Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features
Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features
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DOI：
10.1073/pnas.0905718106
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发表时间：
2009-08-18
影响因子：
11.1
通讯作者：
Chang, Jenny C.
中科院分区：
文献类型：
--
作者：
Creighton, Chad J.;Li, Xiaoxian;Chang, Jenny C.
一些乳腺癌已被证明含有一小部分以CD 44（+）/CD 24（-/低）细胞表面抗原谱为特征的细胞，这些细胞具有高肿瘤引发潜力。此外，在体外增殖的乳腺癌细胞作为乳腺球（MS）也已被证明是富集的细胞能够自我更新。在这项研究中，我们已经确定了一个共同的基因表达签名的CD 44（+）/CD 24（-/低）和MS形成细胞。为了检验其临床意义，我们确定了在常规治疗后存活的肿瘤细胞是否富集了携带这种CD 44（+）/CD 24（-/低）-MS特征的细胞。CD 44（+）/CD 24（-/低）-MS特征主要见于最近鉴定的“claudin-low”分子亚型的人类乳腺肿瘤中，其特征在于许多上皮间质转化（EMT）相关基因的表达。内分泌治疗（来曲唑）或化疗（多西他赛）后残留的肿瘤组织中，CD 44（+）/CD 24（-/低）-MS和claudin-low特征更为明显，这与治疗后肿瘤起始细胞的选择性存活一致。我们证实了间充质标志物的表达增加，包括细胞角蛋白阳性上皮细胞金属蛋白酶2（MMP 2）中的波形蛋白（Vim），在两组独立的来曲唑后与预处理标本。总之，这些数据提供了支持性证据，即常规治疗后存活的残留乳腺肿瘤细胞群可能富集了具有肿瘤起始和间充质特征的细胞亚群。靶向参与EMT的蛋白质可能提供消除存活细胞的治疗策略，以防止复发并提高乳腺癌患者的长期生存率。
Some breast cancers have been shown to contain a small fraction of cells characterized by CD44(+)/CD24(-/low) cell-surface antigen profile that have high tumor-initiating potential. In addition, breast cancer cells propagated in vitro as mammospheres (MSs) have also been shown to be enriched for cells capable of self-renewal. In this study, we have defined a gene expression signature common to both CD44(+)/CD24(-/low) and MS-forming cells. To examine its clinical significance, we determined whether tumor cells surviving after conventional treatments were enriched for cells bearing this CD44(+)/CD24(-/low)-MS signature. The CD44(+)/CD24(-/low)-MS signature was found mainly in human breast tumors of the recently identified "claudin-low" molecular subtype, which is characterized by expression of many epithelial-mesenchymal- transition (EMT)-associated genes. Both CD44(+)/CD24(-/low)-MS and claudin-low signatures were more pronounced in tumor tissue remaining after either endocrine therapy (letrozole) or chemotherapy (docetaxel), consistent with the selective survival of tumor-initiating cells posttreatment. We confirmed an increased expression of mesenchymal markers, including vimentin (VIM) in cytokeratin-positive epithelial cells metalloproteinase 2 (MMP2), in two separate sets of postletrozole vs. pretreatment specimens. Taken together, these data provide supporting evidence that the residual breast tumor cell populations surviving after conventional treatment may be enriched for subpopulations of cells with both tumor-initiating and mesenchymal features. Targeting proteins involved in EMT may provide a therapeutic strategy for eliminating surviving cells to prevent recurrence and improve long-term survival in breast cancer patients.