Characterization of a cancer cachectic factor

Abstract

Cancer cachexia is a syndrome of progressive wasting which has been suggested to be mediated by tumour-necrosis factor-alpha, interleukins 1 and 6, interferon-gamma and leukaemia-inhibitory factor. It has proved difficult to correlate levels of tumour-necrosis factor-alpha and interleukin-6 with cancer cachexia, and the weight loss induced by leukaemia-inhibitory factor may be due to toxicity. In the murine adenocarcinoma MAC16, cachexia is mediated by circulatory catabolic factors, which we have now isolated using an antibody cloned from splenocytes of mice transplanted with the MAC16 tumour, with a delayed cachexia. The material is a proteoglycan of relative molecular mass 24K which produces cachexia in vivo by inducing catabolism of skeletal muscle. The 24K material was also present in urine of cachectic cancer patients, but was absent from normal subjects, patients with weight loss due to trauma, and cancer patients with little or no weight loss. This suggests that cachexia in mice and humans may be produced by the same material.

Effect of a tumour-produced lipid-mobilizing factor on protein synthesis and degradation

“…This process has been attributed to tumour production of PIF, which inhibits protein synthesis and increases protein catabolism in skeletal muscle (Todorov et al, 1996;Lorite et al, 1997). However, the present study shows that LMF, also produced by cachexia-inducing tumours, appears to oppose the action of PIF by increasing protein synthesis and decreasing protein degradation in muscle.…”

“…DEAE-cellulose and hydrophobic interaction chromatography (Todorov et al, 1996 ) Particulate material was removed from urine by centrifugation at 3000 g for 10 min followed by dilution with 4 vol 10 mM Tris. HCl, pH 8.0.…”

Dermcidin expression in hepatic cells improves survival without N-glycosylation, but requires asparagine residues

“…This may be essential to its function as a cachetic factor, as dermcidin expression does not appear sufficient to induce cachexia (Monitto et al, 2004). Similarly, deglycosylated PIF lacks proteolytic activity in murine gastrocnemius muscle (Todorov et al, 1996(Todorov et al, , 1997, and in our experiments it was the fully glycosylated PIF molecule that influenced hepatic cell NF-kB and STAT3 activity and gene expression (Watchorn et al, 2001(Watchorn et al, , 2002. However, the PIF aminoacid sequence lacks typical consensus N-and O-glycosylation sites and the mechanism of glycosylation remains unknown.…”

“…The first product of the dermcidin gene to be identified was proteolysis-inducing factor (PIF), a novel cachectic factor that was purified from a cachexia-inducing murine tumour and the urine of weight-losing patients with pancreatic cancer (Todorov et al, 1996;Wigmore et al, 2000). Screening of tissues for PIF binding demonstrated substantial binding only to skeletal muscle and liver (unpublished observation), and we have investigated the effect of PIF on liver cells.…”

Postsurgery enteral nutrition in head and neck cancer patients

“…Malnutrition is reported in 50% of these patients (Bassett & Dobie, 1990). Malnutrition is due to reduced dietary intake secondary to dysphagia and alcohol consumption (Reilly, 1990); interleukins secreted by the tumor with a catabolic action played a dominant role (Todorov et al, 1996). Immunosupression is related to surgery and the immunosuppressive capacity of the tumor (Katz, 1983).…”