Unraveling the impact of cancer-associated fibroblasts on hypovascular pancreatic neuroendocrine tumors

Abstract

Background Pancreatic neuroendocrine tumors (PNETs) with low microvessel density and fibrosis often exhibit clinical aggressiveness. Given the contribution of cancer-associated fibroblasts (CAFs) to the hypovascular fibrotic stroma in pancreatic ductal adenocarcinoma, investigating whether CAFs play a similar role in PNETs becomes imperative. In this study, we investigated the involvement of CAFs in PNETs and their effects on clinical outcomes. Methods We examined 79 clinical PNET specimens to evaluate the number and spatial distribution of α-smooth muscle actin (SMA)–positive cells, which are indicative of CAFs. Then, the findings were correlated with clinical outcomes. In vitro and in vivo experiments were conducted to assess the effects of CAFs (isolated from clinical specimens) on PNET metastasis and growth. Additionally, the role of the stromal-cell-derived factor 1 (SDF1)–AGR2 axis in mediating communication between CAFs and PNET cells was investigated. Results αSMA-positive and platelet-derived growth factor-α–positive CAFs were detected in the hypovascular stroma of PNET specimens. A higher abundance of α-SMA-positive CAFs within the PNET stroma was significantly associated with a higher level of clinical aggressiveness. Notably, conditioned medium from PNET cells induced an inflammatory phenotype in isolated CAFs. These CAFs promoted PNET growth and metastasis. Mechanistically, PNET cells secreted interleukin-1, which induced the secretion of SDF1 from CAFs. This cascade subsequently elevated AGR2 expression in PNETs, thereby promoting tumor growth and metastasis. The downregulation of AGR2 in PNET cells effectively suppressed the CAF-mediated promotion of PNET growth and metastasis. Conclusion CAFs drive the growth and metastasis of aggressive PNETs. The CXCR4–SDF1 axis may be a target for antistromal therapy in the treatment of PNET. This study clarifies mechanisms underlying PNET aggressiveness and may guide future therapeutic interventions targeting the tumor microenvironment.

AGR2: The Covert Driver and New Dawn of Hepatobiliary and Pancreatic Cancer Treatment

“…Zaytouni et al found that AGR2 expression was increased in obese PDAC patients and AKT-driven PDAC patients, the invasiveness of pancreatic cancer cells was proportional to the level of AGR2 expression [42,117,118], and the silencing of AGR2 in human pancreatic cancer cells (MPanc-96) inhibited tumor growth [42]. In contrast, AGR2 in pancreatic neuroendocrine tumor cells plays a role in promoting tumor growth and metastasis through interaction with cancer-associated fibroblasts [119]. Based on these conclusions, understanding the expression of AGR2 may help to stratify PDAC and be more helpful for clinical treatment.…”