title: Sickness behavior induced by cisplatin chemotherapy and radiotherapy in a murine head and neck cancer model is associated with altered mitochondrial gene expression.
abstract: The present study was undertaken to explore the possible mechanisms of the behavioral alterations that develop in response to cancer and to cancer therapy. For this purpose we used a syngeneic heterotopic mouse model of human papilloma virus (HPV)-related head and neck cancer in which cancer therapy is curative. Mice implanted or not with HPV+ tumor cells were exposed to sham treatment or a regimen of cisplatin and radiotherapy (chemoradiation). Sickness was measured by body weight loss and reduced food intake. Motivation was measured by burrowing, a highly prevalent species specific behavior. Tumor-bearing mice showed a gradual decrease in burrowing over time and increased brain and liver inflammatory cytokine mRNA expression by 28 days post tumor implantation. Chemoradiation administered to healthy mice resulted in a mild decrease in burrowing, body weight, and food intake. Chemoradiation in tumor-bearing mice decreased tumor growth and abrogated liver and brain inflammation, but failed to attenuate burrowing deficits. PCR array analysis of selected hypoxia and mitochondrial genes revealed that both the tumor and chemoradiation altered the expression of genes involved in mitochondrial energy metabolism within the liver and brain and increased expression of genes related to HIF-1α signaling within the brain. The most prominent changes in brain mitochondrial genes were noted in tumor-bearing mice treated with chemoradiation. These findings indicate that targeting mitochondrial dysfunction following cancer and cancer therapy may be a strategy for prevention of cancer-related symptoms.
authors.affiliation: Department of Symptom Research, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 384, Houston, TX 77030, United States. Electronic address: egvichaya@mdanderson.org.
authors.forename: Elisabeth G
authors.initials: EG
authors.lastname: Vichaya
authors.affiliation: Department of Experimental Radiation Oncology, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 66, Houston, TX 77030, United States.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Molkentine
authors.affiliation: Cancer Biology Research Center, Sanford Research, 2301 E. 60th St. N., Sioux Falls, SD 57104, United States.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Vermeer
authors.affiliation: Department of Symptom Research, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 384, Houston, TX 77030, United States.
authors.forename: Adam K
authors.initials: AK
authors.lastname: Walker
authors.affiliation: National Institute of Nursing Research, Building 3, Room 5E14, 3 Center Dr., Bethesda, MD 20892, United States.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Feng
authors.affiliation: National Institute of Nursing Research, Building 3, Room 5E14, 3 Center Dr., Bethesda, MD 20892, United States.
authors.forename: Gerard
authors.initials: G
authors.lastname: Holder
authors.affiliation: Department of Symptom Research, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 384, Houston, TX 77030, United States.
authors.forename: Katherine
authors.initials: K
authors.lastname: Luu
authors.affiliation: Department of Experimental Radiation Oncology, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 66, Houston, TX 77030, United States.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Mason
authors.affiliation: National Institute of Nursing Research, Building 3, Room 5E14, 3 Center Dr., Bethesda, MD 20892, United States.
authors.forename: Leo
authors.initials: L
authors.lastname: Saligan
authors.affiliation: Department of Symptom Research, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 384, Houston, TX 77030, United States.
authors.forename: Cobi J
authors.initials: CJ
authors.lastname: Heijnen
authors.affiliation: Department of Symptom Research, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 384, Houston, TX 77030, United States.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Kavelaars
authors.affiliation: Department of Experimental Radiation Oncology, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 66, Houston, TX 77030, United States.
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Mason
authors.affiliation: Cancer Biology Research Center, Sanford Research, 2301 E. 60th St. N., Sioux Falls, SD 57104, United States.
authors.forename: John H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Symptom Research, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 384, Houston, TX 77030, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Dantzer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000473:pathology / Q000528:radiation effects; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D050259:Genes, Mitochondrial / Q000187:drug effects / Q000528:radiation effects; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D055809:Illness Behavior / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects*; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology / Q000528:radiation effects; D008297:Male; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D009042:Motivation / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009368:Neoplasm Transplantation; D009959:Oropharyngeal Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D027383:Papillomaviridae; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D011838:Radiation-Sensitizing Agents; D002945:Cisplatin
keywords: Cancer; Chemoradiotherapy; Human papilloma virus; Hypoxia; Mitochondria; Sickness behavior