Page 13 - Diagnosis and clinical consequences of cachexia in patients with advanced cancer Susanne Blauwhoff-Buskermolen

mobilizing factor, is found in patients with weight loss and mechanistically related 1 to loss of fat tissue (17;18). PTHrP is produced by the tumor and mechanistically
related to anorexia and food intake in rats, however clinical relevance in humans
remains to be investigated (19).
Furthermore, the systemic in ammatory response of the host in reaction to the presence of a tumor elicits a cascade of reactions leading to anorexia and wasting of muscle mass and fat tissue. Pro-in ammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α) have been related to changes in central neurotransmitters, leading to anorexia (20). TNF-α and IL-1 are also involved in two pathways inducing structural muscle protein breakdown and inhibiting protein synthesis: the nuclear factor-k (NF-kB) pathway and the p38- mitogen-activated protein kinase (MAPK) pathway (21). Furthermore, interleukin-6 (IL-6) causes muscle protein degradation via activation of the STAT3 and the MAPK/ERK cascade (22).TNF-α has also been related to lipolysis in cancer cachexia (13).
A change in the functioning of the hypothalamus has also been suggested in the mechanism of cancer cachexia. The hypothalamus controls energy homeostasis via neurons that secrete appetite inhibiting (anorexigenic) and appetite stimulating (orexigenic) neuropeptides to control food intake. An example of an orexigenic neuropeptide is ghrelin, a 28-amino acid peptide and the natural ligand for the growth hormone secretagogue receptor-1a (23). Ghrelin is produced by endocrine cells of the antrum during periods of fasting; some studies found higher ghrelin levels in patients with weight loss (24-27), however other studies did not (28;29) and ghrelin levels were found to be increased in patients with decreased appetite after chemotherapy (23;24).The clinical relevance of ghrelin in the mechanism of anorexia and weight loss in cancer patients remains to be investigated. Figure 1 displays metabolic alterations in cancer leading to loss of muscle and fat mass and loss of appetite, together referred to as ‘cancer cachexia’.
General introduction
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