Tumor–host interactions

Abstract

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.

The role of Zn-α2 glycoprotein in sperm motility is mediated by changes in cyclic AMP

“…Recently, it has been reported that ZAG activity in rodents is mediated via the b 3 -adrenoreceptor, with upregulation of the cAMP pathway (Russell et al 2004, Tisdale 2004, McDermott et al 2006. In a previous study, we reported that ZAG was primarily related to sperm forward motility in human semen (Ding et al 2007).…”

“…The cAMP signaling pathway is reported to be involved in the process of lipolysis in adipocytes in many mammals, for which the b-adrenergic receptor is directly induced by ZAG (Russell et al 2002, 2004, Sanders & Tisdale 2004, Tisdale 2004, McDermott et al 2006. The crystalline structure of ZAG resembles a class I major histocompatibility complex (MHC) heavy chain, but, unlike other MHC-related proteins, ZAG does not bind the class I light-chain b 2 -microglobulin (Sanchez et al 1997(Sanchez et al , 1999.…”

“…It has subsequently been detected in various physiological and pathological fluids (Jirka et al 1978, Ohkubo et al 1990, Bundred et al 1991, Sanchez et al 1997. Acting as a lipid-mobilizing factor, ZAG is expressed and secreted in mammalian adipose tissue and is markedly upregulated with cancer cachexia (Hale et al 2001, Sanders & Tisdale 2004, Tisdale 2004. The expression level of ZAG is regulated through tumor necrosis factor-a and the peroxisome proliferator-activated receptor-g nuclear receptor (Bao et al 2005).…”

De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy

“…In this aspect, recent determination of the crystal structure of FASN and molecular description of its active sites (Maier et al, 2008) would help in the development of improved inhibitors. Cancer cells also induce lipolysis in adipose tissue, a characteristic feature of cachexia, by producing lipid mobilisation factors (Tisdale, 2004). However, it is still not clear how the exogenous lipid mobilised from adipose tissue could affect the dependence of tumours on de novo fatty-acid synthesis.…”

Oxidative and proteolytic profiles of the right and left heart in a model of cancer-induced cardiac cachexia

“…Depletion of lean body mass is the main characteristic of cachexia [2], but recent evidence has indicated that besides skeletal muscle depletion, cardiac proteins also play a role in affecting cardiac function [3,4].…”