The Effect of Altered Toll-like Receptor 4 Signaling on Cancer Cachexia | Lifestyle Behaviors | JAMA Otolaryngology–Head & Neck Surgery | JAMA Network
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Original Article
December 2007

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

Author Affiliations

Author Affiliations: Department of Otolaryngology–Head & Neck Surgery and The Lineberger Comprehensive Cancer Center (Drs Cannon, Shores, and Couch) and the Doris Duke Research Fellowship Program, General Clinical Research Center (Mr George and Dr Lai), School of Medicine, and Department of Biostatistics, School of Public Health (Dr Bůžková), University of North Carolina, Chapel Hill; and the Division of Human Cancer Genetics, Department of Molecular Virology, Immunology, and Medical Genetics, the Integrated Biomedical Graduate Program, Department of Pathology, and The Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus (Dr Guttridge and Mr Dahlman).

Arch Otolaryngol Head Neck Surg. 2007;133(12):1263-1269. doi:10.1001/archotol.133.12.1263

Objective  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.

Design  Prospective animal study.

Setting  Academic research center.

Subjects  Six- to eight-week-old, female C3H/HeJ mice (17-18 g) and age-, weight-, and sex-matched wild-type C3H/HeN mice, differing in that the HeJ mice have nonfunctional TLR4 due to a TLR4 double mutation (TLR4d/d).

Intervention  The mice were inoculated with equal numbers of SCCF-VII cells and housed in individual cages.

Main Outcome Measures  Food intake, body weight, pretumor and posttumor body composition, circulating cytokines, and levels of a marker of muscle atrophy were analyzed.

Results  The wild-type HeN mice weighed less on average than the TLR4d/d mice (2.6 g vs 4.9 g) (P = .01). They consumed more food, had smaller tumors, and had less lean body mass and fat mass than the TLR4d/d mice. Interleukin 1β level was significantly elevated in the tumor-bearing HeN mice (mean gain of 259 pg/mL) but not in the TLR4d/d mice (P = .03). Both mouse strains had evidence of muscle atrophy.

Conclusions  In spite of increased food intake and smaller tumors, the wild-type HeN mice had more severe cachexia than the TLR4d/d mice. The impaired ability to secrete proinflammatory cytokines such as interleukin 1β may protect these animals from developing severe cancer cachexia. This animal model represents a novel system in which the host contributions to cachexia may be further studied.