TY - JOUR
T1 - Malnutrition in Pancreatic Ductal Adenocarcinoma (PDA)
T2 - Dietary Pancreatic Enzymes Improve Short-Term Health but Stimulate Tumor Growth
AU - Zolghadri, Yalda
AU - Pal Choudhuri, Shreoshi
AU - Ocal, Ozhan
AU - Layeghi-Ghalehsoukhteh, Somayeh
AU - Berhe, Feaven
AU - Hale, Michael A.
AU - Wilkie, Thomas M.
N1 - Funding Information:
Supported by National Cancer Institute grants CA161624 and NIHGMS 61395 (T.M.W.); a University of Texas Southwestern Cancer Center Pilot Project Award (T.M.W.); and Ministry of Science, Research and Technology training fellowships to Shiraz University (Y.Z. and S.L.-G.).
Publisher Copyright:
© 2018 American Society for Investigative Pathology
PY - 2018/3
Y1 - 2018/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85042254219&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85042254219&partnerID=8YFLogxK
U2 - 10.1016/j.ajpath.2017.11.014
DO - 10.1016/j.ajpath.2017.11.014
M3 - Article
C2 - 29248457
AN - SCOPUS:85042254219
SN - 0002-9440
VL - 188
SP - 616
EP - 626
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 3
ER -