CAJ | 학술논문

目的通过甲磺酸伊马替尼耐药细胞系建立人胃肠道间质瘤(GIST)裸鼠移植瘤模型,进一步鉴定和分析其病理学特征,为明确其耐药机制提供一个较理想的实验平台.方法甲磺酸伊马替尼耐药的GIST细胞GIST-R、GIST-PR1和GIST-PR2分别接种裸鼠观察成瘤情况.应用免疫组织化学方法检测移植瘤组织中CD117、结蛋白和myogenin等的表达情况,并进一步检测移植瘤中c-kit和血小板源生长因子受体α(PDGFR-α)基因的突变情况.结果成功地建立了甲磺酸伊马替尼耐药的人GIST裸鼠移植瘤模型.c-kit和PDGFR-α基因突变分析结果显示,移植瘤的突变类型与接种前细胞系突变类型相一致.免疫组织化学结果显示,GIST-PR2耐药移植瘤CD117呈阳性表达,而GIST-R移植瘤CD117阴性表达.GIST-PR1耐药移植瘤呈混合细胞型,部分区域可见横纹肌肉瘤分化,横纹肌肉瘤分化区域CD117阴性表达,但是结蛋白和myogenin阳性表达.结论成功地建立了多个甲磺酸伊马替尼耐药的人GIST裸鼠移植瘤模型,同时发现其在组织病理学和免疫表型方面有着不同于耐药前GIST组织的一些特征.可以以此动物模型作为研究平台,为进一步进行甲磺酸伊马替尼耐药机制的体内外实验研究打下了基础.
목적 통과갑광산이마체니내약세포계건립인위장도간질류(GIST)라서이식류모형,진일보감정화분석기병이학특정,위명학기내약궤제제공일개교이상적실험평태.방법 갑광산이마체니내약적GIST세포GIST-R、GIST-PR1화GIST-PR2분별접충라서관찰성류정황.응용면역조직화학방법검측이식류조직중CD117、결단백화myogenin등적표체정황,병진일보검측이식류중c-kit화혈소판원생장인자수체α(PDGFR-α)기인적돌변정황.결과 성공지건립료갑광산이마체니내약적인GIST라서이식류모형.c-kit화PDGFR-α기인돌변분석결과현시,이식류적돌변류형여접충전세포계돌변류형상일치.면역조직화학결과현시,GIST-PR2내약이식류CD117정양성표체,이GIST-R이식류CD117음성표체.GIST-PR1내약이식류정혼합세포형,부분구역가견횡문기육류분화,횡문기육류분화구역CD117음성표체,단시결단백화myogenin양성표체.결론 성공지건립료다개갑광산이마체니내약적인GIST라서이식류모형,동시발현기재조직병이학화면역표형방면유착불동우내약전GIST조직적일사특정.가이이차동물모형작위연구평태,위진일보진행갑광산이마체니내약궤제적체내외실험연구타하료기출.
Objective To establish and characterize imatinib-resistant gastrointestinal stromal tumor (GIST) xenografts.Further provided an ideal experimental platform through the imatinib-resistant GIST xenografts to investigate the mechanism of resistance to imatinib.Methods Imatinib-resistant GIST cells were injected under the skin of athymic nude mice to establish animal models of human imatinib-resistant GIST.The molecular and histopathologic features of GIST xenografts were also analysed and compared with their counterpart of cell lines.Results The xenograft tumor models had been established by subcutaneously injection of GIST cells into nude mice.Immunohistochemistry results showed CD117 expression was positive in GIST-PR2 xenograft tumor,but negative in GIST-R.In GIST-PR1,tumor areas showing rhabdomyoblastic differentiation were presented next to areas with classic GIST morphology.The rhabdomyoblastic component demonstrated consistently positivity for desmin and myogenin,whereas CD117 was completely negative.The mutation profiles of these xenograft tumors were the same as their counterpart of cell lines.Conclusions Human GIST xenografts with mutation in c-kit have been established from imatinib-resistant GIST lines.Those models will enable further studies on mechanisms of resistance,combination therapies and allow testing of novel targeted therapies.