Preliminary Exploration Of The Correlation And Mechanism Between FAP,CD10 And GPR77-Labeled CAFs And Neoadjuvant Chemotherapy Resistance In Gastric Cancer

Objective: Neoadjuvant chemotherapy(NCT)can reduce the size of the lesion,reduce the stage of the tumour and improve the rate of complete surgical resection and survival,but a significant proportion of patients do not benefit from NCT due to drug resistance.Cancer-associated fibroblasts(CAF)are important components of the immune microenvironment and influence many biological behaviours of tumours,including drug resistance.But do CAFs expressing FAP,CD10 and GPR77 affect the efficacy of neoadjuvant chemotherapy and the prognosis of patients with gastric cancer? It is unclear whether they can affect the efficacy of neoadjuvant chemotherapy in gastric cancer patients by affecting epithelial to mesenchymal transition(EMT)or cancer stem cells(CSC).Methods: A total of 171 patients with locally progressive gastric adenocarcinoma who underwent NCT and radical surgery were collected,and the expression of FAP,CD10 and GPR77 in CAFs;the markers N-cadherin,Snail1 and Twist1 of EMT and the CSC markers ALDH1,CD44 and LGR5 in gastric cancer cells were examined using immunohistochemistry expression 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 of the cases,as well as the relationship between CAF markers and EMT and 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,as well as the relationship between CAF,EMT,CSC markers and OS;Kaplan-Meier analysis was used for survival analysis and plotting the curves.Results: 1.The positive rates for CAF markers FAP,CD10 and GPR77 were 39.8%,18.1% and 12.3% respectively.the positive rates for EMT markers N-cadherin,Snail1 and Twist1 were 37.4%,28.7% and 45.6% respectively.the positive rates for CSC markers ALDH1,CD44 and LGR5 were 64.3%,46.2% and 57.9% respectively.2.FAP,CD10 and GPR77 as markers of CAF were closely related to clinicopathological factors,and all three were significantly correlated with T stage,TNM stage and tumor Mandard TRG grade(P<0.05).FAP was associated with tumour size(P=0.002),N stage(P=0.034),degree of differentiation(P=0.031),lymphovascular invasion(P=0.016)and nerve invasion(P=0.029).CD10 expression was significantly associated with tumour size(P=0.006),N stage(P=0.034)and Lauren staging(P= 0.006).3.The markers FAP,CD10 and GPR77 of CAF were closely correlated with the EMT markers N-cadherin,Snail1 and Twist1: FAP expression in CAF was positively correlated with N-cadherin(P=0.002),Snail1(P<0.001)and Twist1(P=0.012);CD10expression was positively correlated with N-cadherin(P=0.001)and Snail1(P<0.001);GPR77 expression was positively correlated with N-cadherin(P=0.046)and Snail1(P=0.002).The markers FAP and CD10 of CAF were closely related to CSC markers.FAP expression was positively correlated with ALDH1(P=0.041),LGR5(P=0.006)and CD44(P=0.039).CD10 expression was positively correlated with ALDH1(P=0.012),LGR5(P=0.039)and CD44(P=0.024);while there was no significant correlation between GPR77 expression and any of the CSC markers.4.In a univariate analysis of pathological response,the CAF markers FAP(OR=24.826,P <0.001),CD10(OR=20.602,P=0.003),GPR77(OR=12.258,P=0.016),the EMT markers N-cadherin(OR=2.847,P=0.004),Snail1(OR=2.983,P=0.008),Twist1(OR=10.174,P <0.001),and the CSC markers ALDH1(OR=2.024,P=0.035),LGR5(OR=2.796,P=0.002),CD44(OR=2.324,P=0.012),all closely correlated with pathological response,with higher expression associated with higher TRG grading.In multifactorial analysis,Twist1(OR=14.238,P=0.001)expression was an independent factor influencing pathological response.5.In a univariate analysis of OS,expression of FAP(OR=1.843,P=0.013)and CD10(OR=1.832,P=0.032)in CAF,as well as expression of the EMT markers Ncadherin(OR=2.158,P=0.002)and Snail1(OR=1.735,P=0.033),were important factors influencing patient prognosis,with higher expression associated with poorer prognosis.A multifactorial analysis of prognosis identified the expression of EMT marker N-cadherin(OR=1.908,P=0.032),Snail1(OR=2.081,P=0.028),as independent prognostic factors affecting patients with gastric cancer.Conclusion: CAFs’ markers FAP,CD10,and GPR77 were associated with adverse clinicopathological factors,and CAFs expressing FAP,CD10,and GPR77 promoted gastric cancer progression;CAFs’ markers FAP,CD10,and GPR77 were associated with high Mandard TRG grade,and CAFs expressing FAP,CD10,and GPR77 may lead to neo-adjuvant chemotherapy resistance in gastric cancer EMT and CSC markers were closely associated with both CAF marker expression and TRG grading,and CAFs expressing FAP,CD10 and GPR77 may lead to neoadjuvant chemotherapy resistance by inducing EMT or CSC in gastric cancer cells;tumour site and EMT markers(Ncadherin and Snail1)were independent factors affecting patient prognosis.