Anterior Gradient 2 and Mucin 4 Expression Mirrors Tumor Cell Differentiation in Pancreatic Adenocarcinomas, But Aberrant Anterior Gradient 2 Expression Predicts Worse Patient Outcome in Poorly Differentiated Tumors

Objectives This study aimed to determine anterior gradient 2 (AGR2) expression in biopsies from pancreatic ductal adenocarcinomas (PDACs) and to evaluate AGR2 as a potential independent prognostic factor. Methods Tissue sample sections from a cohort of 135 consecutive surgically resectable PDACs were subjected to semiquantitative immunohistochemical analysis of AGR2 and mucin 4 (MUC4) expression. Results Anterior gradient 2 was over-expressed in PDAC compared with normal ductal cells. Since tumor lesions of PDAC are heterogeneous and constitute structures with various differentiation states, expression of both AGR2 and MUC4 was evaluated in each separate component. Expression levels of both proteins reflected the degree of tumor differentiation. Generally, well differentiated regions of tumor lesions expressed high levels of both proteins, moderately differentiated regions showed less AGR2 and MUC4, and poorly differentiated structures showed only weak positivity or were entirely negative. Of particular interest were occasional cases of strong AGR2 expression in high-grade tumors, where elevated protein levels were associated with shorter patient survival. Conclusions Anterior gradient 2 and MUC4 reflect the level of differentiation of PDACs. However, in less differentiated tumors, aberrantly elevated AGR2 expression predicts poor patient outcome.