Prognostic significance of fibroblast senescence and senescence-associated secretory phenotype factor expression in the tumor microenvironment of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrous stroma, within which a subset of fibroblasts function as cancer‑associated fibroblasts (CAFs) and contribute to tumor progression. Some of these fibroblasts undergo senescence and promote malignancy through the senescence‑associated secretory phenotype (SASP). The present study investigated SASP factor expression in senescent fibroblasts within the PDAC microenvironment and evaluated their impact on tumor progression. The expression levels of the senescence marker p16 and the SASP factor interleukin‑6 (IL‑6) were assessed using fluorescence immunostaining in resected specimens from 90 patients with PDAC who underwent pancreaticoduodenectomy. Senescence was induced in primary human pancreatic fibroblasts via X‑ray irradiation in vitro, followed by evaluation of SASP factor expression. These senescent fibroblasts were then co‑cultured with human pancreatic cancer Panc‑1 cells to assess their effects on cancer cell invasion, migration and proliferation. Immunostaining demonstrated the presence of p16‑ and IL‑6‑expressing fibroblasts in the PDAC stroma of patient samples. A positive correlation was observed between p16 and IL‑6 expression levels in fibroblasts. Notably, increased expression levels of IL‑6‑positive fibroblasts were associated with reduced postoperative survival. Multivariate analysis identified high IL‑6 expression and lymph node metastasis as independent prognostic indicators of poor outcome. In co‑culture experiments, senescent fibroblasts enhanced Panc‑1 cell invasion, migration and proliferation. These findings suggested that senescent fibroblasts within the PDAC stroma, with high SASP factor expression, contribute to tumor aggressiveness and are associated with poor prognosis. The present study demonstrated that IL‑6‑expressing senescent fibroblasts are potential prognostic markers and therapeutic targets in PDAC, therefore the targeted elimination of senescent cells may represent a promising therapeutic strategy.