Malnutrition in Pancreatic Ductal Adenocarcinoma (PDA) Dietary Pancreatic Enzymes Improve Short-Term Health but Stimulate Tumor Growth

摘要

Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer that resists efforts to identify better chemotherapeutics. PDA is associated with chronic pancreatitis and acinar cell dedifferentiation. This reduces enzyme production by the exocrine pancreas, resulting in digestive insufficiencies. Malabsorption of partially digested food causes bloating, overfilled intestines, abdominal pain, excessive feces, steatorrhea, and malnutrition. These maladies affect quality of life and restrict treatment options for pancreatitis and PDA. Here, we characterize health benefits and risks of dietary pancreatic enzymes in three mouse models of PDA-KC, KCR8-16, and KIC. KC expresses oncogenic Kras(G12D) in pancreatic tissue whereas KCR8-16 also has deletions of the Rgs8 and Rgs16 genes. Rgs proteins inhibit the release of digestive enzymes evoked by G-protein-coupled-receptor agonists. KC and KCR8-16 mice developed dedifferentiated exocrine pancreata within 2 months of age and became malnourished, underweight, hypoglycemic, and hypothermic. KC mice adapted but KCR8-16 mice rapidly transitioned to starvation after mild metabolic challenges. Dietary pancreatic enzyme supplements reversed these symptoms in KC and KCR8-16 animals, and extended survival. Therefore, we tested the benefits of pancreatic enzymes in an aggressive mouse model of PDA (KIC). Median survival improved with dietary pancreatic enzyme supplements and was extended further when combined with warfarin and gemcitabine chemotherapy. However, dietary pancreatic enzymes stimulated tumor growth in the terminal stages of disease progression in KIC mice.