Wedemeyer Jochen, Galli Stephen J
Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Hannover, Germany.
Lab Invest. 2005 Mar;85(3):388-96. doi: 10.1038/labinvest.3700232.
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.
给予1,2 - 二甲基肼（DMH）可诱发小鼠肠道上皮肿瘤。据报道，在包括DMH诱发的肠道肿瘤在内的多种不同肿瘤内部及附近，肥大细胞数量均会增加。我们通过给c - kit突变型肥大细胞缺陷小鼠和同基因正常小鼠给予DMH，研究了酪氨酸激酶受体c - kit和肥大细胞在该模型中的作用。我们试图通过给WBB6F1 - Kit+/+（+/+）野生型小鼠、同基因肥大细胞缺陷的WBB6F1 - Kit(W)/Kit(W - v)（W/W(v)）小鼠以及通过转输同基因+/+小鼠来源的骨髓细胞修复了肥大细胞缺陷的W/W(v)小鼠给予DMH（20 mg/kg体重，皮下注射，每周一次，共20周）来诱发结肠肿瘤。评估了对DMH诱发结肠肿瘤的易感性以及与这些肿瘤相关的肥大细胞数量。正常（+/+）小鼠在DMH诱发的肠道肿瘤中的肥大细胞数量显著高于宏观正常的结肠黏膜。给予DMH治疗使97%的+/+小鼠发生了结肠肿瘤，但W/W(v)小鼠中只有32%发生。通过转输+/+骨髓细胞修复了肥大细胞缺陷的W/W(v)小鼠对结肠肿瘤发生的易感性与野生型小鼠相似。这些结果表明，c - kit功能的基因损伤降低了小鼠对DMH诱发结肠肿瘤的易感性，并且W/W(v)小鼠中骨髓来源细胞的缺陷对这一结果有显著影响。我们的发现还与肥大细胞促进小鼠DMH诱发的结肠上皮肿瘤发生的可能性一致。
