title: Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1.
abstract: It is well-established that prostaglandins (PGs) affect tumorigenesis, and evidence indicates that PGs also are important for the reduced food intake and body weight loss, the anorexia-cachexia syndrome, in malignant cancer. However, the identity of the PGs and the PG producing cyclooxygenase (COX) species responsible for cancer anorexia-cachexia is unknown. Here, we addressed this issue by transplanting mice with a tumor that elicits anorexia. Meal pattern analysis revealed that the anorexia in the tumor-bearing mice was due to decreased meal frequency. Treatment with a non-selective COX inhibitor attenuated the anorexia, and also tumor growth. When given at manifest anorexia, non-selective COX-inhibitors restored appetite and prevented body weight loss without affecting tumor size. Despite COX-2 induction in the cerebral blood vessels of tumor-bearing mice, a selective COX-2 inhibitor had no effect on the anorexia, whereas selective COX-1 inhibition delayed its onset. Tumor growth was associated with robust increase of PGE(2) levels in plasma - a response blocked both by non-selective COX-inhibition and by selective COX-1 inhibition, but not by COX-2 inhibition. However, there was no increase in PGE(2)-levels in the cerebrospinal fluid. Neutralization of plasma PGE(2) with specific antibodies did not ameliorate the anorexia, and genetic deletion of microsomal PGE synthase-1 (mPGES-1) affected neither anorexia nor tumor growth. Furthermore, tumor-bearing mice lacking EP(4) receptors selectively in the nervous system developed anorexia. These observations suggest that COX-enzymes, most likely COX-1, are involved in cancer-elicited anorexia and weight loss, but that these phenomena occur independently of host mPGES-1, PGE(2) and neuronal EP(4) signaling.
authors.affiliation: Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, S-581 85 Linköping, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Ruud
authors.affiliation: Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, S-581 85 Linköping, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Nilsson
authors.affiliation: Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, S-581 85 Linköping, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Engström Ruud
authors.affiliation: Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, Sahlgrenska University Hospital, S-413 45 Gothenburg, Sweden.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Wang
authors.affiliation: Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, S-581 85 Linköping, Sweden.
authors.forename: Camilla
authors.initials: C
authors.lastname: Nilsberth
authors.affiliation: Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, Sahlgrenska University Hospital, S-413 45 Gothenburg, Sweden.
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Iresjö
authors.affiliation: Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, Sahlgrenska University Hospital, S-413 45 Gothenburg, Sweden.
authors.forename: Kent
authors.initials: K
authors.lastname: Lundholm
authors.affiliation: Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, S-581 85 Linköping, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Engblom
authors.affiliation: Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, S-581 85 Linköping, Sweden. Electronic address: anders.blomqvist@liu.se.
authors.forename: Anders
authors.initials: A
authors.lastname: Blomqvist
mesh_terms: D000818:Animals; D000855:Anorexia / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology*; D001831:Body Temperature / Q000502:physiology; D051545:Cyclooxygenase 1 / Q000096:biosynthesis / Q000235:genetics*; D051546:Cyclooxygenase 2 / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D015232:Dinoprostone / Q000097:blood / Q000134:cerebrospinal fluid; D004435:Eating / Q000187:drug effects / Q000502:physiology; D005260:Female; D007150:Immunohistochemistry; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000150:complications / Q000201:enzymology* / Q000523:psychology*; D000071876:Prostaglandin-E Synthases; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D060888:Real-Time Polymerase Chain Reaction; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D016861:Cyclooxygenase Inhibitors; D018076:DNA, Complementary; C545651:Ptger4 protein, mouse; D058309:Receptors, Prostaglandin E, EP4 Subtype; D012313:RNA; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone