Growth-induced stress enhances epithelial-mesenchymal transition induced by IL-6 in clear cell renal cell carcinoma via the Akt/GSK-3β/β-catenin signaling pathway.
Growth-induced stress enhances epithelial-mesenchymal transition induced by IL-6 in clear cell renal cell carcinoma via the Akt/GSK-3β/β-catenin signaling pathway.
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生长诱导的应激通过 Akt/GSK-3 β/β-连环蛋白信号通路增强透明细胞肾细胞癌中 IL-6 诱导的上皮间质转化
DOI：
10.1038/oncsis.2017.74
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发表时间：
2017-08-28
期刊：
影响因子：
6.2
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Chen Q;Yang D;Zong H;Zhu L;Wang L;Wang X;Zhu X;Song X;Wang J
肿瘤微环境（TME）中的基质细胞群在肾癌的发生和转移中起关键作用。在这项研究中，我们发现透明细胞肾细胞癌（ccRCC）组织间质中存在α-平滑肌肌动蛋白阳性（α-SMA（+））细胞，它们的数量与ccRCC患者的生存率显著相关。白细胞介素6（IL-6）是一种重要的趋化因子，通过促进上皮细胞向间质细胞转化（EMT）诱导ccRCC组织中的α-SMA（+）细胞，并刺激ccRCC中的迁移和侵袭。肿瘤周围的CD 4 + T细胞是ccRCC组织中IL-6的主要来源。除了生物化学因素外，肿瘤内的机械压迫也会影响肿瘤细胞的行为。在有限空间中生长的肿瘤表现出肿瘤内压缩应力，并且在足够的压力下，应力刺激癌细胞的迁移。此外，由CD 4 + T细胞分泌的IL-6和生长诱导的固体应激的组合进一步有助于调节癌细胞形态发生、EMT和干性表型的获得。联合治疗组的效果由Akt/GSK-3β/β-catenin信号通路驱动，β-catenin表达失调可预测ccRCC患者的不良结局。值得注意的是，癌症干细胞标志物CD 44的表达与ccRCC中的T分期、高Fuhrman分级和转移相关。这些数据为癌症治疗中新的减压和IL-6靶向策略提供了证据。
Stromal cell populations in the tumor microenvironment (TME) play a critical role in the oncogenesis and metastasis of renal cell carcinoma. In this study, we found that there are α-smooth muscle actin positive (α-SMA (+)) cells in the stroma of clear cell renal cell carcinoma (ccRCC) tissues, and their numbers are significantly associated with poor survival in ccRCC patients. Interleukin 6 (IL-6) is a critical diver that induces α-SMA (+) cells in ccRCC tissues via promotion of epithelial to mesenchymal transition (EMT) and stimulates migration and invasion in ccRCC. Peritumoral CD4+ T cells are the main source of IL-6 in ccRCC tissues. In addition to biochemical factors, mechanical compression within tumors affects tumor cell behavior. Tumors grown in a confined space exhibit intratumoral compressive stress and, with sufficient pressure, stress-stimulated migration of cancer cells. Moreover, a combination of IL-6 secreted by CD4+ T cells and growth-induced solid stress further contributes to the regulation of cancer cell morphogenesis, EMT and acquisition of a stemness phenotype. The effects in the combination group were driven by the Akt/GSK-3β/β-catenin signaling pathway, and deregulation of β-catenin expression was predictive of poor outcome in ccRCC patients. Notably, the expression of a cancer stem cell marker, CD44, was correlated with T stage, high Fuhrman grade and metastasis in ccRCC. These data provide evidence for new stress-reducing and IL-6 targeting strategies in cancer therapy.
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