Systemic effects of cancer: role of multiple proteases and their toxic peptide products.

Cachexia, or the loss of skeletal muscle, adipose tissue and immunological competence, is a common systemic condition in advanced cases of cancer, and is a frequent cause of death. There have been many reports that small peptides isolated from tumors induce systemic effects correlated with cachexia upon injection into mice or addition to cell cultures. Only recently has evidence been presented for the origin of these peptides from the large increase in proteolytic enzymes found in tumors. Additional evidence is presented here for a major role of tumor peptides in producing effects associated with cachexia. Such peptides of low molecular weight were found to produce lipolysis in adipose tissue. Fibrinogen degradation products from the plasma of cancer patients and other chronic diseases suppress activation of the immune response. Some proteases of the cathepsin class occur in high concentration at the surface of transformed cells where the pH is low enough to allow digestion of pericellular proteins; other cathepsins elevated in tumors are highly active at physiological pH. Cathepsin L is the major excreted protein of cultured cells transformed by viruses or chemicals and is likely to form toxic peptides by digestion of extracellular proteins. Even normal liver and skeletal muscle of some cancer patients and tumor-bearing animals exhibit significant increases in cathepsins and components of the ubiquitin-proteasesome pathway which would add to circulating peptides. These observations argue for a central role of multiple proteases and their proteolytic products in producing the debilitating systemic effects of cancer.