成纤维细胞活化蛋白α阳性的胰腺星状细胞通过CXCL1介导的Akt磷酸化促进胰腺癌的迁移和侵袭。
Fibroblast activation protein α-positive pancreatic stellate cells promote the migration and invasion of pancreatic cancer by CXCL1-mediated Akt phosphorylation.
作者信息
Wen Zhang, Liu Qiaofei, Wu Jihua, Xu Banghao, Wang Jilong, Liang Lizhou, Guo Ya, Peng Minhao, Zhao Yupei, Liao Quan
机构信息
Department of Hepatobiliary Surgery and Liver Transplantation, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China.
Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100730, China.
出版信息
Ann Transl Med. 2019 Oct;7(20):532. doi: 10.21037/atm.2019.09.164.
BACKGROUND
Pancreatic stellate cells (PSCs) is a highly heterogeneic stroma cell population in pancreatic cancer tissue. Interaction between PSCs and pancreatic cancer cells has not been well elucidated. This research was aimed to study the relationship between fibroblast activation protein α (FAPα)-positive (FAPα+) PSCs and the pathological features and prognosis of pancreatic cancer. The effects and mechanisms of FAPα + PSCs in pancreatic cancer were also explored.
METHODS
Tissue microarray analysis was used to detect FAPα expression in tumor and adjacent tissues. The relationship between FAPα expression and pancreatic pathological features and prognosis were analyzed. The effects of FAPα+ PSCs on the proliferation, migration and invasion of pancreatic cancer were detected and . A cytokine chip was used to detect the differential expression of cytokines in FAPα-positive (FAPα+) and FAPα-negative (FAPα-) PSCs. Phosphorylated tyrosine kinase receptors were detected by a human phosphotyrosine kinase receptor protein chip. The interaction between differential cytokine and tyrosine kinase receptors was detected by immunoprecipitation.
RESULTS
Compared with the adjacent tissues, pancreatic cancer stromal tissues showed high FAPα expression. FAPα was mainly expressed in the PSCs. FAPα+ PSCs were associated with lymph node metastasis. Higher numbers of FAPα+ PSCs predicted shorter survival. Pancreatic cancer cells released TGFβ1 and induced PSCs to express FAPα. FAPα+ PSCs released the chemokine CXCL1 and promoted the phosphorylation of the tyrosine kinase receptors EphB1 and EphB3 in pancreatic cancer cells. CXCL1, EphrinB1, and EphrinB3 worked together to promote the migration and invasion of pancreatic cancer cells by Akt phosphorylation. Talabostat (PT100), an FAPα inhibitor, inhibited the roles of FAPα+ PSCs.
CONCLUSIONS
FAPα+ PSCs can promote the migration, invasion, and metastasis of pancreatic cancer by the Akt signaling pathway. This interaction of FAPα+ PSCs with pancreatic cancer cells may become a new strategy for the comprehensive treatment of pancreatic cancer.
背景
胰腺星状细胞（PSCs）是胰腺癌组织中高度异质性的基质细胞群体。PSCs与胰腺癌细胞之间的相互作用尚未完全阐明。本研究旨在探讨成纤维细胞活化蛋白α（FAPα）阳性（FAPα+）PSCs与胰腺癌病理特征及预后的关系。同时也探讨了FAPα+ PSCs在胰腺癌中的作用及机制。
方法
采用组织芯片分析检测肿瘤及癌旁组织中FAPα的表达。分析FAPα表达与胰腺病理特征及预后的关系。检测FAPα+ PSCs对胰腺癌细胞增殖、迁移和侵袭的影响。使用细胞因子芯片检测FAPα阳性（FAPα+）和FAPα阴性（FAPα-）PSCs中细胞因子的差异表达。通过人磷酸酪氨酸激酶受体蛋白芯片检测磷酸化酪氨酸激酶受体。通过免疫沉淀检测差异细胞因子与酪氨酸激酶受体之间的相互作用。
结果
与癌旁组织相比，胰腺癌基质组织中FAPα表达较高。FAPα主要表达于PSCs。FAPα+ PSCs与淋巴结转移相关。FAPα+ PSCs数量较多预示生存期较短。胰腺癌细胞释放转化生长因子β1（TGFβ1）并诱导PSCs表达FAPα。FAPα+ PSCs释放趋化因子CXCL1并促进胰腺癌细胞中酪氨酸激酶受体EphB1和EphB3的磷酸化。CXCL1、EphrinB1和EphrinB3共同作用通过Akt磷酸化促进胰腺癌细胞的迁移和侵袭。FAPα抑制剂他拉泊司他（PT100）可抑制FAPα+ PSCs的作用。
结论
FAPα+ PSCs可通过Akt信号通路促进胰腺癌的迁移、侵袭和转移。FAPα+ PSCs与胰腺癌细胞之间的这种相互作用可能成为胰腺癌综合治疗的新策略。
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