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Tumor-derived IL-6 and trans-signaling among tumor, fat, and muscle mediate pancreatic cancer cachexia
- Source :
- The Journal of Experimental Medicine
- Publication Year :
- 2019
-
Abstract
- Cachexia increases morbidity and mortality. Rupert et al. show PDAC cachexia results from tissue crosstalk via an IL-6 trans-signaling loop. Malignant cells signal via IL-6 to muscle and fat, muscle to fat via sIL6R, and fat to muscle via lipids and IL-6.<br />Most patients with pancreatic adenocarcinoma (PDAC) suffer cachexia; some do not. To model heterogeneity, we used patient-derived orthotopic xenografts. These phenocopied donor weight loss. Furthermore, muscle wasting correlated with mortality and murine IL-6, and human IL-6 associated with the greatest murine cachexia. In cell culture and mice, PDAC cells elicited adipocyte IL-6 expression and IL-6 plus IL-6 receptor (IL6R) in myocytes and blood. PDAC induced adipocyte lipolysis and muscle steatosis, dysmetabolism, and wasting. Depletion of IL-6 from malignant cells halved adipose wasting and abolished myosteatosis, dysmetabolism, and atrophy. In culture, adipocyte lipolysis required soluble (s)IL6R, while IL-6, sIL6R, or palmitate induced myotube atrophy. PDAC cells activated adipocytes to induce myotube wasting and activated myotubes to induce adipocyte lipolysis. Thus, PDAC cachexia results from tissue crosstalk via a feed-forward, IL-6 trans-signaling loop. Malignant cells signal via IL-6 to muscle and fat, muscle to fat via sIL6R, and fat to muscle via lipids and IL-6, all targetable mechanisms for treatment of cachexia.
- Subjects :
- 0301 basic medicine
Male
Cachexia
Muscle Fibers, Skeletal
Adipose tissue
Innate immunity and inflammation
chemistry.chemical_compound
Mice
0302 clinical medicine
Adipocyte
Adipocytes
Immunology and Allergy
Myocyte
Wasting
Aged, 80 and over
Mice, Knockout
Myogenesis
3T3 Cells
Adipose Tissue
030220 oncology & carcinogenesis
Female
medicine.symptom
Signal Transduction
Lipolysis
Immunology
Adenocarcinoma
Article
Cell Line
03 medical and health sciences
Atrophy
Cell Line, Tumor
medicine
Animals
Humans
Solid Tumors
Muscle, Skeletal
Aged
business.industry
Interleukin-6
medicine.disease
Mice, Inbred C57BL
Pancreatic Neoplasms
Disease Models, Animal
030104 developmental biology
Metabolism
chemistry
Cancer research
business
Subjects
Details
- ISSN :
- 15409538
- Volume :
- 218
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- The Journal of experimental medicine
- Accession number :
- edsair.doi.dedup.....004a94792c710d50ed2aee4903aca6d9