PPIC-labeled CAFs: Key players in neoadjuvant chemotherapy resistance for gastric cancer

Abstract

Background: Gastric cancer (GC) is the fourth leading cause of cancer deaths, with advanced cases having a median survival of less than one year. Neoadjuvant chemotherapy (NCT) is vital but faces drug resistance issues, partly due to cancer-associated fibroblasts (CAFs). Yet, specific CAF subpopulations contributing to resistance are poorly understood. Methods: Differentially expressed genes (DEGs) between chemosensitive and resistant GC patients were identified using GEO2R. Single-cell sequencing (scRNA-seq) identified CAF-related genes. Immunohistochemistry verified key genes in NCT-treated GC samples, analyzing their correlation with tumor regression grade (TRG) and clinicopathological characteristics. Results: PPIC as a gene highly expressed in CAFs was closely associated with NCT resistance in gastric cancer. Immunohistochemistry results revealed positivity for the expression of cyclophilin C (CypC), encoded by PPIC, in the 5-fluorouracil and cisplatin NCT resistant and -sensitive groups of gastric cancer patients at rates of 69.7 % (76/109) and 43.6 % (24/55), respectively (p < 0.001). The high expression of CypC in CAFs was positively correlated to tumor size (p = 0.025), T stage (p = 0.004), TNM stage (p = 0.004), and vascular invasion (p = 0.027). In cancer cells the expression of CypC was associated with OS (p = 0.026). However, in CAFs, CypC expression was not related to OS (p = 0.671). Conclusions: PPIC-labeled CAF subgroups are related to NCT resistance and poor prognosis in GC and they may cause drug resistance through signaling pathways such as glucose metabolism and extracellular matrix remodeling. However, the exact mechanism behind the involvement of PPIC-labeled CAF in drug resistance of GC requires further study.

Keywords

• PPIC
• CypC
• CAF
• Gastric cancer
• Chemoresistance
• Immune microenvironment