Expression of the Galanin system in the human pancreas, pancreatitis, and pancreatic cancer: Association with nodal involvement and perineural invasion.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with a five-year survival rate of 6%, yet the underlying causes remain poorly understood. The neuropeptide galanin (GAL) and its three receptors (GAL1-3-R) are known to modulate tumor biology. This study characterizes the expression patterns of the GAL system in healthy and diseased pancreas to evaluate its potential as a biomarker for disease progression. Immunohistochemical staining for GAL and GAL1-3-R was performed on tissue samples from healthy controls (n = 10), pancreatitis (n = 10), and PDAC (n = 34). Immunoreactive scores were quantified across histological compartments and were correlated with TNM stage, perineural invasion, and Union for International Cancer Control classification. GAL was widely expressed, with significant upregulation in lobular ducts and nerve bundles of PDAC compared to controls. Intra-neural GAL expression in PDAC positively correlated with advanced nodal stages and perineural invasion. In pancreatitis, GAL1-R expression was selectively increased in lobular ducts. Although GAL2-R expression peaked in endocrine cells, intra-neural GAL2-R was significantly downregulated in PDAC compared to healthy tissue, with further decreases in advanced stages. GAL3-R was predominantly localized to ducts and acini, showing higher expression in PDAC endocrine compartments than in pancreatitis or healthy tissue. Our findings demonstrate significant remodeling of the galaninergic system during pancreatic inflammation and carcinogenesis. Stage-dependent intra-neural GAL increases correlate with nodal involvement and perineural invasion, suggesting its potential as a prognostic biomarker for tumor aggressiveness. Progressive intra-neural GAL2-R loss in PDAC may limit receptor-agonist therapy efficacy, necessitating receptor-status screening for personalized patient stratification in future clinical applications.