The effect of altered Toll-like receptor 4 signaling on cancer cachexia.
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.


METHODS
Prospective animal study.


METHODS
Academic research center.


METHODS
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 (TLR4(d/d)).


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


METHODS
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 TLR4(d/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 TLR4(d/d) mice. Interleukin 1beta level was significantly elevated in the tumor-bearing HeN mice (mean gain of 259 pg/mL) but not in the TLR4(d/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 TLR4(d/d) mice. The impaired ability to secrete proinflammatory cytokines such as interleukin 1beta 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.
Cannon
Trinitia Y
TY
Department of Otolaryngology, Head & Neck Surgery, G0412 Neurosciences Hospital, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7070, USA.
Guttridge
Denis
D
Dahlman
Jason
J
George
Jonathan R
JR
Lai
Victor
V
Shores
Carol
C
Buzková
Petra
P
Couch
Marion E
ME
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001835:Body Weight; D002100:Cachexia / Q000209:etiology / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006258:Head and Neck Neoplasms / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D011446:Prospective Studies; D015398:Signal Transduction / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D051197:Toll-Like Receptor 4