Sex specificity of pancreatic cancer cachexia phenotypes, mechanisms, and treatment in mice and humans: role of Activin

Autor: Xiaoling Zhong, Ashok Narasimhan, Libbie M. Silverman, Andrew R. Young, Safi Shahda, Sheng Liu, Jun Wan, Yunlong Liu, Leonidas G. Koniaris, Teresa A. Zimmers
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Journal of Cachexia, Sarcopenia and Muscle, Vol 13, Iss 4, Pp 2146-2161 (2022)
Druh dokumentu: article
ISSN: 2190-6009
2190-5991
DOI: 10.1002/jcsm.12998
Popis: Abstract Background Cachexia is frequent, deadly, and untreatable for patients with pancreatic ductal adenocarcinoma (PDAC). The reproductive hormone and cytokine Activin is a mediator of PDAC cachexia, and Activin receptor targeting was clinically tested for cancer cachexia therapy. However, sex‐specific manifestations and mechanisms are poorly understood, constraining development of effective treatments. Methods Cachexia phenotypes, muscle gene/protein expression, and effects of the Activin blocker ACVR2B/Fc were assessed in LSL‐KrasG12D/+, LSL‐Trp53R172H/+, and Pdx‐1‐Cre (KPC) mice with autochthonic PDAC. Effects of PDAC and sex hormones were modelled by treating C2C12 myotubes with KPC‐cell conditioned medium (CM) and estradiol. Muscle gene expression by RNAseq and change in muscle from serial CT scans were measured in patients with PDAC. Results Despite equivalent tumour latency (median 17 weeks) and mortality (24.5 weeks), male KPC mice showed earlier and more severe cachexia than females. In early PDAC, male gastrocnemius, quadriceps, and tibialis anterior muscles were reduced (−21.7%, −18.9%, and −20.8%, respectively, all P
Databáze: Directory of Open Access Journals
Externí odkaz: