Fibroblast activation protein α-positive pancreatic stellate cells promote the migration and invasion of pancreatic cancer by CXCL1-mediated Akt phosphorylation
Authors: Minhao Peng
Lizhou Liang
Jihua Wu
Banghao Xu
Jilong Wang
Yupei Zhao
Qiaofei Liu
Zhang Wen
Ya Guo
Quan Liao
Journal: Annals of translational medicine (2019)
Discipline: CLINICAL MEDICINE
Keywords: FAPα; invasion; migration; pancreatic cancer; pancreatic stellate cells (PSCs).
Affiliations: 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.

Abstract:  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 in vitro and in vivo. 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. 

Retracted: No

PubPeer comments:
 Figure3C ![file] , 
 #1 Dear Dr. Anchovia Surinamensis. Thank you for your valuale comment on our paper. We are sorry for the delayed reply, since we just noticed the comment. We checked the primary data carefully and discussed with the one who performed the experiment and the one who drew Fig.3C. We confirmed there was an un-intentional error of Fig.3C as marked by you, which would not affect or change the final results or conclusions. Fortunately, we have all of the primary files and figures. We are now working with the editorial office of the Journal to issue a correction to fix the problem. We will update you the information later. We are sure the Author Correction will be published soon. Thanks pubpeer as well! , 
 #1 Dear Dr. Anchovia Surinamensis. Thank you for your valuale comment on our paper. We are sorry for the delayed reply, since we just noticed the comment. We checked the primary data carefully and discussed with the one who performed the experiment and the one who drew Fig.3C. We confirmed there was an un-intentional error of Fig.3C as marked by you, which would not affect or change the final results or conclusions. Fortunately, we have all of the primary files and figures. We are now working with the editorial office of the Journal to issue a correction to fix the problem. We will update you the information later. We are sure the Author Correction will be published soon. Thanks pubpeer as well! ,