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An alternative proposed method is to augment endogenous APN levels using PPARg ligands [196] . Using
synthetic PPARg ligands, one group demonstrated that expression and secretion of APN increased in a dose
and time dependent manner [197] . Efatutazone, a selective PPARg agonist, showed promise on a phase I trial in
metastatic solid tumours [198] , metastatic colorectal cancer [199] , and thyroid cancer patients [200] . However, trials
were terminated after phase 2 due to insufficient efficacy [201,202] .

Another PPARg agonist Troglitazone has gained much attention in recent years. Troglitazone has been shown
to inhibit migration and invasion in human prostate cancer cells [203] , inhibit matrix metalloproteinase-9
expression and invasion of breast cancer cells [204] , and have anti-tumour effects without marked adverse
effects [205] . One study showed that Troglitazone mediated PPARg activation enhances human lung cell cancer
cells to TRIAL-induced apoptosis [206] . Suggesting that if used in combination with TRIAL protein it could
be useful against TRIAL-resistant cancer cells. That said, phase II studies in refractory breast cancer [207] and
metastatic colorectal cancer [208] have had disappointing results. A synthetic derivative of Troglitazone, Δ2-
Troglitazone was shown to be more potent in reducing cancer cell proliferation, however no clinical value
has been found [209] .

Rosiglitazone, a PPARg agonist, has been shown to have beneficial effects on atherosclerosis, insulin
resistance, and type 2 diabetes [210,211] . However, a phase II trial using Rosiglitazone in liposarcoma patients
concluded that this agonist was not an effective anti-tumour drug [212] . It is important to highlight the
side-effect profile of these trial drugs. Rosiglitazone has been shown to increase risk of cardiovascular
disease [213] and Troglitazone presents concerns regarding hepatotoxicity [207] . Additional cautions should be
taken with chronically elevated APN levels which can be linked to infertility and reduced bone density [214] .
Furthermore, interfering with the AdipoR1/R2 pathways can have adverse effects for anti-tumour immune
response [145] , consequently a fine balance must be achieved to ensure the anti-cancer pathways are promoted.

With there being limited success with current therapeutic agents one current use for APN is as prognostic
markers for cancer [215] . Both serum APN levels, the expression of AdipoR1/R2, and SNPs could all provide
avenues for prognostic and predictive molecular tests in cancer. A number of SNPs in ADIPOQ or APNs
[65]
receptors have been found associated with BC, CRC, EC, GC, PC, HC, RCC, PrC, and LC . The question
arises whether there would be any change in clinical decision making through screening these SNPs or
whether they would give any benefit above currently used biomarkers. That said, if well targeted, these tests
could help early diagnosis, aid post-operative recovery, and initiate APN modulatory therapy

It has been shown that a Mediterranean-type diet, reduction in body weight, and exercise can increase
circulating APN levels [189,216] . Furthermore, aerobic exercise was shown to increase expression of AdipoR1
and AdipoR2 in young men [217] . Therefore, using programmes that promote weight loss and a healthy diet
in parallel with new APN promoting agents may enable more favourable outcome. Similarly, new APN
therapeutic agents may show more promise when being used in combination with traditional treatment by
sensitising cancer cells.

A number of cancers are strongly associated with chronic inflammatory processes, for example the
association between inflammatory bowel disease and CRC, or Helicobacter pylori infection and GC [218] .
These type of cancers could greatly benefit from the anti-inflammatory properties of APN. In cancer there
is often defective inflammatory responses, the goal is to restore the normal overall host response, without
undesirable side effects. However, one needs to acknowledge that by altering these metabolic pathways there
is a chance of detrimental changes to anti-tumour immunity. Moreover, as carcinogenesis progresses, there
are changes to the way the tumour environment harnesses the immune system, therefore the timing of
treatment may greatly alter the efficacy.

When considering APN as a therapeutic agent it is important to highlight several points. Firstly, many
factors influence the levels of circulating APN. Sex, age, ethnicity, and intra-abdominal fat all have