Establishment and characterization of a novel murine model of pancreatic cancer cachexia

Katherine A. Michaelis, Xinxia Zhu, Kevin G. Burfeind, Stephanie Krasnow, Peter R. Levasseur, Terry Morgan, Daniel Marks

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Background: Cachexia is a complex metabolic and behavioural syndrome lacking effective therapies. Pancreatic ductal adenocarcinoma (PDAC) is one of the most important conditions associated with cachexia, with >80% of PDAC patients suffering from the condition. To establish the cardinal features of a murine model of PDAC-associated cachexia, we characterized the effects of implanting a pancreatic tumour cell line from a syngeneic C57BL/6 KRASG12D P53R172H Pdx-Cre+/+ (KPC) mouse. Methods: Male and female C57BL/6 mice were inoculated subcutaneously, intraperitoneally, or orthotopically with KPC tumour cells. We performed rigorous phenotypic, metabolic, and behavioural analysis of animals over the course of tumour development. Results: All routes of administration produced rapidly growing tumours histologically consistent with moderate to poorly differentiated PDAC. The phenotype of this model was dependent on route of administration, with orthotopic and intraperitoneal implantation inducing more severe cachexia than subcutaneous implantation. KPC tumour growth decreased food intake, decreased adiposity and lean body mass, and decreased locomotor activity. Muscle catabolism was observed in both skeletal and cardiac muscles, but the dominant catabolic pathway differed between these tissues. The wasting syndrome in this model was accompanied by hypothalamic inflammation, progressively decreasing brown and white adipose tissue uncoupling protein 1 (Ucp1) expression, and increased peripheral inflammation. Haematological and endocrine abnormalities included neutrophil-dominant leukocytosis and anaemia, and decreased serum testosterone. Conclusions: Syngeneic KPC allografts are a robust model for studying cachexia, which recapitulate key features of the PDAC disease process and induce a wide array of cachexia manifestations. This model is therefore ideally suited for future studies exploring the physiological systems involved in cachexia and for preclinical studies of novel therapies.

Original languageEnglish (US)
Pages (from-to)824-838
Number of pages15
JournalJournal of Cachexia, Sarcopenia and Muscle
Volume8
Issue number5
DOIs
StatePublished - Oct 1 2017

Fingerprint

Cachexia
Pancreatic Neoplasms
Adenocarcinoma
Neoplasms
Wasting Syndrome
Inflammation
White Adipose Tissue
Leukocytosis
Adiposity
Locomotion
Tumor Cell Line
Inbred C57BL Mouse
Allografts
Testosterone
Anemia
Myocardium
Skeletal Muscle
Neutrophils
Eating
Phenotype

Keywords

  • Cachexia
  • Cachexia models
  • Pancreatic cancer
  • Systemic inflammation

ASJC Scopus subject areas

  • Biophysics
  • Applied Microbiology and Biotechnology
  • Orthopedics and Sports Medicine
  • Physiology (medical)

Cite this

Establishment and characterization of a novel murine model of pancreatic cancer cachexia. / Michaelis, Katherine A.; Zhu, Xinxia; Burfeind, Kevin G.; Krasnow, Stephanie; Levasseur, Peter R.; Morgan, Terry; Marks, Daniel.

In: Journal of Cachexia, Sarcopenia and Muscle, Vol. 8, No. 5, 01.10.2017, p. 824-838.

Research output: Contribution to journalArticle

Michaelis, Katherine A. ; Zhu, Xinxia ; Burfeind, Kevin G. ; Krasnow, Stephanie ; Levasseur, Peter R. ; Morgan, Terry ; Marks, Daniel. / Establishment and characterization of a novel murine model of pancreatic cancer cachexia. In: Journal of Cachexia, Sarcopenia and Muscle. 2017 ; Vol. 8, No. 5. pp. 824-838.
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