title: The 'cancer cachectic factor'.
abstract: The object of this study was to summarize information on catabolic factors produced by tumours which lead to tissue catabolism in cancer cachexia and to use this information for the development of effective therapy. The study population was made up of patients with cancer cachexia and weight loss greater than 1 kg month(-1). They had a varied range of carcinomas, particularly pancreatic, but also of the breast, ovary, lung, colon and rectum. Cachectic factors were isolated by standard biochemical methods, and the mechanism of tissue catabolism was evaluated in vitro and in vivo. We isolated a 24-kDa sulphated glycoprotein produced by cachexia-inducing murine and human tumours, which induces catabolism of myofibrillar proteins in skeletal muscle and for this reason has been named proteolysis-inducing factor (PIF). PIF was shown to be present in a diverse range of carcinomas in patients whose rate of weight loss exceeded 1.0 kg month(-1). Administration of PIF to normal mice produced a rapid decrease in body weight, which arose primarily from a loss of skeletal muscle, accompanied by increased mRNA levels for ubiquitin, the ubiquitin-carrier protein (E2(14k)), and proteasome subunits. This suggests that PIF induces protein catabolism through an increased expression of the key components of the ATP-ubiquitin-dependent proteolytic pathway. The action of PIF was attenuated both in vitro and in vivo by eicosapentaenoic acid (EPA). Oral EPA has been found to stabilize the body weight of patients with advanced pancreatic cancer and, when combined with an energy- and protein-rich nutritional supplement, to produce weight gain arising solely from an increase in lean body mass. Nutritional supplementation alone is unable to reverse the process of muscle wasting in cancer patients, since this arises from activation of the ubiquitin proteasome pathway by PIF, which is independent of nutrient intake. EPA is able to down-regulate the increased expression of this pathway and prevents muscle wasting in cancer patients.
authors.affiliation: Pharmaceutical Sciences Research Institute, Aston University, Birmingham B4 7ET, United Kingdom. M.J.Tisdale@aston.ac.uk
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Tisdale
mesh_terms: D001798:Blood Proteins / Q000032:analysis / Q000494:pharmacology*; D002100:Cachexia / Q000209:etiology / Q000503:physiopathology* / Q000628:therapy; D003546:Cysteine Endopeptidases / Q000494:pharmacology*; D015536:Down-Regulation; D015118:Eicosapentaenoic Acid; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D009097:Multienzyme Complexes / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000473:pathology; D009369:Neoplasms / Q000150:complications*; D018529:Nutritional Support; D046988:Proteasome Endopeptidase Complex; D011509:Proteoglycans; D012333:RNA, Messenger; D012307:Risk Factors; D025801:Ubiquitin / Q000494:pharmacology*; D015431:Weight Loss
chemical_list: D001798:Blood Proteins; D005231:Fatty Acids, Unsaturated; D009097:Multienzyme Complexes; D011509:Proteoglycans; D012333:RNA, Messenger; D025801:Ubiquitin; C042057:proteolysis-inducing peptide; D015118:Eicosapentaenoic Acid; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex