TY - JOUR
T1 - TGF-β blockade reduces mortality and metabolic changes in a validated murine model of pancreatic cancer cachexia
AU - Greco, Stephanie H.
AU - Tomkötter, Lena
AU - Vahle, Anne Kristin
AU - Rokosh, Rae
AU - Avanzi, Antonina
AU - Mahmood, Syed Kashif
AU - Deutsch, Michael
AU - Alothman, Sara
AU - Alqunaibit, Dalia
AU - Ochi, Atsuo
AU - Zambirinis, Constantinos
AU - Mohaimin, Tasnima
AU - Rendon, Mauricio
AU - Levie, Elliot
AU - Pansari, Mridul
AU - Torres-Hernandez, Alejandro
AU - Daley, Donnele
AU - Barilla, Rocky
AU - Pachter, H. Leon
AU - Tippens, Daniel
AU - Malik, Hassan
AU - Boutajangout, Allal
AU - Wisniewski, Thomas
AU - Miller, George
N1 - Publisher Copyright:
© 2015 Greco et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2015/7/14
Y1 - 2015/7/14
N2 - Cancer cachexia is a debilitating condition characterized by a combination of anorexia, muscle wasting, weight loss, and malnutrition. This condition affects an overwhelming majority of patients with pancreatic cancer and is a primary cause of cancer-related death. However, few, if any, effective therapies exist for both treatment and prevention of this syndrome. In order to develop novel therapeutic strategies for pancreatic cancer cachexia, appropriate animal models are necessary. In this study, we developed and validated a syngeneic, metastatic, murine model of pancreatic cancer cachexia. Using our model, we investigated the ability of transforming growth factor beta (TGF-β) blockade to mitigate the metabolic changes associated with cachexia. We found that TGF-β inhibition using the anti- TGF-β antibody 1D11.16.8 significantly improved overall mortality, weight loss, fat mass, lean body mass, bone mineral density, and skeletal muscle proteolysis in mice harboring advanced pancreatic cancer. Other immunotherapeutic strategies we employed were not effective. Collectively, we validated a simplified but useful model of pancreatic cancer cachexia to investigate immunologic treatment strategies. In addition, we showed that TGF-βinhibition can decrease the metabolic changes associated with cancer cachexia and improve overall survival.
AB - Cancer cachexia is a debilitating condition characterized by a combination of anorexia, muscle wasting, weight loss, and malnutrition. This condition affects an overwhelming majority of patients with pancreatic cancer and is a primary cause of cancer-related death. However, few, if any, effective therapies exist for both treatment and prevention of this syndrome. In order to develop novel therapeutic strategies for pancreatic cancer cachexia, appropriate animal models are necessary. In this study, we developed and validated a syngeneic, metastatic, murine model of pancreatic cancer cachexia. Using our model, we investigated the ability of transforming growth factor beta (TGF-β) blockade to mitigate the metabolic changes associated with cachexia. We found that TGF-β inhibition using the anti- TGF-β antibody 1D11.16.8 significantly improved overall mortality, weight loss, fat mass, lean body mass, bone mineral density, and skeletal muscle proteolysis in mice harboring advanced pancreatic cancer. Other immunotherapeutic strategies we employed were not effective. Collectively, we validated a simplified but useful model of pancreatic cancer cachexia to investigate immunologic treatment strategies. In addition, we showed that TGF-βinhibition can decrease the metabolic changes associated with cancer cachexia and improve overall survival.
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U2 - 10.1371/journal.pone.0132786
DO - 10.1371/journal.pone.0132786
M3 - Article
C2 - 26172047
AN - SCOPUS:84940703446
SN - 1932-6203
VL - 10
JO - PloS one
JF - PloS one
IS - 7
M1 - e0132786
ER -