Decreased susceptibility of mast cell-deficient Kit(W)/Kit(W-v) mice to the development of 1, 2-dimethylhydrazine-induced intestinal tumors.
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.
Wedemeyer
Jochen
J
Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Hannover, Germany.
Galli
Stephen J
SJ
D019813:1,2-Dimethylhydrazine / Q000633:toxicity*; D000818:Animals; D016026:Bone Marrow Transplantation; D002273:Carcinogens / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D004198:Disease Susceptibility; D007414:Intestinal Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008407:Mast Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*
D002273:Carcinogens; D019009:Proto-Oncogene Proteins c-kit; D019813:1,2-Dimethylhydrazine