Cytokeratin-18 is a useful serum biomarker for early determination of response of breast carcinomas to chemotherapy
Cytokeratin-18 is a useful serum biomarker for early determination of response of breast carcinomas to chemotherapy
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DOI：
10.1158/1078-0432.ccr-07-0009
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发表时间：
2007-06-01
影响因子：
11.5
通讯作者：
Linder, Stig
中科院分区：
文献类型：
--
作者：
Olofsson, Maria Hagg;Ueno, Takayuki;Linder, Stig
目的：随着癌症治疗方法的不断扩大，开发治疗特异性预测标记物和方法以快速评估治疗效果是很重要的。我们评估了细胞角蛋白-18(CK18)作为监测化疗诱导的乳腺癌细胞死亡的血清生物标志物的应用。实验设计：通过特异性的ELISA法评估不同分子形式的CK18(半胱氨酸天冬氨酸氨基转移酶裂解和总)。药物诱导乳腺癌细胞和组织释放CK18。检测血清中CK18蛋白组成。检测61例乳腺癌患者在多西紫杉醇或环磷酰胺/表柔比星/5-氟尿嘧啶(CEF)治疗期间血清中CK18的水平。结果：Caspase裂解的CK18分子从单层培养和肿瘤器官培养中释放到细胞外。CK18存在于血清中与其他细胞角蛋白的复合体中。这种CK18蛋白复合体非常稳定，这使得CK18生物标记物分析在临床研究中具有良好的性能。多西紫杉醇诱导乳腺癌患者血清中caspase裂解的CK18水平升高，表明细胞凋亡。CEF治疗主要导致未裂解的CK18的增加，表明在许多肿瘤中诱导坏死性细胞死亡。CEF治疗后24小时血清总CK18水平的升高与CEF治疗的临床疗效相关(P<；0.0001)。结论：细胞坏死的诱导可能解释了以蒽环类药物为基础的化疗方案对细胞凋亡通路缺陷乳腺癌的临床疗效。我们认为，CK18生物标志物有助于早期预测乳腺癌CEF治疗的疗效，并可能成为临床试验的有用生物标志物。
Purpose: With a widening arsenal of cancer therapies available, it is important to develop therapy-specific predictive markers and methods to rapidly assess treatment efficacy. We here evaluated the use of cytokeratin-18 (CK18) as a serum biomarker for monitoring chemotherapy-induced cell death in breast cancer.Experimental Design: Different molecular forms of CK18 (caspase cleaved and total) were assessed by specific ELISA assays. Drug-induced release of CK18 was examined from breast carcinoma cells and tissue. CK18 protein composition was examined in serum. CK18 levels were determined in serum from 61 breast cancer patients during docetaxel or cyclophosphamide/ epirubicin/5-fluorouracil (CEF) therapy.Results: Caspase-cleaved CK18 molecules were released from monolayer cultures and tumor organ cultures to the extracellular compartment. CK18 was present in complexes with other cytokeratins in serum. Such CK18 protein complexes are remarkably stable, leading to favorable performance of CK18 biomarker assays for clinical investigations. Docetaxel induced increased levels of caspase-cleaved CK18 in serum from breast cancer patients, indicating apoptosis. CEF therapy led to increases predominantly in uncleaved CK18, indicating induction of necrotic cell death in many tumors. The increase in total CK18 at 24 h of the first treatment cycle correlated to the clinical response to CEF therapy (P < 0,0001).Conclusions: Induction of necrotic cell death may explain the clinical efficacy of anthracycline-based therapy for breast carcinomas with defective apoptosis pathways. We suggest that CK18 biomarkers are useful for early prediction of the response to CEF therapy in breast cancer and may be useful biomarkers for clinical trials.