Facteurs lipolytiques et protéolytiques de la cachexie cancéreuse

Abstract

Patients with cancer cachexia experience a profound loss of both adipose tissue and skeletal muscle mass. Depletion of adipose tissue arises primarily from an increased hydrolysis of triglycerides mediated by a tumour factor, lipid mobilizing factor (LMF). LMF induces stimulation of adipocyte adenylate cyclase in a GTP-dependent process through binding to a β-adrenergic receptor, as for lipolytic hormones, resulting in specific depletion of carcass fat. Loss of muscle mass results from a decrease in protein synthesis and an increase in protein degradation, the latter being mediated through an increased expression of the components of the ubiquitin-proteasome pathway. Both murine and human cachexia-inducing tumours have been shown to secrete a proteolysis-inducing factor (PIF), a 24 kDa sulphated glycoprotein capable of inducing catabolism of skeletal muscle proteins both in vitro and in vivo. PIF initiates muscle protein catabolism by upregulation of the expression of the ubiquitin-proteasome pathway, possibly through the mediation of 15-hydroxyeicosatetraenoic acid (15-HETE). This process is attenuated by the polyunsaturated fatty acid, eicosapentaenoic acid (EPA), which has also been shown to completely stabilize weight loss in patients with unresectable pancreatic carcinoma. This suggests that knowledge of the catabolic mediators involved in cancer cachexia well lead to effective therapeutic intervention.