Department of Oncology, University of Cambridge, Cambridge CB1 9RN, UK.
Breast Cancer Res. 2011;13(6):R118. doi: 10.1186/bcr3061. Epub 2011 Nov 23.
The cancer stem cell (CSC) hypothesis states that tumours consist of a cellular hierarchy with CSCs at the apex driving tumour recurrence and metastasis. Hence, CSCs are potentially of profound clinical importance. We set out to establish the clinical relevance of breast CSC markers by profiling a large cohort of breast tumours in tissue microarrays (TMAs) using immunohistochemistry (IHC).
We included 4, 125 patients enrolled in the SEARCH population-based study with tumours represented in TMAs and classified into molecular subtype according to a validated IHC-based five-marker scheme. IHC was used to detect CD44/CD24, ALDH1A1, aldehyde dehydrogenase family 1 member A3 (ALDH1A3) and integrin alpha-6 (ITGA6). A 'Total CSC' score representing expression of all four CSC markers was also investigated. Association with breast cancer specific survival (BCSS) at 10 years was assessed using a Cox proportional-hazards model. This study was complied with REMARK criteria.
In ER negative cases, multivariate analysis showed that ITGA6 was an independent prognostic factor with a time-dependent effect restricted to the first two years of follow-up (hazard ratio (HR) for 0 to 2 years follow-up, 2.4; 95% confidence interval (95% CI), 1.2 to 4.8; P = 0.009). The composite 'Total CSC' score carried independent prognostic significance in ER negative cases for the first four years of follow-up (HR for 0 to 4 years follow-up, 1.3; 95% CI, 1.1 to 1.6; P = 0.006).
Breast CSC markers do not identify identical subpopulations in primary tumours. Both ITGA6 and a composite Total CSC score show independent prognostic significance in ER negative disease. The use of multiple markers to identify tumours enriched for CSCs has the greatest prognostic value. In the absence of more specific markers, we propose that the effective translation of the CSC hypothesis into patient benefit will necessitate the use of a panel of markers to robustly identify tumours enriched for CSCs.
癌症干细胞（CSC）假说指出，肿瘤由一个细胞层次结构组成，CSC 位于顶端，驱动肿瘤复发和转移。因此，CSC 具有潜在的深远临床意义。我们着手通过在组织微阵列（TMA）中使用免疫组织化学（IHC）对大量乳腺癌肿瘤进行分析，以确定乳腺癌 CSC 标志物的临床相关性。
我们纳入了 4125 名参与基于人群的 SEARCH 研究的患者，这些患者的肿瘤在 TMA 中有代表性，并根据经过验证的基于 IHC 的五标志物方案分为分子亚型。使用 IHC 检测 CD44/CD24、ALDH1A1、醛脱氢酶家族 1 成员 A3（ALDH1A3）和整合素 alpha-6（ITGA6）。还研究了代表所有四个 CSC 标志物表达的“总 CSC”评分。使用 Cox 比例风险模型评估与 10 年乳腺癌特异性生存（BCSS）的关联。本研究符合 REMARK 标准。
在 ER 阴性病例中，多变量分析显示 ITGA6 是一个独立的预后因素，其时间依赖性效应仅限于随访的前两年（0 至 2 年随访的风险比（HR），2.4；95%置信区间（95%CI），1.2 至 4.8；P=0.009）。在 ER 阴性病例中，复合“总 CSC”评分在随访的前四年具有独立的预后意义（0 至 4 年随访的 HR，1.3；95%CI，1.1 至 1.6；P=0.006）。
乳腺癌 CSC 标志物不能在原发性肿瘤中识别出相同的亚群。ITGA6 和复合总 CSC 评分在 ER 阴性疾病中均具有独立的预后意义。使用多个标志物来识别富含 CSC 的肿瘤具有最大的预后价值。在没有更特异的标志物的情况下，我们提出，将 CSC 假说有效地转化为患者受益，将需要使用一组标志物来稳健地识别富含 CSCs 的肿瘤。
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