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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >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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Tumor-initiating stem cells of squamous cell carcinomas and their control by TGF-β and integrin/focal adhesion kinase (FAK) signaling

机译：鳞状细胞癌的肿瘤起始干细胞及其受TGF-β和整联蛋白/粘着斑激酶（FAK）信号的控制

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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[a]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~(lo) or CD34~(i), α6~(hi)β1~(hi) populations can initiate secondary tumors by serial limit-dilution transplantation assays, but α6~(lo)β1~(lo) populations cannot. Moreover, secondary tumors generated from a single CSC of either subtype contain both CD34~(lo) and CD34~(hi) α6~(hi)β1~(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 CD34~(hi) hair follicle stem cell signature. Although closely related, α6~(hi)β1~(hi)CD34~(lo) and α6~(hi)β1~(hi)CD34~(hi) CSCs differ in cell-cycle gene expression and proliferation characteristics. Indeed, proliferation and expansion of α6~(hi)β1~(hi)CD34~(hi) CSCs is sensitive to whether they can initiate a TGF-β receptor ll-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.
机译：癌症干细胞（CSC）通过自身更新和产生分化后代的能力来维持肿瘤的生长。这些功能使CSCs有可能引发继发性肿瘤，其特征与亲本相似。最近，毛囊干细胞标记物CD34被用于从7,12-二甲基苯并[a]蒽/ 12-o-十四烷酰phorbol-13-乙酸盐治疗产生的早期皮肤肿瘤中纯化CSC样细胞群，通常产生良性乳头状瘤有时会发展成鳞状细胞癌（SCC）。在本研究中，我们鉴定并鉴定了从恶性SCC中纯化的CSC。我们显示，SCC包含两个高度致癌的CSC群体，它们的CD34水平不同，但富含整联蛋白并共存于SCC-基质界面。有趣的是，无论是CD34〜（lo）还是CD34〜（i），α6〜（hi）β1〜（hi）种群均可通过连续稀释稀释移植试验引发继发性肿瘤，而α6〜（lo）β1〜（lo）种群不能。此外，由任一亚型的单个CSC产生的继发性肿瘤均包含CD34〜（lo）和CD34〜（hi）α6〜（hi）β1〜（hi）CSC，这表明它们具有非等级组织。基因组图谱分析和层次聚类分析表明，这两种CSC亚型具有不同于CD34〜-表皮或CD34〜（hi）毛囊干细胞签名的分子签名。尽管α6〜（hi）β1〜（hi）CD34〜（lo）和α6〜（hi）β1〜（hi）CD34〜（hi）CSCs密切相关，但它们在细胞周期基因表达和增殖特性上却有所不同。确实，α6〜（hi）β1〜（hi）CD34〜（hi）CSCs的增殖和扩展对它们是否可以启动TGF-β受体ll介导的抗衡平衡黏着斑激酶介导的整联蛋白信号转导敏感。瘤。总体而言，对微环境敏感性不同的CSC的共存和互换性给SCC癌症治疗带来了挑战和机遇。

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