Tumor-Initiating Cells of HER2-Positive Carcinoma Cell Lines Express the Highest Oncoprotein Levels and Are Sensitive to Trastuzumab
Tumor-Initiating Cells of HER2-Positive Carcinoma Cell Lines Express the Highest Oncoprotein Levels and Are Sensitive to Trastuzumab
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DOI：
10.1158/1078-0432.ccr-08-1327
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发表时间：
2009-03-15
影响因子：
11.5
通讯作者：
Tagliabue, Elda
中科院分区：
文献类型：
--
作者：
Magnifico, Alessandra;Albano, Luisa;Tagliabue, Elda
目的：乳腺癌中肿瘤起始细胞的存在对肿瘤治疗具有重要意义。在这项研究中，我们研究了从人表皮生长因子受体2型（HER 2）过表达癌细胞系中分离的肿瘤起始细胞对曲妥珠单抗（一种用于乳腺癌靶向治疗的化合物）的敏感性。通过间接免疫荧光法分析球体的HER 2细胞表面表达，并通过真实的免疫荧光法分析球体的HER 2细胞表面表达。在存在或不存在Notch 1信号传导抑制剂（GSI）或Notch 1小干扰RNA的情况下，用于HER 2 mRNA表达的时间PCR。用曲妥珠单抗或多柔比星处理HER 2过表达乳腺肿瘤细胞的异种移植物。球体形成效率（SFE）和系列移植性的肿瘤进行了assessed.Results：在HER 2过表达的癌细胞系，细胞与肿瘤起始细胞的属性提出了增加HER 2水平相比，散装细胞群体没有修改HER 2基因扩增。HER 2水平受Notch 1信号传导控制，如通过γ-分泌酶抑制或Notch 1特异性沉默后HER 2细胞表面表达的降低和较低的SFE所示。我们还表明，曲妥珠单抗是能够有效地针对肿瘤起始细胞的HER 2阳性癌细胞系，所示的SFE的显着减少和损失的串行transplantability，治疗后的HER 2-overexpressing xenotransplants.Conclusions：在这里，我们提供了证据的治疗效果曲妥珠单抗在减瘤和靶向肿瘤起始细胞的HER 2-overexpressing肿瘤。我们还提出Notch信号调节HER 2表达，从而代表肿瘤起始细胞的关键存活途径。
Purpose: The existence of tumor-initiating cells in breast cancer has profound implications for cancer therapy. In this study, we investigated the sensitivity of tumor-initiating cells isolated from human epidermal growth factor receptor type 2 (HER2)-overexpressing carcinoma cell lines to trastuzumab, a compound used for the targeted therapy of breast cancer.Experimental Design: Spheres were analyzed by indirect immunofluorescence for HER2 cell surface expression and by real-time PCR for HER2 mRNA expression in the presence or absence of the Notch1 signaling inhibitor (GSI) or Notch1 small interfering RNA. Xenografts of HER2-overexpressing breast tumor cells were treated with trastuzumab or doxorubicin. The sphere-forming efficiency (SFE) and serial transplantability of tumors were assessed.Results: In HER2-overexpressing carcinoma cell lines, cells with tumor-initiating cell properties presented increased HER2 levels compared with the bulk cell population without modification in HER2 gene amplification. HER2 levels were controlled by Notch1 signaling, as shown by the reduction of HER2 cell surface expression and lower SFE following gamma-secretase inhibition or Notch1 specific silencing. We also show that trastuzumab was able to effectively target tumor-initiating cells of HER2-positive carcinoma cell lines, as indicated by the significant decrease in SFE and the loss of serial transplantability, following treatment of HER2-overexpressing xenotransplants.Conclusions: Here, we provide evidence for the therapeutic efficacy of trastuzumab in debulking and in targeting tumor-initiating cells of HER2-overexpressing tumors. We also propose that Notch signaling regulates HER2 expression, thereby representing a critical survival pathway of tumor-initiating cells.