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MyD88 signalling is critical in the development of pancreatic cancer cachexia
BACKGROUND: Up to 80% of pancreatic cancer patients suffer from cachexia, a devastating condition that exacerbates underlying disease, reduces quality of life, and increases treatment complications and mortality. Tumour‐induced inflammation is linked to this multifactorial wasting syndrome, but mech...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463469/ https://www.ncbi.nlm.nih.gov/pubmed/30666818 http://dx.doi.org/10.1002/jcsm.12377 |
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author | Zhu, Xinxia Burfeind, Kevin G. Michaelis, Katherine A. Braun, Theodore P. Olson, Brennan Pelz, Katherine R. Morgan, Terry K. Marks, Daniel L. |
author_facet | Zhu, Xinxia Burfeind, Kevin G. Michaelis, Katherine A. Braun, Theodore P. Olson, Brennan Pelz, Katherine R. Morgan, Terry K. Marks, Daniel L. |
author_sort | Zhu, Xinxia |
collection | PubMed |
description | BACKGROUND: Up to 80% of pancreatic cancer patients suffer from cachexia, a devastating condition that exacerbates underlying disease, reduces quality of life, and increases treatment complications and mortality. Tumour‐induced inflammation is linked to this multifactorial wasting syndrome, but mechanisms and effective treatments remain elusive. Myeloid differentiation factor (MyD88), a key component of the innate immune system, plays a pivotal role in directing the inflammatory response to various insults. In this study, we tested whether MyD88 signalling is essential in the development of pancreatic cancer cachexia using a robust mouse tumour model. METHODS: Sex, age, and body weight‐matched wide type (WT) and MyD88 knockout (MyD88 KO) mice were orthotopically or intraperitoneally implanted with a pancreatic tumour cell line from a syngeneic C57BL/6 KRAS(G12D/+) P53(R172H/+) Pdx‐Cre (KPC) mouse. We observed the effects of MyD88 signalling during pancreatic ductal adenocarcinoma progression and the cachexia development through behavioural, histological, molecular, and survival aspects. RESULTS: Blocking MyD88 signalling greatly ameliorated pancreatic ductal adenocarcinoma‐associated anorexia and fatigue, attenuated lean mass loss, reduced muscle catabolism and atrophy, diminished systemic and central nervous system inflammation, and ultimately improved survival. Our data demonstrate that MyD88 signalling plays a critical role in mediating pancreatic cancer‐induced inflammation that triggers cachexia development and therefore represents a promising therapeutic target. CONCLUSIONS: MyD88‐dependent inflammation is crucial in the pathophysiology of pancreatic cancer progression and contributes to high mortality. Our findings implicate the importance of innate immune signalling pathways in pancreatic cancer cachexia and a novel therapeutic target. |
format | Online Article Text |
id | pubmed-6463469 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-64634692019-04-22 MyD88 signalling is critical in the development of pancreatic cancer cachexia Zhu, Xinxia Burfeind, Kevin G. Michaelis, Katherine A. Braun, Theodore P. Olson, Brennan Pelz, Katherine R. Morgan, Terry K. Marks, Daniel L. J Cachexia Sarcopenia Muscle Original Articles BACKGROUND: Up to 80% of pancreatic cancer patients suffer from cachexia, a devastating condition that exacerbates underlying disease, reduces quality of life, and increases treatment complications and mortality. Tumour‐induced inflammation is linked to this multifactorial wasting syndrome, but mechanisms and effective treatments remain elusive. Myeloid differentiation factor (MyD88), a key component of the innate immune system, plays a pivotal role in directing the inflammatory response to various insults. In this study, we tested whether MyD88 signalling is essential in the development of pancreatic cancer cachexia using a robust mouse tumour model. METHODS: Sex, age, and body weight‐matched wide type (WT) and MyD88 knockout (MyD88 KO) mice were orthotopically or intraperitoneally implanted with a pancreatic tumour cell line from a syngeneic C57BL/6 KRAS(G12D/+) P53(R172H/+) Pdx‐Cre (KPC) mouse. We observed the effects of MyD88 signalling during pancreatic ductal adenocarcinoma progression and the cachexia development through behavioural, histological, molecular, and survival aspects. RESULTS: Blocking MyD88 signalling greatly ameliorated pancreatic ductal adenocarcinoma‐associated anorexia and fatigue, attenuated lean mass loss, reduced muscle catabolism and atrophy, diminished systemic and central nervous system inflammation, and ultimately improved survival. Our data demonstrate that MyD88 signalling plays a critical role in mediating pancreatic cancer‐induced inflammation that triggers cachexia development and therefore represents a promising therapeutic target. CONCLUSIONS: MyD88‐dependent inflammation is crucial in the pathophysiology of pancreatic cancer progression and contributes to high mortality. Our findings implicate the importance of innate immune signalling pathways in pancreatic cancer cachexia and a novel therapeutic target. John Wiley and Sons Inc. 2019-01-21 2019-04 /pmc/articles/PMC6463469/ /pubmed/30666818 http://dx.doi.org/10.1002/jcsm.12377 Text en © 2019 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Articles Zhu, Xinxia Burfeind, Kevin G. Michaelis, Katherine A. Braun, Theodore P. Olson, Brennan Pelz, Katherine R. Morgan, Terry K. Marks, Daniel L. MyD88 signalling is critical in the development of pancreatic cancer cachexia |
title | MyD88 signalling is critical in the development of pancreatic cancer cachexia |
title_full | MyD88 signalling is critical in the development of pancreatic cancer cachexia |
title_fullStr | MyD88 signalling is critical in the development of pancreatic cancer cachexia |
title_full_unstemmed | MyD88 signalling is critical in the development of pancreatic cancer cachexia |
title_short | MyD88 signalling is critical in the development of pancreatic cancer cachexia |
title_sort | myd88 signalling is critical in the development of pancreatic cancer cachexia |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463469/ https://www.ncbi.nlm.nih.gov/pubmed/30666818 http://dx.doi.org/10.1002/jcsm.12377 |
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