
adenocarcinoma; mast cells; colonic tumors; mast cell-deficient mice; 1,2-dimethylhydrazine
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Funding
- NCI NIH HHS [CA 72074] Funding Source: Medline
- NHLBI NIH HHS [HL 67674] Funding Source: Medline
- NIAID NIH HHS [AI 23990] Funding Source: Medline
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Administration of 1,2- dimethylhydrazine ( DMH) induces intestinal epithelial tumors in mice. Increased numbers of mast cells have been reported to occur both within and near a variety of different neoplasms, including DMH-induced intestinal tumors. We investigated the role of the tyrosine kinase receptor, c- kit, and mast cells, in this model by administering DMH to c- kit mutant mast cell- deficient mice and the congenic normal mice. We attempted to induce colonic tumors by administering DMH ( 20 mg/ kg body weight, s. c., weekly for 20 weeks) to WBB6F1- Kit(+/+) ( +/+) wild- type mice, the congenic mast cell- deficient WBB6F1- Kit(W)/ Kit(W- v) ( W/ W-v) mice and W/ W-v mice that had been repaired of their mast cell deficiency by adoptive transfer of bone marrow cells derived from the congenic +/+ mice. The susceptibility to the development of DMH- induced colonic tumors, and the numbers of mast cells associated with these tumors, was evaluated. Normal ( +/+) mice exhibited significantly higher numbers of mast cells in DMH- induced intestinal tumors than in macroscopically normal colonic mucosa. Treatment with DMH induced development of colonic tumors in 97% of +/ + mice, but in only 32% of the W/ W-v mice. W/ W-v mice that had been repaired of their mast cell deficiency by transfer of +/ + bone marrow cells expressed susceptibility to the development of colonic tumors that was similar to that of wild- type mice. These results show that genetic impairment of c- kit function reduces the susceptibility of mice to DMH- induced colonic tumors, and that defects in bone marrow- derived cells in the W/ W-v mice contribute significantly to this result. Our findings also are consistent with the possibility that mast cells promote the development of DMH-induced colonic epithelial tumors in mice.
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