title: New cancer cachexia rat model generated by implantation of a peritoneal dissemination-derived human stomach cancer cell line.
abstract: Cancer cachexia (CC), a syndrome characterized by anorexia and body weight loss due to low fat-free mass levels, including reduced musculature, markedly worsens patient quality of life. Although stomach cancer patients have the highest incidence of cachexia, few experimental models for the study of stomach CC have been established. Herein, we developed stomach CC animal models using nude rats subcutaneously implanted with two novel cell lines, i.e., MKN45c185, established from the human stomach cancer cell line MKN-45, and 85As2, derived from peritoneal dissemination of orthotopically implanted MKN45c185 cells in mice. Both CC models showed marked weight loss, anorexia, reduced musculature and muscle strength, increased inflammatory markers, and low plasma albumin levels; however, CC developed earlier and was more severe in rats implanted with 85As2 than in those implanted with MKN45cl85. Moreover, human leukemia inhibitory factor (LIF), a known cachectic factor, and hypothalamic orexigenic peptide mRNA levels increased in the models, whereas hypothalamic anorexigenic peptide mRNA levels decreased. Surgical removal of the tumor not only abolished cachexia symptoms but also reduced plasma LIF levels to below detectable limits. Importantly, oral administration of rikkunshito, a traditional Japanese medicine, substantially ameliorated CC-related anorexia and body composition changes. In summary, our novel peritoneal dissemination-derived 85As2 rat model developed severe cachexia, possibly caused by LIF from cancer cells, that was ameliorated by rikkunshito. This model should provide a useful tool for further study into the mechanisms and treatment of stomach CC.
authors.affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan;
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Terawaki
authors.forename: Yumi
authors.initials: Y
authors.lastname: Sawada
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kashiwase
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hashimoto
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yoshimura
authors.forename: Masami
authors.initials: M
authors.lastname: Suzuki
authors.forename: Kanako
authors.initials: K
authors.lastname: Miyano
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sudo
authors.forename: Seiji
authors.initials: S
authors.lastname: Shiraishi
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Higami
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Yanagihara
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kase
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ueta
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Uezono
mesh_terms: D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002100:Cachexia / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D045744:Cell Line, Tumor / Q000637:transplantation*; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000627:therapeutic use; D006801:Humans; D007028:Hypothalamic Hormones / Q000235:genetics / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000378:metabolism; D008297:Male; D008543:Melanins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D010101:Oxygen Consumption; D010907:Pituitary Hormones / Q000235:genetics / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011923:Rats, Nude; D013274:Stomach Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
chemical_list: D054369:Agouti-Related Protein; D016207:Cytokines; D004365:Drugs, Chinese Herbal; D007028:Hypothalamic Hormones; D053605:Leukemia Inhibitory Factor; D008543:Melanins; D009419:Nerve Tissue Proteins; D009478:Neuropeptide Y; D010907:Pituitary Hormones; D012333:RNA, Messenger; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; C084136:liu-jun-zi-tang; D011333:Pro-Opiomelanocortin; C019463:melanin-concentrating hormone; D003346:Corticotropin-Releasing Hormone
keywords: anorexia; cachexia; leukemia inhibitory factor; rikkunshito; stomach cancer model