Chen Q, Yang D, Zong H, Zhu L, Wang L, Wang X, Zhu X, Song X, Wang J
Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Department of Biomedical Engineering, Dalian University of Technology, Dalian, China.
Oncogenesis. 2017 Aug 28;6(8):e375. doi: 10.1038/oncsis.2017.74.
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.
肿瘤微环境（TME）中的基质细胞群体在肾细胞癌的发生和转移中起着关键作用。在本研究中，我们发现透明细胞肾细胞癌（ccRCC）组织的基质中存在α-平滑肌肌动蛋白阳性（α-SMA(+)）细胞，其数量与ccRCC患者的不良生存显著相关。白细胞介素6（IL-6）是一种关键因子，它通过促进上皮-间质转化（EMT）诱导ccRCC组织中的α-SMA(+)细胞，并刺激ccRCC的迁移和侵袭。瘤周CD4+T细胞是ccRCC组织中IL-6的主要来源。除了生化因素外，肿瘤内的机械压迫也会影响肿瘤细胞的行为。在受限空间内生长的肿瘤表现出瘤内压应力，在足够的压力下，应力刺激癌细胞迁移。此外，CD4+T细胞分泌的IL-6与生长诱导的固体应力相结合，进一步促进了癌细胞形态发生、EMT和干性表型获得的调节。联合组的效应由Akt/GSK-3β/β-连环蛋白信号通路驱动，β-连环蛋白表达失调预示着ccRCC患者的不良预后。值得注意的是，癌症干细胞标志物CD44的表达与ccRCC的T分期、高Fuhrman分级和转移相关。这些数据为癌症治疗中减轻应激和靶向IL-6的新策略提供了证据。
