Expression of TNF-α and CD44 is implicated in poor prognosis, cancer cell invasion, metastasis and resistance to the sunitinib treatment in clear cell renal cell carcinomas
Expression of TNF-α and CD44 is implicated in poor prognosis, cancer cell invasion, metastasis and resistance to the sunitinib treatment in clear cell renal cell carcinomas
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DOI：
10.1002/ijc.29137
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发表时间：
2015-04-01
影响因子：
6.4
通讯作者：
Okada, Yasunori
中科院分区：
文献类型：
--
作者：
Mikami, Shuji;Mizuno, Ryuichi;Okada, Yasunori
肿瘤坏死因子- (TNF-)参与多种癌症的上皮-间质转化（EMT）和CD44（一种癌症干细胞标志物）的表达。本研究旨在阐明TNF-和CD44在透明细胞肾细胞癌（ccRCCs）中的意义。免疫组化法检测120例ccrcc中TNF-和CD44的表达。通过监测培养的ccRCC细胞株中EMT相关基因和CD44的表达及侵袭情况，分析TNF-参与EMT和诱导CD44的作用。TNF-和CD44主要免疫定位于高级别ccrcc的癌细胞，与原发肿瘤分期呈正相关。TNF-和CD44的表达也呈正相关，TNF-和CD44的共同上调与肿瘤的原发分期、远处转移和预后不良有关。TNF-增强ccRCC细胞的迁移和侵袭，下调E-cadherin的表达，上调基质金属蛋白酶9和CD44的表达。TNF-也上调了ccRCC细胞中TNF-本身的表达。在接受舒尼替尼治疗转移性疾病的25例ccRCC患者中，高CD44表达与不良治疗结果相关。重要的是，舒尼替尼治疗的转移性ccrcc中残留的癌细胞CD44强烈阳性，并且舒尼替尼治疗患者的肿瘤中CD44的表达明显高于未治疗的患者。我们的数据显示TNF-通过诱导EMT和CD44的表达在ccrcc的进展中发挥重要作用，提示TNF-诱导的CD44可能参与了对舒尼替尼治疗的耐药。有什么新鲜事吗?癌症相关的炎症帮助肿瘤像野火一样扩散，而肿瘤坏死因子-使炎症持续下去。在某些癌症中，TNF-驱动细胞转移并促进CD44的表达，CD44是癌症干细胞的标志物。TNF-在透明细胞肾细胞癌（ccRCC）中的作用？这些作者发现TNF-表达与CD44表达相关，两者都与肿瘤分期和预后不良有关。此外，当患者接受舒尼替尼治疗时，对治疗反应不佳的患者CD44表达较高，这表明TNF-可以通过提高CD44水平来增强化疗耐药性。
Tumor necrosis factor- (TNF-) is involved in epithelial-mesenchymal transition (EMT) and expression of CD44, a cancer stem cell marker, in several cancers. This study was performed to clarify the significance of TNF- and CD44 in clear cell renal cell carcinomas (ccRCCs). Expression of TNF- and CD44 was examined by immunohistochemistry in 120 ccRCCs. Involvement of TNF- in EMT and induction of CD44 was analyzed by monitoring expression of EMT-related genes and CD44, and invasion in cultured ccRCC cell lines. TNF- and CD44 were immunolocalized mainly to carcinoma cells of high-grade ccRCCs with positive correlations with primary tumor stage. A positive correlation was also obtained between TNF- and CD44 expression, and co-upregulation of TNF- and CD44 was associated with primary tumor stage, distant metastasis, and poor prognosis. TNF- enhanced migration and invasion of ccRCC cells together with down-regulation of E-cadherin expression and up-regulation of matrix metalloproteinase 9 and CD44 expression. TNF- also up-regulated the expression of TNF- itself in ccRCC cells. Among the 25 ccRCC patients treated with sunitinib for metastatic disease, high CD44 expression was associated with poor treatment outcome. Importantly, residual carcinoma cells in the sunitinib-treated metastatic ccRCCs were strongly positive for CD44, and the CD44 expression was significantly higher in the tumors from the sunitinib-treated patients than in those from untreated ones. Our data show that TNF- plays an important role in progression of ccRCCs by inducing EMT and CD44 expression, and suggest that CD44 induced by TNF- may be involved in the resistance to the sunitinib treatment.What's New? Cancer-related inflammation helps tumors spread like wildfire, and TNF- gets that inflammation going. In some cancers, TNF- drives cells toward metastasis and boosts expression of CD44, a marker of cancer stem cells. What is the role of TNF- in clear cell renal cell carcinoma (ccRCC)? These authors found that TNF- expression correlates with CD44 expression, and both are associated with tumor stage and poor prognosis. In addition, when patients were treated with sunitinib, the ones that didn't respond well to the treatment had high CD44 expression, suggesting that TNF- can bolster chemotherapy resistance by driving up CD44 levels.