Mechanisms behind anorexia in experimental cancer
Cancer anorexia-cachexia syndrome (CACS) is observed in 80% of patients with advanced cancer and is one of the most frequent causes of death in cancer. CACS is multifactorial in origin and involves interactions of cytokines, neuropeptides, neurotransmitters and tumor-derived factors. The present work was aimed to investigate the mechanisms behind CACS in tumor-bearing hosts with particular emphasis on effects in the central nervous system (CNS). The role of intrinsically produced pro-inflammatory cytokines, serotonin (5-HT), nitric oxide (NO) and eicosanoids in development of anorexia was evaluated in a model with CACS , the MCG 101 sarcoma model in mice. This model has been extensively described and validated as a relevant model of experimental cancer cachexia.Tumor-bearing mice, pair-fed and freely-fed controls as well as mice treated with various drugs were used. Pro-inflammatory cytokines (IL-1beta, TNF-alpha, IL-6, IL-1RI and gp130), cyclooxygenase (COX)-2, NO synthases (NOS) in CNS, prostaglandin (PG) E receptors (EP) and prostacyclin receptor (IP) in CNS and peripheral tissues were measured by immunohistochemical staining combining image analysis or RT-PCR analysis. The role of PGE2, tricyclic antidepressants (TCA), 5-HT inhibitors, NOS inhibitors and indomethacin (an unselective COX inhibitor) in tumor-bearing mice were evaluated. EP1 and EP3 knock out mice were used to assess the role of EP receptors in development of CACS.The results showed that IL-1beta, TNF-alpha, IL-6, IL-1RI and gp130 as well as COX-2 content in hippocampus and VMH were similar in CACS animals and pair-fed nontumor-bearing controls. PGE2 provision to normal mice caused reduction of food intake and subsequently body weight with significant upregulation of IL-1beta, particularly in VMH. Provision of TCA or 5-HT inhibitors had no effects on CACS. nNOS, eNOS and iNOS increased differentially in various investigated brain nuclei of MCG tumor-bearing mice, similarly observed in pair-fed controls. Provision of unspecific NOS-inhibitors increased nNOS, eNOS and iNOS in several brain nuclei without effects on the development of CACS. Expression of EP and IP receptors in brain tissue of MCG tumor-bearing mice was not significantly responsive to elevated systemic PGE2 and IL-6 levels. Increased expression of EP1 in liver and of EP4 in fat tissue from tumor-bearing mice were normalized by indomethacin treatment, while depressed EP3 expression in skeletal muscles from tumor-bearing mice was not so. Tumor growth was significantly inhibited in EP1 knockout mice, and promoted in EP3 knockout mice. Indomethacin treatment improved food intake in wild type tumor-bearing mice, but not in EP1 or EP3 knockouts. However, body composition was preserved by indomethacin to the same extent in EP1 or EP3 knockouts as in wild type tumor-bearing mice.In conclusion, brain expression of pro-inflammatory cytokines, COX-2, EP and IP receptors as well as NOS did not clear cut explain tumor-induced anorexia in the MCG-101 tumor model. TCA and 5-HT inhibitors could not reverse tumor-induced anorexia-cachexia. In contract to CNS, EP receptor expression in peripheral tissues seemed to be related to progression of cancer cachexia. Thus, the current findings propose that COX pathways in peripheral tissues, rather than in CNS, are the most important to explain progressive CACS in this model.
Göteborgs universitet/University of Gothenburg
Department of Surgery
Avdelningen för kirurgi
S2, Sahlgrenska universitetssjukhuset/Sahlgrenska, Göteborg, kl. 09.00
Date of defence
Wang, Wenhua 1960-