A number of malignant
tumors interact with the host to cause a syndrome of
cachexia, characterized by extensive loss of adipose tissue and skeletal muscle mass, but with preservation of
proteins in visceral tissues. Although
anorexia is frequently present, the body composition changes in
cancer cachexia cannot be explained by nutritional deprivation alone. Loss of skeletal muscle mass is a result of depression in
protein synthesis and an increase in protein degradation. The main degradative pathway that has been found to have increased expression and activity in the skeletal muscle of cachectic patients is the
ubiquitin-
proteasome proteolytic pathway.
Cachexia-inducing
tumors produce catabolic factors such as proteolysis-inducing factor (PIF), a 24 kDa sulfated
glycoprotein, which inhibit
protein synthesis and stimulate degradation of intracellular
proteins in skeletal muscle by inducing an increased expression of regulatory components of the
ubiquitin-
proteasome proteolytic pathway. While the
oligosaccharide chains in PIF are required to initiate protein degradation the central
polypeptide core may act as a growth and survival factor. Only
cachexia-inducing
tumors are capable of elaborating fully glycosylated PIF, and the selectivity of production possibly rests with the acquisition of the necessary glycosylating
enzymes, rather than expressing the gene for the
polypeptide core. Loss of adipose tissue is probably the result of an increase in catabolism rather than a defect in anabolism. A
lipid mobilizing factor (LMF), identical with the
plasma protein Zn-alpha2-glycoprotein (ZAG) is found in the urine of cachectic
cancer patients and is produced by
tumors causing a decrease in carcass
lipid. LMF causes
triglyceride hydrolysis in adipose tissue through a
cyclic AMP-mediated process by interaction with a beta3-adrenoreceptor. Thus, by producing circulating factors certain malignant
tumors are able to interfere with host metabolism even without
metastasis to that particular site.