FAP, CD10, GPR77-labeled CAFs cause neoadjuvant chemotherapy resistance by inducing EMT and CSC in gastric cancer

Abstract

Objective: A significant proportion of patients can not benefit from neoadjuvant chemotherapy (NCT) due to drug resistance. Cancer-associated fibroblasts (CAFs) influence many biological behaviours of tumours, including chemo-resistance. The aim of this study is to explore whether CAFs expressing FAP, CD10 and GPR77 affect the efficacy of NCT and the prognosis of patients with gastric cancer, and its mechanism. Methods: 171 patients with locally progressive gastric adenocarcinoma who had undergone NCT and radical surgery were collected. Immunohistochemistry was used to detect the expression of FAP, CD10 and GPR77 in CAFs; the EMT markers (N-cadherin, Snail1 and Twist1) and the CSC markers (ALDH1, CD44 and LGR5) in gastric cancer cells. The χ2 test was used to analyse the relationship between the expression of CAF, EMT, and CSC markers and the clinicopathological factors, as well as the relationship between CAF markers and EMT, CSC markers. Logist regression and Cox risk regression were used to analyse the relationship between the expression of CAF, EMT, and CSC markers and TRG grading and OS; Kaplan-Meier analysis was used for survival analysis and plotting the curves. Results: The expression of CAF markers FAP, CD10, and GPR77 were closely associated with that of EMT markers; FAP and CD10 were closely related to CSC markers. In the univariate analysis of pathological response, CAF markers (FAP, CD10, GPR77), EMT markers (N-cadherin, Snail1, Twist1), and CSC markers (ALDH1, LGR5, CD44), were all closely associated with pathological response (all p < 0.05). Only Twist1 was an independent factor affecting pathological response in multifactorial analysis (p=0.001). In a univariate analysis of OS, expression of FAP and CD10 in CAF, as well as expression of EMT biomarkers (N-cadherin, Snail1), were significant factors influencing patient prognosis (all p<0.05). Multifactorial analysis revealed N-cadherin (p=0.032) and Snail1 (p=0.028), as independent prognostic factors affecting OS. Conclusion: FAP, CD10, and GPR77 labled CAF subgroup can lead to NCT resistance and poor prognosis by inducing EMT and CSC of gastric cancer cells in locally advanced gastric cancer patients.