Fibroblast activation protein α-positive pancreatic stellate cells promote the migration and invasion of pancreatic cancer by CXCL1-mediated Akt phosphorylation

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 a (FAP alpha)-positive (FAP alpha+) PSCs and the pathological features and prognosis of pancreatic cancer. The effects and mechanisms of FAP alpha + PSCs in pancreatic cancer were also explored. Methods: Tissue microarray analysis was used to detect FAP alpha expression in tumor and adjacent tissues. The relationship between FAP alpha expression and pancreatic pathological features and prognosis were analyzed. The effects of FAP alpha+ 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 FAP alpha-positive (FAP alpha+) and FAP alpha-negative (FAP alpha-) 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 FAP alpha expression. FAP alpha was mainly expressed in the PSCs. FAP alpha+ PSCs were associated with lymph node metastasis. Higher numbers of FAP alpha+ PSCs predicted shorter survival. Pancreatic cancer cells released TGF beta 1 and induced PSCs to express FAP alpha. FAP alpha+ 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. Talalx)stat (PT100), an FAP alpha inhibitor, inhibited the roles of FAP alpha+ PSCs. Conclusions: FAP alpha+ PSCs can promote the migration, invasion, and metastasis of pancreatic cancer by the Akt signaling pathway. This interaction of FAP alpha+ PSCs with pancreatic cancer cells may become a new strategy for the comprehensive treatment of pancreatic cancer.