Tumor-initiating stem cells of squamous cell carcinomas and their control by TGF-β and integrin/focal adhesion kinase (FAK) signaling
Tumor-initiating stem cells of squamous cell carcinomas and their control by TGF-β and integrin/focal adhesion kinase (FAK) signaling
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DOI：
10.1073/pnas.1107807108
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发表时间：
2011-06-28
影响因子：
11.1
通讯作者：
Fuchs, Elaine
中科院分区：
文献类型：
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作者：
Schober, Markus;Fuchs, Elaine
肿瘤干细胞（CSCs）通过其自我更新和产生分化后代的能力来维持肿瘤生长。这些功能使csc具有启动继发性肿瘤的潜力，具有与亲本肿瘤相似的特征。最近，毛囊干细胞标志物CD34被用于从7,12-二甲基苯[α]蒽/12-o-十四烷酰基磷酸-13-乙酸治疗引起的早期皮肤肿瘤中纯化csc样细胞群，该肿瘤通常产生良性乳头状瘤，偶尔进展为鳞状细胞癌（SCCs）。在本研究中，我们鉴定和表征了从恶性SCCs中纯化的CSCs。我们发现SCCs包含两个高度致瘤性的CSC群体，它们在CD34水平上不同，但富含整合素，并在scc -基质界面共存。有趣的是，无论是CD34（Io）还是CD34(hi), α 6(hi) β 1（hi）群体都可以通过一系列极限稀释移植试验引发继发性肿瘤，但α 6(Io) β 1（Io）群体却不能。此外，由单个CSC产生的继发性肿瘤包含CD34（Io）和CD34(hi) α 6(hi) β 1(hi)CSC，表明它们的非分层组织。基因组分析和分层聚类分析表明，这两种CSC亚型具有不同于CD34（-）表皮细胞或CD34hi毛囊干细胞的分子特征。尽管密切相关，α 6(hi) β 1(hi)CD34（Io）和α 6(hi) β 1(hi)CD34(hi) CSCs在细胞周期基因表达和增殖特性上存在差异。事实上，α 6(hi) β 1(hi)CD34(hi) CSCs的增殖和扩增对它们是否能启动tgf - β受体ii介导的反应来平衡肿瘤内局灶黏附激酶介导的升高的整合素信号传导是敏感的。总之，具有不同微环境敏感性的csc的共存和相互转化为SCC癌症治疗带来了挑战和机遇。
Cancer stem cells (CSCs) sustain tumor growth through their ability to self-renew and to generate differentiated progeny. These functions endow CSCs with the potential to initiate secondary tumors bearing characteristics similar to those of the parent. Recently the hair follicle stem cell marker CD34 was used to purify a CSC-like cell population from early skin tumors arising from treatment with 7,12-dimethylbenz[alpha] anthracene/12-o-tetradecanoylphorbol-13-acetate, which typically generates benign papillomas that occasionally progress to squamous cell carcinomas (SCCs). In the present study, we identify and characterize CSCs purified from malignant SCCs. We show that SCCs contain two highly tumorigenic CSC populations that differ in CD34 levels but are enriched for integrins and coexist at the SCC-stroma interface. Intriguingly, whether CD34(Io) or CD34(hi), alpha 6(hi)beta 1(hi) populations can initiate secondary tumors by serial limitdilution transplantation assays, but alpha 6(io)beta 1(io) populations cannot. Moreover, secondary tumors generated from a single CSC of either subtype contain both CD34(Io) and CD34(hi) alpha 6(hi)beta 1(hi)CSCs, indicating their nonhierarchical organization. Genomic profiling and hierarchical cluster analysis show that these two CSC subtypes share a molecular signature distinct from either the CD34(-) epidermal or the CD34hi hair follicle stem cell signature. Although closely related, alpha 6(hi)beta 1(hi)CD34(Io) and alpha 6(hi)beta 1(hi)CD34(hi) CSCs differ in cell-cycle gene expression and proliferation characteristics. Indeed, proliferation and expansion of alpha 6(hi)beta 1(hi)CD34(hi) CSCs is sensitive to whether they can initiate a TGF-beta receptor II-mediated response to counterbalance elevated focal adhesion kinase-mediated integrin signaling within the tumor. Overall, the coexistence and interconvertibility of CSCs with differing sensitivities to their microenvironment pose challenges and opportunities for SCC cancer therapies.