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[32]
process of carcinogenesis in an attempt to counteract the change and restore . Others studies suggested
[63]
poor HC prognosis was associated with lower AdipoR1/R2 expression . AdipoR1 expression was correlated
with the absence of vascular invasion and AdipoR2 was associated with a low stage and a lower histological
grade. Although the role of APN in HC is unclear, APN may have a role pre-malignant hepatic conditions
[32]
such as non-alcoholic steatohepatitis (NASH) . APN can suppress the hepatic damage caused by TNF-α
in early NASH, thus highlighting an area where targeted APN treatment could help halt progression to
cirrhosis and cancer.

Lung cancer
The majority of studies have not found a significant correlation between APN levels and lung cancer (LC)
[Table 1]. Yet, one study demonstrated that there were lower levels of APN were present in patients with
[64]
advanced disease compared to limited stage disease . AdipoR1 and AdipoR2 were only expressed in the
cancerous tissue, with non-found in normal control tissue. Further studies are needed to determine a link
between APN and LC.

Genetic polymorphisms
Multiple genetic polymorphisms have been associated with altered risk of malignancy in ADIPOQ,
[65]
ADIPOR1, and ADIPOR2 . These SNPs have been associated with a wide number of cancers and may
enable screening and identification of high risk patients. This can allow for primary preventive measures,
[66]
such as losing weight, diet, and exercise, as well as chemoprevention . Going forward we need to be take
into consideration the interaction between various SNPs, ensure that a large and diverse group of the
population are screened for more SNPs, and determine how SNPs can be applied to clinical decision making.

DIRECT EFFECT OF APN PATHWAY ON CANCER BIOLOGY
Insulin resistance and hypoadiponectinemia have been associated with multiple cancers. The binding of
APN to AdipoR1/R2 triggers a number of downstream signalling cascades which have effects on cancer
biology and anti-cancer immunity. Understanding these pathways can help give light to the multitude of
APNs metabolic and immunological effects. These pathways are summarised in Figure 2.

Central to much of APNs actions is the AMP-activated protein kinase (AMPK) pathway [102,103] . AMPK
can act as a tumour suppressor by modulating inflammation, inducing cell-cycle arrest, and opposing
metabolic changes during carcinogenesis [104] . AMPK activation has been shown to have a beneficial effect
on insulin sensitivity by increasing glucose uptake and fatty acid oxidation in muscles, and inhibiting
gluconeogenesis in the liver. Interestingly, disruption of AdipoR1 reduced the AMPK activation, increased
glucose production and impaired insulin resistance. While, AdipoR2 disruption enhanced insulin
[20]
resistance and decreased PPARα signalling . Downstream inhibition of the mTOR pathway contributes to
AMPKs tumour suppressive qualities [105,106] . This is due to mTORs central role as a regulator of cell growth,
autophagy, and cell survival [107] . AMPK activation has also been shown to be cytotoxic to cancer cell lines
and cause apoptosis via p21 and p53 signalling [108] . AMPK has the ability to monitor and respond to cellular
energy requirements. In times of hypoxia, nutrient starvation, and redox imbalance, liver kinase B1 (LKB1)
- its upstream kinase - activates AMPK. The importance of LKB1 can be seen in patients with Peutz-
Jegher syndrome who are heterozygous for a LKB1 gene mutation. Development of a second mutation in
life then greatly increases the risk of multiple cancers. It is hypothesised that the loss of AMPK activation
may contribute to this development of malignancy [109] . LC and HC patients have shown evidence of LKB1
mutations and low LKB1 expression respectively [104] . Therefore, APN mediated AMPK activation could help
prognosis and disease progression in these specific cancers.

The PI3K/AKt pathway promotes cellular survival, growth, and proliferation [110] . This signalling pathway
is specifically known to be involved in gastrointestinal cancers (GI) whereby upstream mutations lead to