肿瘤细胞与中性粒细胞之间的“对话”促进肾癌进展：基于ERβ介导的TGFβ/TGFβR相关外泌体的研究

Late-stage renal carcinoma is an incurable disease because of the metastasis. The current target therapy of renal carcinoma mainly focuses on aberrant signal pathways in cancer cell itself, such as PI3K/AKT/ VEGF and mTOR signal pathway. However, the result is dissatisfactory. In the past years, increasing evidences showed that stromal cells, especially the dominant neutrophils in tumor microenvironment, play crucial roles on tumor progression. It is reported that neutrophils in tumor microenvironment could differentiate from anti-tumor TAN1 to pro-tumor TAN2 during tumor progression. In the previous study, we found that TAN2-like neutrophils promoted renal carcinoma progression through up-regulating ERβ. However, the mechanisms by which neutrophil differentiate from TAN1 to TAN2 in renal carcinoma remain unknown. More importantly, we also found in the previous study that ERβstimulated cancer cells to secrete TGFβ/TGFβR associated exosome into tumor microenvironment. Thus, we hypothesized that ERβmediated TGFβ/TGFβR associated exosome from renal carcinoma might educate neutrophils and promote the differentiation from TAN1 to TAN2, and then accelerate cancer progression of renal carcinoma.

晚期肾癌因发生肿瘤转移且对靶向治疗效果不理想而成为一种难治性疾病。近年来研究发现，肿瘤微环境中占主导的中性粒细胞在肿瘤进展中扮演了重要角色。随着肿瘤进展，中性粒细胞可从抗肿瘤活性的TAN1分化为促进肿瘤进展的TAN2，进而加速肿瘤发展。申请人在前期研究中发现具有TAN2特性的中性粒细胞可通过上调ERβ表达促进肾癌进展。然而肾癌微环境中的中性粒细胞如何从TAN1到TAN2的分化尚不清楚。在预实验中我们发现ERβ促使肾癌细胞分泌TGFβ及其受体TGFβR相关的外泌素至肿瘤微环境。因此我们推测ERβ可促进肾癌细胞分泌TGFβ/TGFβR相关外泌素，进而将TGFβ/TGFβR信号传递至中性粒细胞，“驯化”中性粒细胞使其从抗肿瘤的TAN1分化为促进肿瘤发展的TAN2，进一步引起ERβ及其下游基因上调，形成正反馈效应并促进肾癌进展。该研究对于了解肾癌进展机制及寻找新的治疗靶点具有重要意义。

晚期肾癌因发生肿瘤转移而成为一种难治性疾病。目前肾癌治疗主要是基于PI3K/AKT/ VEGF和mTOR等肿瘤自身异常信号的靶向治疗，但效果并不理想。近年来多项研究发现，肿瘤微环境中的间质细胞成分，尤其是数量占主导优势的中性粒细胞，也在肿瘤进展中扮演了重要角色。随着肿瘤进展，中性粒细胞可从具有抗肿瘤活性的TAN1分化为能促进肿瘤进展的TAN2，进而加速肿瘤发展。申请人在前期研究中发现具有TAN2特性的中性粒细胞可通过上调ERβ表达促进肾癌进展。在本项目中，我们进一步探讨了ERβ在肾癌进展中的作用，我们发现ERβ可显著促进肾癌的体内外生长及转移。更重要的是，ERβ抑制剂ICI182,780 (Faslodex，ICI) 和PHTPP可在体内显著抑制肾癌的生长及转移，提示针对ERβ的治疗可能在肾癌治疗中具有应用前景。此外，我们也开展了miR-9-5p及蛋白乙酰化修饰的参与肾癌进展的相关研究。