TGF-β blockade reduces mortality and metabolic changes in a validated murine model of pancreatic cancer cachexia

Stephanie H. Greco, Lena Tomkötter, Anne Kristin Vahle, Rae Rokosh, Antonina Avanzi, Syed Kashif Mahmood, Michael Deutsch, Sara Alothman, Dalia Alqunaibit, Atsuo Ochi, Constantinos Zambirinis, Tasnima Mohaimin, Mauricio Rendon, Elliot Levie, Mridul Pansari, Alejandro Torres-Hernandez, Donnele Daley, Rocky Barilla, H. Leon Pachter, Daniel TippensHassan Malik, Allal Boutajangout, Thomas Wisniewski, George Miller

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Abstract

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.

Original languageEnglish (US)
Article numbere0132786
JournalPloS one
Volume10
Issue number7
DOIs
StatePublished - Jul 14 2015

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All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Greco, S. H., Tomkötter, L., Vahle, A. K., Rokosh, R., Avanzi, A., Mahmood, S. K., Deutsch, M., Alothman, S., Alqunaibit, D., Ochi, A., Zambirinis, C., Mohaimin, T., Rendon, M., Levie, E., Pansari, M., Torres-Hernandez, A., Daley, D., Barilla, R., Pachter, H. L., ... Miller, G. (2015). TGF-β blockade reduces mortality and metabolic changes in a validated murine model of pancreatic cancer cachexia. PloS one, 10(7), [e0132786]. https://doi.org/10.1371/journal.pone.0132786