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, 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.

ER Stress and Unfolded Protein Response in Cancer Cachexia

“…Ablation of MyD88 also prevented the activation of p38 MAPK and NF-κB pathways and gene expression of a few components of UPS and autophagy in skeletal muscle of LLC tumor-bearing mice [34]. Consistent with our findings with LLC tumor-bearing mice, another study recently demonstrated that genetic ablation of MyD88 attenuates muscle wasting and improves survival in a mouse model of pancreatic cancer cachexia further suggesting that the TLR/MyD88 signaling axis mediates the loss of skeletal muscle mass during cancer cachexia [35]. Major pathways involved in muscle loss in cancer cachexia.…”

The Toll-Like Receptor/MyD88/XBP1 Signaling Axis Mediates Skeletal Muscle Wasting during Cancer Cachexia

“…2). These results are consistent with a recently published report that also suggests that inhibition of MyD88 signaling attenuates pancreatic ductal adenocarcinoma-associated muscle wasting in mice (43). Our results further suggest that the inhibition of TLR/MyD88 signaling may prevent muscle wasting through the inhibition of the UPS and autophagy.…”

Melatonin pretreatment alleviates renal ischemia‐reperfusion injury by promoting autophagic flux via TLR4/MyD88/MEK/ERK/mTORC1 signaling

“…It is well known that the TLR4 signaling pathway has two downstream cascades, MyD88-dependent and MyD88independent pathways. 35 Given that the expression levels of MyD88 increased substantially in the IR group in our results, we investigated the MAPK signaling pathways, which are the key downstream pathways of MyD88 activation. 36 Many studies have revealed that downregulation of MAPKs, including ERK, JNK, and P38, in part induce autophagy-mediated F I G U R E 8 A proposed model of melatonin-induced autophagy protection against oxidative stress and apoptosis.…”