Matsuda Akira, Tanaka Akane, Amagai Yosuke, Ohmori Keitaro, Nishikawa Sho, Xia Yan, Karasawa Kaoru, Okamoto Noriko, Oida Kumiko, Jang Hyosun, Matsuda Hiroshi
Laboratory of Veterinary Molecular Pathology and Therapeutics, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
Vet Immunol Immunopathol. 2011 Dec 15;144(3-4):321-8. doi: 10.1016/j.vetimm.2011.08.013. Epub 2011 Aug 26.
Glucocorticoid (GC) administration with or without other chemotherapeutic reagents is a commonly used option in the treatment of mast cell malignancies. However, the responsiveness of mast cell tumors to GC treatment varies in individuals, and the regulatory mechanisms determining the GC sensitivity of malignant mast cells remain unclear. Since the expression of the GC receptor (GR) has been reported to be associated with GC sensitivity in human neoplastic lymphocytes, we attempted to investigate the relationship between GR levels and GC sensitivity by using neoplastic mast cells derived from canine mast cell tumors (MCTs). To elucidate the regulatory mechanisms involved in GC responsiveness, we analyzed various canine MCT cell lines and tissue samples from dogs with MCT. While the proliferation of canine MCT cells was suppressed by the addition of GC to the culture, we found that MCT cells derived from humans and rodents, as well as canine lymphoma cells, responded poorly to GC. However, there were also some variations in responsiveness to GC treatment among canine MCT cell lines used in this study. Using real-time polymerase chain reaction and Western blot analysis, we elucidated the relationship between GR expression and responsiveness to GC in canine MCT cells. Furthermore, to assess the involvement of GR expression in GC sensitivity in vivo, clinical investigations were conducted on dogs with cutaneous MCT. Written informed consent was obtained from owners, and the affected dogs were treated with prednisolone (0.5-2.0 mg kg(-1)day(-1), administered orally) 1 or 2 weeks prior to the surgical removal of the tumors. Tumor volume was measured according to WHO criteria both before and after prednisolone treatment, and the GC sensitivity of each MCT was determined on the basis of the reduction in tumor volume. Of the 15 dogs with MCT, 11 responded to treatment with prednisolone completely or partially, whereas 4 dogs showed no response. Examination of clinical samples obtained by surgical removal revealed that GR expression levels were significantly lower in GC-resistant MCT tissues than in GC-sensitive MCT tissues. Thus, these results strongly indicate that GR expression may contribute to GC sensitivity in canine MCT.
在肥大细胞恶性肿瘤的治疗中，单独或联合其他化疗药物使用糖皮质激素（GC）是一种常用的选择。然而，肥大细胞瘤对GC治疗的反应在个体间存在差异，且决定恶性肥大细胞GC敏感性的调控机制仍不清楚。由于据报道糖皮质激素受体（GR）的表达与人肿瘤性淋巴细胞的GC敏感性相关，我们试图通过使用源自犬肥大细胞瘤（MCT）的肿瘤性肥大细胞来研究GR水平与GC敏感性之间的关系。为了阐明参与GC反应性的调控机制，我们分析了各种犬MCT细胞系以及患有MCT的犬的组织样本。虽然向培养物中添加GC可抑制犬MCT细胞的增殖，但我们发现源自人类和啮齿动物的MCT细胞以及犬淋巴瘤细胞对GC反应不佳。然而，本研究中使用的犬MCT细胞系对GC治疗的反应也存在一些差异。通过实时聚合酶链反应和蛋白质印迹分析，我们阐明了犬MCT细胞中GR表达与对GC反应性之间的关系。此外，为了评估GR表达在体内GC敏感性中的作用，对患有皮肤MCT的犬进行了临床研究。获得了犬主的书面知情同意，在手术切除肿瘤前1或2周，对患病犬口服泼尼松龙（0.5 - 2.0 mg·kg⁻¹·d⁻¹）进行治疗。根据WHO标准在泼尼松龙治疗前后测量肿瘤体积，并根据肿瘤体积的减小确定每个MCT的GC敏感性。在15只患有MCT的犬中，11只对泼尼松龙治疗完全或部分有反应，而4只犬无反应。对手术切除获得的临床样本进行检查发现，GC耐药的MCT组织中GR表达水平明显低于GC敏感的MCT组织。因此，这些结果有力地表明GR表达可能有助于犬MCT的GC敏感性。
