CD49f and CD61 identify Her2/neu-induced mammary tumor-initiating cells that are potentially derived from luminal progenitors and maintained by the integrin-TGFβ signaling.
CD49f and CD61 identify Her2/neu-induced mammary tumor-initiating cells that are potentially derived from luminal progenitors and maintained by the integrin-TGFβ signaling.
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DOI：
10.1038/onc.2011.439
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发表时间：
2012-05-24
期刊：
影响因子：
8
通讯作者：
Chen, H.
中科院分区：
文献类型：
--
作者：
Lo, P-K;Kanojia, D.;Liu, X.;Singh, U. P.;Berger, F. G.;Wang, Q.;Chen, H.
HER2/Neu在20-30%的乳腺癌中高表达，并与侵袭性表型和不良预后有关。为了解释HER2/neu在乳腺癌中的作用，已经建立了小鼠乳腺肿瘤病毒(MMTV)-Her2/neu转基因小鼠，其发生的乳腺肿瘤类似于人类HER2亚型乳腺癌。最近的一些研究表明，HER2/Neu在乳腺肿瘤起始细胞(TICs)中过表达并调节其自我更新。然而，在MMTV-Her2/neu转基因小鼠模型中，尽管先前的研究表明在Her2/neu诱导的乳腺肿瘤中存在抽搐，但抽搐的身份仍然难以确定。通过系统的筛选和鉴定，我们发现表面标志物CD49f、CD61和ESA在Her2过表达的乳腺肿瘤细胞中异常过表达。对这些标志物和CD24的分析发现，在Her2/neu转基因小鼠的癌前病变小鼠乳腺中，腔祖细胞群体异常扩张，表明异常的腔祖细胞起源于Her2诱导的乳腺肿瘤。CD49f和CD61的联合标记进一步将CD49fHighCD61高分选部分描述为TIC富集组，显示出增强的肿瘤球体形成能力、增强的体内外致瘤性以及对紫杉醇和阿霉素的耐药性。此外，富含TIC的群体表现出转化生长因子β信号的增加，并表现出干性、转化生长因子β信号和上皮向间充质转化的基因表达特征。我们的发现通过药物抑制转化生长因子β信号通路抑制了TIC的自我更新和克隆形成，进一步表明转化生长因子β通路对于维持TIC种群是至关重要的。最后，我们证明了整合素β3(CD61)信号通路是维持活跃的转化生长因子β信号和TICS自我更新所必需的。我们首次开发了一种从HER2/neu转基因小鼠的乳腺肿瘤中高度浓缩TICS的技术，揭示了它们的性质，并确定了整合素β3-转化生长因子β信号轴作为治疗HER2诱导的TICS的潜在靶点。
HER2/Neu is overexpressed in 20-30% of breast cancers and associated with aggressive phenotypes and poor prognosis. For deciphering the role of HER2/Neu in breast cancer, mouse mammary tumor virus (MMTV)-Her2/neu transgenic mice that develop mammary tumors resembling human HER2-subtype breast cancer have been established. Several recent studies have revealed that HER2/Neu is overexpressed in and regulates self renewal of breast tumor initiating cells (TICs). However, in the MMTV-Her2/neu transgenic mouse model, the identity of TICs remains elusive, despite previous studies showing supportive evidence for existence of TICs in Her2/neu-induced mammary tumors. Through systematic screening and characterization, we identified surface markers CD49f, CD61 and ESA were aberrantly overexpressed in Her2-overexpressing mammary tumor cells. Analysis of these markers as well as CD24 detected anomalous expansion of the luminal progenitor population in preneoplastic mammary glands of Her2/neu-transgenic mice, indicating that aberrant luminal progenitors originated Her2-induced mammary tumors. The combined markers, CD49f and CD61, further delineated the CD49fhighCD61high-sorted fraction as a TIC-enriched population, which displayed increased tumorsphere formation ability, enhanced tumorigenicity both in vitro and in vivo and drug resistance to pacitaxel and doxorubicin. Moreover, the TIC-enriched population manifested increased TGFβ signaling and exhibited gene expression signatures of stemness, TGFβ signaling and Epithelial-to-Mesenchymal Transition. Our findings that self-renewal and clonogenicity of TICs were suppressed by pharmacologically inhibiting the TGFβ signaling further indicate that the TGFβ pathway is vital for maintenance of the TIC population. Finally, we showed that the integrin β3 (CD61) signaling pathway was required for sustaining active TGFβ signaling and self-renewal of TICs. We for the first time developed a technique to highly enrich TICs from mammary tumors of Her2/neu-transgenic mice, unraveled their properties and identified the cooperative integrin β3-TGFβ signaling axis as a potential therapeutic target for HER2-induced TICs.
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