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Miller et al. J Cancer Metastasis Treat 2019;5:68 I http://dx.doi.org/10.20517/2394-4722.2019.001 Page 3 of 11
[23]
of weight loss . These discrepancies between studies may be due to differences in measuring techniques,
possible auto or paracrine roles for TNF-α in adipose tissue, or heterogeneity between patients, sexes and
tumours.

In summary, TNF-α is involved in systemic inflammation, but as cachexia is likely to be multifactorial, it is
difficult to implicate TNF-α as the sole cause. More clinical studies are required to fully isolate its effects in
patients.

Interferon gamma
Interferons are multifunctional cytokines that block viral infections and affect cell proliferation and
[24]
differentiation . Interferon gamma (IFNg) is produced by activated T and NK cells, and is arguably
[25]
the most potent monocyte-macrophage activating factor . In the context of cancer, tumour‐infiltrating
lymphocytes (TILs), which have shown to be of particular importance in tumour immunosurveillance, are
[26]
the main source of IFNg . There is an overwhelming body of evidence for both beneficial and detrimental
roles of IFNg in a range of diseases, including cancer. However, its role in patients with cachexia is a
relatively underexplored area.

Several animal studies have indicated a central role for IFNg in the pathogenesis of cachexia. Central
administration of rat interferon resulted in decreased food intake whereas peripheral administration failed
[27]
to do so . Mice overexpressing IFNg producing tumour cells developed loss of body weight, atrophy of
adipose tissue, and reduced appetite, all of which were then reversed by pre-treatment of the mice with
[28]
anti-IFNg antibodies . Mice with LLC also demonstrated a reduction in weight loss after treatment with
[29]
anti-IFNg antibody, significantly reducing fat wasting in particular . In rats that had received transplants
of MCG 101 sarcoma, anti-IFNg antibody reduced weight loss, but the effect of treatment was short-
[30]
lived . Similarly to TNF-α, IFNg has been shown to inhibit LPL activity in adipocyte cells in vitro, as well
[31]
as that of glycerol phosphate dehydrogenase in cultures of rat adipocytes .
IL-1α
Levels of IL-1α have been shown to be increased in animal models of cachexia. It is thought to cause
[32]
similar effects to that of TNF-α . IL-1α is a pro-inflammatory cytokine produced mainly by macrophages
and endothelial cells and is known for being a trigger of the acute phase response, thus playing a role in
[33]
cancer pathogenesis, as well as shock and autoimmune disorders . In a similar fashion to other cytokines
[34]
discussed, it is also able to inhibit LPL activity and stimulate lipolysis in cultured adipocytes . The ability
[35]
of IL-1 to induce anorexia is thought to be due to a central effect on appetite suppression involving
blockade of neuropeptide Y. It also increases plasma concentrations of tryptophan and serotonin leading to
[36]
early satiety and suppression of hunger .
Again, there is evidence for the role of IL-1α in animal models of cachexia, but little in humans. IL-1α can
induce cachexia and anorexia in rats. IL-1α treated rats showed loss of body weight. Administration of
IL-1α receptor antagonist (IL-1rα) to tumourbearing rats however, did not result in any improvement
[37]
in body weight . Following direct tumour injection with IL-1rα, C26 mice demonstrated significantly
reduced weight loss (without an effect on tumour burden) compared with mice who had systemic
[38]
injection . Cultures of C26 cells also demonstrated raised levels of IL-6 after stimulation with IL-1α, which
[38]
were suppressed by monoclonal antibody to IL-6 . In tumour samples from patients undergoing surgical
resection for upper gastrointestinal malignancy, IL-1b and IL-6 were also significantly overexpressed in the
cancer specimens, at both mRNA and protein levels, compared with control mucosa. Protein levels were
[39]
seen to correlate with CRP, indicating that tumour may be the source of IL-1b .