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 Tippens; Hassan Malik; Allal Boutajangout; Thomas Wisniewski; George Miller

doi:10.1371/journal.pone.0132786

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 Tippens

Hassan Malik, Allal Boutajangout, Thomas Wisniewski, George Miller

Surgery

New York University

Research output: Contribution to journal › Article › peer-review

72 Scopus citations

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 language	English
Article number	e0132786
Pages (from-to)	e0132786
Journal	PLoS ONE
Volume	10
Issue number	7
DOIs	https://doi.org/10.1371/journal.pone.0132786
State	Published - Jul 14 2015

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Animals
Antibodies/immunology
Body Composition
Cachexia/complications
Cell Line, Tumor
Disease Models, Animal
Immunotherapy
Male
Mice
Mice, Inbred C57BL
Muscular Atrophy/complications
Neoplasm Metastasis
Pancreatic Neoplasms/complications
Survival Analysis
Transforming Growth Factor beta/immunology

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10.1371/journal.pone.0132786

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. Article e0132786. https://doi.org/10.1371/journal.pone.0132786

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

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.",

keywords = "Animals, Antibodies/immunology, Body Composition, Cachexia/complications, Cell Line, Tumor, Disease Models, Animal, Immunotherapy, Male, Mice, Mice, Inbred C57BL, Muscular Atrophy/complications, Neoplasm Metastasis, Pancreatic Neoplasms/complications, Survival Analysis, Transforming Growth Factor beta/immunology",

author = "Greco, \{Stephanie H.\} and Lena Tomk{\"o}tter and Vahle, \{Anne Kristin\} and Rae Rokosh and Antonina Avanzi and Mahmood, \{Syed Kashif\} and Michael Deutsch and Sara Alothman and Dalia Alqunaibit and Atsuo Ochi and Constantinos Zambirinis and Tasnima Mohaimin and Mauricio Rendon and Elliot Levie and Mridul Pansari and Alejandro Torres-Hernandez and Donnele Daley and Rocky Barilla and Pachter, \{H. Leon\} and Daniel Tippens and Hassan Malik and Allal Boutajangout and Thomas Wisniewski and George Miller",

note = "Publisher Copyright: {\textcopyright} 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.",

year = "2015",

month = jul,

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doi = "10.1371/journal.pone.0132786",

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Greco, SH, Tomkötter, L, Vahle, AK, Rokosh, R, Avanzi, A, Mahmood, SK, 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, HL, Tippens, D, Malik, H, Boutajangout, A, Wisniewski, T & Miller, G 2015, 'TGF-β blockade reduces mortality and metabolic changes in a validated murine model of pancreatic cancer cachexia', PLoS ONE, vol. 10, no. 7, e0132786, pp. e0132786. https://doi.org/10.1371/journal.pone.0132786

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.

KW - Animals

KW - Antibodies/immunology

KW - Body Composition

KW - Cachexia/complications

KW - Cell Line, Tumor

KW - Disease Models, Animal

KW - Immunotherapy

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Muscular Atrophy/complications

KW - Neoplasm Metastasis

KW - Pancreatic Neoplasms/complications

KW - Survival Analysis

KW - Transforming Growth Factor beta/immunology

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U2 - 10.1371/journal.pone.0132786

DO - 10.1371/journal.pone.0132786

M3 - Article

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SN - 1932-6203

VL - 10

SP - e0132786

JO - PLoS ONE

JF - PLoS ONE

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M1 - e0132786

ER -

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

Abstract

UN SDGs

Keywords

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