School of Dentistry, University of California, Los Angeles, CA 90095, USA.
Biochem Biophys Res Commun. 2012 Jul 20;424(1):58-64. doi: 10.1016/j.bbrc.2012.06.065. Epub 2012 Jun 20.
Cancer stem-like cell (CSC; also known as tumor initiating cell) is defined as a small subpopulation of cancer cells within a tumor and isolated from various primary tumors and cancer cell lines. CSCs are highly tumorigenic and resistant to anticancer treatments. In this study, we found that prolonged exposure to tumor necrosis factor alpha (TNFα), a major proinflammatory cytokine, enhances CSC phenotype of oral squamous cell carcinoma (OSCC) cells, such as an increase in tumor sphere-forming ability, stem cell-associated genes expression, chemo-radioresistance, and tumorigenicity. Moreover, activation of Notch1 signaling was detected in the TNFα-exposed cells, and suppression of Notch1 signaling inhibited CSC phenotype. Furthermore, we demonstrated that inhibition of a Notch downstream target, Hes1, led to suppression of CSC phenotype in the TNFα-exposed cells. We also found that Hes1 expression is commonly upregulated in OSCC lesions compared to precancerous dysplastic lesions, suggesting the possible involvement of Hes1 in OSCC progression and CSC in vivo. In conclusion, inflammatory cytokine exposure may enhance CSC phenotype of OSCC, in part by activating the Notch-Hes1 pathway.
癌症干细胞样细胞（CSC；也称为肿瘤起始细胞）被定义为肿瘤内的一小部分肿瘤细胞，并从各种原发性肿瘤和癌细胞系中分离出来。CSC 具有高度致瘤性和对抗癌治疗的耐药性。在这项研究中，我们发现，长时间暴露于肿瘤坏死因子 alpha（TNFα），一种主要的促炎细胞因子，可增强口腔鳞状细胞癌（OSCC）细胞的 CSC 表型，例如增加肿瘤球体形成能力、干细胞相关基因表达、化疗和放疗耐药性以及致瘤性。此外，在 TNFα 暴露的细胞中检测到 Notch1 信号的激活，而 Notch1 信号的抑制抑制了 CSC 表型。此外，我们证明抑制 Notch 下游靶点 Hes1 可抑制 TNFα 暴露细胞中的 CSC 表型。我们还发现，与癌前发育不良病变相比，Hes1 在 OSCC 病变中普遍上调，表明 Hes1 可能参与 OSCC 进展和体内 CSC。总之，炎症细胞因子的暴露可能会增强 OSCC 的 CSC 表型，部分原因是激活了 Notch-Hes1 通路。
