Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1.
Anorexia and weight loss are part of the wasting syndrome of late-stage cancer, are a major cause of morbidity and mortality in cancer, and are thought to be cytokine mediated. Macrophage inhibitory cytokine-1 (MIC-1) is produced by many cancers. Examination of sera from individuals with advanced prostate cancer showed a direct relationship between MIC-1 abundance and cancer-associated weight loss. In mice with xenografted prostate tumors, elevated MIC-1 levels were also associated with marked weight, fat and lean tissue loss that was mediated by decreased food intake and was reversed by administration of antibody to MIC-1. Additionally, normal mice given systemic MIC-1 and transgenic mice overexpressing MIC-1 showed hypophagia and reduced body weight. MIC-1 mediates its effects by central mechanisms that implicate the hypothalamic transforming growth factor-beta receptor II, extracellular signal-regulated kinases 1 and 2, signal transducer and activator of transcription-3, neuropeptide Y and pro-opiomelanocortin. Thus, MIC-1 is a newly defined central regulator of appetite and a potential target for the treatment of both cancer anorexia and weight loss, as well as of obesity.
Johnen
Heiko
H
Centre for Immunology, St. Vincent's Hospital and University of New South Wales, Sydney, New South Wales 2010, Australia.
Lin
Shu
S
Kuffner
Tamara
T
Brown
David A
DA
Tsai
Vicky Wang-Wei
VW
Bauskin
Asne R
AR
Wu
Liyun
L
Pankhurst
Greg
G
Jiang
Lele
L
Junankar
Simon
S
Hunter
Mark
M
Fairlie
W Douglas
WD
Lee
Nicola J
NJ
Enriquez
Ronaldo F
RF
Baldock
Paul A
PA
Corey
Eva
E
Apple
Fred S
FS
Murakami
Maryann M
MM
Lin
En-Ju
EJ
Wang
Chuansong
C
During
Matthew J
MJ
Sainsbury
Amanda
A
Herzog
Herbert
H
Breit
Samuel N
SN
D000818:Animals; D000855:Anorexia / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D000906:Antibodies / Q000008:administration & dosage / Q000502:physiology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D055436:Growth Differentiation Factor 15; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D005810:Multigene Family / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000097:blood / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000502:physiology; D015431:Weight Loss / Q000235:genetics / Q000276:immunology
D000906:Antibodies; D016207:Cytokines; C526140:GDF15 protein, human; C526141:Gdf15 protein, mouse; D055436:Growth Differentiation Factor 15; D016212:Transforming Growth Factor beta