MyD88 signalling is critical in the development of pancreatic cancer cachexia
Abstract 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,...
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Online Access: | https://doi.org/10.1002/jcsm.12377 |
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doaj-f7d21eb0c8d0469eb60e37d9204f3ebe2020-11-25T01:06:31ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092019-04-0110237839010.1002/jcsm.12377MyD88 signalling is critical in the development of pancreatic cancer cachexiaXinxia Zhu0Kevin G. Burfeind1Katherine A. Michaelis2Theodore P. Braun3Brennan Olson4Katherine R. Pelz5Terry K. Morgan6Daniel L. Marks7Papé Family Pediatric Research Institute Oregon Health & Science University Portland OR 97239 USAPapé Family Pediatric Research Institute Oregon Health & Science University Portland OR 97239 USAPapé Family Pediatric Research Institute Oregon Health & Science University Portland OR 97239 USAKnight Cancer Institute Oregon Health & Science University Portland USAPapé Family Pediatric Research Institute Oregon Health & Science University Portland OR 97239 USAPapé Family Pediatric Research Institute Oregon Health & Science University Portland OR 97239 USADepartment of Pathology Oregon Health & Science University Portland USAPapé Family Pediatric Research Institute Oregon Health & Science University Portland OR 97239 USAAbstract 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 KRASG12D/+ P53R172H/+ 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.https://doi.org/10.1002/jcsm.12377Pancreatic cancerCachexiaMyD88InflammationOrthotopic model |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xinxia Zhu Kevin G. Burfeind Katherine A. Michaelis Theodore P. Braun Brennan Olson Katherine R. Pelz Terry K. Morgan Daniel L. Marks |
spellingShingle |
Xinxia Zhu Kevin G. Burfeind Katherine A. Michaelis Theodore P. Braun Brennan Olson Katherine R. Pelz Terry K. Morgan Daniel L. Marks MyD88 signalling is critical in the development of pancreatic cancer cachexia Journal of Cachexia, Sarcopenia and Muscle Pancreatic cancer Cachexia MyD88 Inflammation Orthotopic model |
author_facet |
Xinxia Zhu Kevin G. Burfeind Katherine A. Michaelis Theodore P. Braun Brennan Olson Katherine R. Pelz Terry K. Morgan Daniel L. Marks |
author_sort |
Xinxia Zhu |
title |
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_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_sort |
myd88 signalling is critical in the development of pancreatic cancer cachexia |
publisher |
Wiley |
series |
Journal of Cachexia, Sarcopenia and Muscle |
issn |
2190-5991 2190-6009 |
publishDate |
2019-04-01 |
description |
Abstract 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 KRASG12D/+ P53R172H/+ 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. |
topic |
Pancreatic cancer Cachexia MyD88 Inflammation Orthotopic model |
url |
https://doi.org/10.1002/jcsm.12377 |
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