The Effect of Altered Toll-like Receptor 4 Signaling on Cancer Cachexia

Cannon, Trinitia; Guttridge, Denis C.; Dahlman, Jason M.; George, Julia D.; Lai, Victor; Shores, Carol; Bůžková, Petra; Couch, Marion E.

doi:10.1001/archotol.133.12.1263

Cited by 25 publications

(22 citation statements)

References 25 publications

(28 reference statements)

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“…Genetic phenotypes, especially associated with immune signaling pathways, seem to be involved in the magnitude of the cachexia that develops. Inducing head and neck cancer in a preclinical model using cogenic murine strains with a double mutation in the toll‐like receptor 4 signaling pathway identified that the mouse strain with an intact inflammatory signaling pathway had more cachexia with smaller tumors than the strain with the defect in the toll‐like receptor 4 pathway . A handful of candidate genes to explain genetic polymorphisms in cancer cachexia have been reviewed recently and necessitate further study in patients and trials.…”

Section: Methodsmentioning

confidence: 99%

Cancer cachexia update in head and neck cancer: Definitions and diagnostic features

et al. 2014

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Cachexia is a profoundly debilitating wasting syndrome that affects patients with head and neck cancer and often contributes to their demise. A comprehensive literature search was performed up to April 2013 using PubMed, the Cochrane Library, CINAHL, and the Google search engine. For the meta-analyses, pooled prevalence estimates were calculated with a confidence interval of 95% (95% CI) by using random effects modeling. In this review, we outlined the unique challenges of cancer cachexia among patients with head and neck cancer by reviewing its impacts on quality of life (QOL), morbidity, and mortality. We explored the prevalence of different clinical markers of cachexia at the time of diagnosis and before and after treatment. Finally, we present updates regarding the diagnosis of cancer cachexia and recent findings, such as cardiac dysfunction that warrant clinical attention to more carefully identify patients at risk and potentially lead to better outcomes.

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Section: Methodsmentioning

confidence: 99%

Cancer cachexia update in head and neck cancer: Definitions and diagnostic features

et al. 2014

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“…80 Both wild-type and TLR-non-functional mice were inoculated with squamous carcinoma cells and compared. The wild-type mice weighed less on average than the TLR-non-functional mice.…”

Section: Role Of Inflammatory Molecules In Cancer-related Symptomsmentioning

confidence: 99%

“…These results indicated that the impaired ability to secrete IL-1 β may protect TLR-deficient mice from developing severe cancer cachexia. 80 One study of gastric cancer patients from China examined the predictive value of IL-1 β gene polymorphism for cachexia. Of the four alleles (IL-1 β -31 T/C, −511 C/T, +3954 C/T, IL-1RN), IL-1 β + 3954 C/T was found to be a major risk for cachexia in gastric cancer patients.…”

Section: Role Of Inflammatory Molecules In Cancer-related Symptomsmentioning

confidence: 99%

Role of nuclear factor-κB-mediated inflammatory pathways in cancer-related symptoms and their regulation by nutritional agents

Gupta

Kim

Kannappan

et al. 2011

Exp Biol Med (Maywood)

129

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Cancer is a disease characterized by dysregulation of multiple genes and is associated with symptoms such as cachexia, anorexia, fatigue, depression, neuropathic pain, anxiety, cognitive impairment, sleep disorders and delirium (acute confusion state) in medically ill patients. These symptoms are caused by either the cancer itself or the cancer treatment. During the past decade, increasing evidence has shown that the dysregulation of inflammatory pathways contributes to the expression of these symptoms. Cancer patients have been found to have higher levels of proinflammatory cytokines such as interleukin-6. The nuclear factor (NF)- κB is a major mediator of inflammatory pathways. Therefore, anti-inflammatory agents that can modulate the NF-κB activation and inflammatory pathways may have potential in improving cancer-related symptoms in patients. Because of their multitargeting properties, low cost, low toxicity and immediate availability, natural agents have gained considerable attention for prevention and treatment of cancer-related symptoms. How NF-κB and inflammatory pathways contribute to cancer-related symptoms is the focus of this review. We will also discuss how nutritional agents such as curcumin, genistein, resveratrol, epigallocatechin gallate and lycopene can modulate inflammatory pathways and thereby reduce cancer-related symptoms in patients.

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“…Previously Cannon et al . observed that mice with nonfunctional TLR4 due to a TLR4 double mutation (TLR4 d/d ) were resistant to cachexia induced by squamous cell carcinoma SCCF VII cells, and suggested that TLR4 mediated muscle wasting by increasing circulating IL-1β 22 . However, the detailed mechanism through which TLR4 mediates cancer-induced muscle wasting remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Toll-like receptor 4 mediates Lewis lung carcinoma-induced muscle wasting via coordinate activation of protein degradation pathways

Zhang

Liu

Ding

et al. 2017

Sci Rep

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Cancer-induced cachexia, characterized by muscle wasting, is a lethal metabolic syndrome with undefined etiology. Current consensus is that multiple factors contribute to cancer-induced muscle wasting, and therefore therapy requires combinational strategies. Here, we show that Toll-like receptor 4 (TLR4) mediates cancer-induced muscle wasting by directly activating muscle catabolism as well as stimulating an innate immune response in mice bearing Lewis lung carcinoma (LLC), and targeting TLR4 alone effectively abrogate muscle wasting. Utilizing specific siRNAs we observed that LLC cell-conditioned medium (LCM)-treated C2C12 myotubes underwent a rapid catabolic response in a TLR4-dependent manner, including activation of the p38 MAPK−C/EBPβ signaling pathway as well as the ubiquitin-proteasome and autophagy-lysosome pathways, resulting in myotube atrophy. Utilizing a reporter cell-line it was confirmed that LCM activated TLR4. These results suggest that LLC-released cachexins directly activate muscle catabolism via activating TLR4 on muscle cells independent of immune responses. Critically, LLC tumor-bearing TLR4−/− mice were spared from muscle wasting due to a blockade in muscle catabolic pathways. Further, tumor-induced elevation of circulating TNFα and interleukin-6 (IL-6) was abolished in TLR4−/− mice. These data suggest that TLR4 is a central mediator and therapeutic target of cancer-induced muscle wasting.

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The Effect of Altered Toll-like Receptor 4 Signaling on Cancer Cachexia

Abstract: To determine whether mice unable to mount an intact inflammatory response because of a Toll-like receptor (TLR) pathway defect will develop less severe cancer cachexia.

Cited by 25 publications

References 25 publications

Cancer cachexia update in head and neck cancer: Definitions and diagnostic features

Cancer cachexia update in head and neck cancer: Definitions and diagnostic features

Role of nuclear factor-κB-mediated inflammatory pathways in cancer-related symptoms and their regulation by nutritional agents

Toll-like receptor 4 mediates Lewis lung carcinoma-induced muscle wasting via coordinate activation of protein degradation pathways

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