Toll-Like Receptor-4 Disruption Suppresses Adipose Tissue Remodeling and Increases Survival in Cancer Cachexia Syndrome

Felipe Henriques,Kaltinaitis B Santos,Alexander Birbrair,Adilson Guilherme,Felipe O Franco,Luana L Bueno,Sidney B Peres,Stephen R Farmer,Miguel L Batista,Victor A Correa,Pamela Knobl,Magno A Lopes,Alexander H Bedard

doi:10.1038/s41598-018-36626-3

Abstract

Cancer-induced cachexia, characterized by systemic inflammation, body weight loss, adipose tissue (AT) remodeling and muscle wasting, is a malignant metabolic syndrome with undefined etiology. Here, we show that both genetic ablation and pharmacological inhibition of TLR4 were able to attenuate the main clinical markers of cachexia in mice bearing Lewis lung carcinoma (LLC). AT remodelling was not found in LLC tumor-bearing (TB) TLR4−/− mice due to reduced macrophage infiltration and adipocyte atrophy. TLR4−/− mice were also resistant to cold-induced browning of subcutaneous AT (scAT). Importantly, pharmacological inhibition of TLR4 (Atorvastatin) reproduced the main protective effect against AT remodeling found in TLR4−/− TB mice. Moreover, the treatment was effective in prolonging survival and attenuating tumor mass growth when compared to non-treated-TB animals. Furthermore, tumor-induced elevation of circulating pro-inflammatory cytokines was similarly abolished in both genetic ablation and pharmacological inhibition of TLR4. These data suggest that TLR4 is a critical mediator and a promising target for novel anti-cachexia therapies.

Highlights

A plethora of evidence from both patients and animal studies suggest a compelling link between activation of the inflammatory pathways and development of cancer cachexia[10,11]
We utilized the existing TLR4−/− mice[14] to examine the role of TLR4 in cancer cachexia. 28 days after Lewis Lung Carcinoma (LLC) cell inoculation a 12% reduction in body weight was measured in tumor-bearing wild-type (WT TB) mice, a classic sign of cachexia (Fig. 1A)
Since triglyceride (TG) turnover is affected by cachexia and partially diminished by TLR4 deletion, we evaluated genes involved in fatty acid metabolism in adipocytes

Summary

Introduction

A plethora of evidence from both patients and animal studies suggest a compelling link between activation of the inflammatory pathways and development of cancer cachexia[10,11]. It is likely that pathways responding to similar pro-inflammatory cytokines that mediate both sterile and infectious inflammation are critical in cancer cachexia. The stimulation of TLR4 by LPS induces the release of critical proinflammatory cytokines that are necessary to activate potent immune responses[12,13]. An elegant study showed that TLR4 is a crucial mediator of cancer-induced muscle wasting due to its integration of catabolic signaling by directly activating muscle protein degradation and indirectly increasing cytokine release[10]. The role of the TLR4 pathway in AT remodeling during cancer cachexia development remains unexplored. Our study sheds light on TLR4 pathway as a promising target for therapeutic intervention for cachexia

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Discussion

Conclusion