Tumor necrosis factor-alpha induces the expression of carbonic anhydrase II in pancreatic adenocarcinoma cells.

TNF is a 17kD cytokine classically known for its cytotoxic effects on malignant cells. More recent cell culture studies demonstrated TNF induced cytostasis associated with the expression of a terminally differentiated phenotype. This was best characterized in malignant hematopoietic models, although a similar action on cells derived from solid tumors is now increasingly recognized. In the present study, six day exposure to TNF (40 ng/ml) stimulated morphologic changes in a human pancreatic adenocarcinoma cell line (HPAC), including increased cellular homogeneity, decreased nuclear to cytoplasmic ratio and detachment from the cell monolayer. Proliferation and DNA synthesis were reversibly inhibited while cellular viability was maintained. Parallel to the changes in morphology and growth was the delayed appearance of carbonic anhydrase II (CA II, E.C. 4.2.1.1), an accepted marker for pancreatic cells of ductal origin. A concomitant increase in the steady-state level of CA II mRNA was also observed over the time-course of TNF exposure. These results suggest a novel role for TNF in the induction of a more terminally differentiated ductal cell phenotype in a human pancreatic carcinoma model.