Adams S F, Hickson J A, Hutto J Y, Montag A G, Lengyel E, Yamada S D
Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA.
Gynecol Oncol. 2007 Mar;104(3):524-8. doi: 10.1016/j.ygyno.2006.09.013. Epub 2006 Oct 17.
Uterine sarcomas are a heterogeneous group of tumors with a propensity for metastasis and resistance to conventional therapy. Recent success in the treatment of other solid tumors with the targeted tyrosine kinase inhibitor imatinib mesylate offers new avenues for investigation. The primary target of imatinib is c-kit, but the drug also inhibits PDGFR-alpha and PDGFR-beta. Given the lack of identified molecular targets in endometrial stromal sarcomas, leiomyosarcomas, and carcinosarcomas, the purpose of this study was to determine the protein expression of c-kit, PDGFR-alpha, and PDGFR-beta in these tumors as a preliminary step to determining their susceptibility to directed therapy. A secondary goal was to identify specific gene mutations that might be associated with activation of these proteins in uterine sarcomas.
Archived tissue from 42 cases of uterine sarcomas was stained for c-kit, PDGFR-alpha, and PDGFR-beta using immunohistochemistry. Laser-capture microdissected samples of uterine carcinosarcomas, or homogeneous areas of leiomyosarcomas or endometrial stromal sarcomas, were subjected to genetic analysis of PDGFR-alpha exons 12 and 18.
The majority (38/42, 90%) of uterine sarcomas lacked c-kit expression and 90% (38/42) demonstrated negative or weak staining for PDGFR-beta. In contrast, 70% (30/42) of cases had strong staining for PDGFR-alpha in the tumor but not in normal myometrium or endometrium. Sequencing results revealed no mutations in exons 12 or 18 of PDGFR-alpha.
c-kit and PDGFR-beta are unlikely to represent primary treatment targets in uterine sarcomas. The strong expression of PDGFR-alpha in uterine sarcoma specimens suggests a role for this receptor in tumor development, although its potential as a therapeutic target requires further investigation.
子宫肉瘤是一组异质性肿瘤，具有转移倾向且对传统治疗耐药。靶向酪氨酸激酶抑制剂甲磺酸伊马替尼在治疗其他实体瘤方面的近期成功为研究提供了新途径。伊马替尼的主要靶点是c-kit，但该药物也抑制血小板衍生生长因子受体α（PDGFR-α）和血小板衍生生长因子受体β（PDGFR-β）。鉴于子宫内膜间质肉瘤、平滑肌肉瘤和癌肉瘤中缺乏已确定的分子靶点，本研究的目的是确定这些肿瘤中c-kit、PDGFR-α和PDGFR-β的蛋白表达，作为确定它们对定向治疗敏感性的初步步骤。第二个目标是识别可能与子宫肉瘤中这些蛋白激活相关的特定基因突变。
采用免疫组织化学方法对42例子宫肉瘤的存档组织进行c-kit、PDGFR-α和PDGFR-β染色。对子宫癌肉瘤的激光捕获显微切割样本，或平滑肌肉瘤或子宫内膜间质肉瘤的均匀区域，进行PDGFR-α外显子12和18的基因分析。
大多数（38/42，90%）子宫肉瘤缺乏c-kit表达，90%（38/42）的PDGFR-β染色为阴性或弱阳性。相比之下，70%（30/42）的病例肿瘤中PDGFR-α染色强，但正常子宫肌层或子宫内膜中无染色。测序结果显示PDGFR-α外显子12或18无突变。
c-kit和PDGFR-β不太可能是子宫肉瘤的主要治疗靶点。子宫肉瘤标本中PDGFR-α的强表达表明该受体在肿瘤发生中起作用，尽管其作为治疗靶点的潜力需要进一步研究。
