MCT4 Expression in Pancreatic Cancer: Association with Prognosis, and Potential for Targeting Cancer Metabolism
Jeanne McFalls, Noah D Buboltz, Erik Knudsen, Agnieszka Witkiewicz. Thomas Jefferson University Hospital, Philadelphia, PA; Jefferson Medical College, Philadelphia, PA; Thomas Jefferson University, Philadelphia, PA
Background: Pancreatic ductal carcinoma (PDA) carries a poor prognosis, with a five-year survival rate of 6% despite treatment with surgery and chemotherapy. An emerging approach is to target the tumor's microenvironment and metabolic dependencies. PDA is known to have a glycolytic metabolism, producing large amounts of lactic acid. The monocarboxylate transporters (MCTs) are a group of membrane proteins that facilitate transport of lactic acid, preventing a fall in tumor cytosolic pH. We evaluated the expression, prognostic significance, and potential therapeutic relevance of MCT1 and MCT4 in cell cultures and clinical specimens of PDA.
Design: PDA tumor epithelial and stromal cell lines from human pancreatic adenocarcinoma were grown separately and in co-cultures. Cultures were treated with 20 nM gemcitabine for 48 hrs. Expression of MCT1 and MCT4 was assessed by immunofluorescence and Western blotting. Silencing of MCT4 expression was performed using siRNA. A tissue microarray containing 226 PDAs was immunohistochemically stained for MCT1 and MCT4 and scored using published criteria. Survival curves were computed by expression strata using the Kaplan-Meier method.
Results: MCT1 expression in pancreatic cancer cell lines was largely static, and there was no statistically significant association (p>0.05) of MCT1 expression with overall survival of PDA patients. In contrast, MCT4 expression varied across cell culture models and was induced by gemcitabine challenge or co-culture with cancer associated fibroblasts. Correspondingly, elevated MCT4 expression in both tumor epithelial cells (p=0.0012) and stromal cells (p=0.0018) was associated with a poor outcome in PDAs. This result remained significant in multivariate analyses. The attenuation of MCT4 expression by RNA-interference was associated with loss of pancreatic cancer cell viability both in mono and co-culture experiments.
Conclusions: MCT4 is highly expressed in pancreatic cancer cases and is associated with poor disease outcome. Functionally, MCT4 is induced by a variety of stress conditions, and could represent a viable target for therapeutic intervention.
Tuesday, March 5, 2013 1:00 PM
Poster Session IV # 162, Tuesday Afternoon