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Monks et al. J Cancer Metastasis Treat 2019;5:24 I http://dx.doi.org/10.20517/2394-4722.2018.79 Page 3 of 23
[16]
are confined to adipocytes, the oligomeric isoforms are present in the circulation , and the globular form
(gAcrp) trimerise to form a stable complex in the circulation.

These different isoforms are thought to have varying biological effects with the HMW isoform being the
most biologically active and having the highest plasma concentration. The normal plasma concentration
[17]
levels of APN range from 2-30 g/mL . APN levels have been shown to be altered in many disease processes.
[20]
[18]
[18]
[19]
[20]
Coronary heart disease , atherosclerosis , type 2 diabetes , obesity , insulin-resistance , and many
cancers are correlated with lower APN levels. Understanding how different isoforms exert effects upon
various tissues may be central to understanding the pleiotropic actions of APN within the body.
APN receptors
[21]
[19]
[19]
Three receptors are known to bind with APN: AdipoR1 , AdipoR2 , and T-cadherin . AdipoR1 and
AdipoR2 have an internal N-terminal region and an external C-terminal region with a central seven
transmembrane domain. The topology of these receptors are extremely similar, sharing 67% of their protein
[22]
sequences . However, compared to G-protein coupled receptors, their topology is completely opposite.
AdipoR1 shows high-affinity binding to globular APN, and also binding to full-length APN and is highly
expressed in skeletal muscle. While AdipoR2 shows intermediate-affinity binding to both forms and is
predominantly expressed in the liver. More recently, T-cadherin was identified as an additional APN
[21]
receptor . It is a glycosylphospatidylinositol-anchored protein that is highly expressed in endothelial and
[23]
smooth muscle cells, and has shown specific binding to MMW and HMW isoforms .

APN AND CANCER
A number of cancers have been correlated with hypoadiponectinemia and altered levels of AdipoR1/R2 and
T-cadherin. Therefore, APN may be a novel modifiable risk factor with uses as a prognostic or diagnostic
biomarker.

Colorectal cancer
It has been long acknowledged that obesity, hyperinsulinaemia, and insulin-resistance are associated with
colorectal cancer (CRC) pathogenesis. More recently it has been shown that APN levels are negatively
correlated with a risk of developing CRC [Table 1]. This has been confirmed by three meta-analyses [24-26] and
multiple studies summarised in Table 1. Not only did CRC patients have lower levels of APN, but one study
[27]
showed that men with high APN had a 60% reduced risk of CRC . A following study showed a similar
[28]
reduced risk in CRC among men, however no link was seen in females . This highlights the point that the
expression and response to APN can differ between sexes. APN also seems to have a role at the later stages
of CRC and an influence on its clinicopathological characteristics. Two studies showed an inverse correlation
between tumour stage/grade and APN [29,30] . Furthermore, low pre-surgical APN levels were found in a higher
proportion of relapsing patients, suggesting that APN may have potential to act an adjunctive tool to predict
relapse. Mice knock-out models have suggested that interactions with AdipoR1, rather than AdipoR2, have a
[31]
more protective role as only AdipoR1-KO mice demonstrated increased proliferative activity .
To aid development of any therapy it is important to understand changes that occur to APN within CRC
tumour cells. FlAcrp can be post-translationally modified to Acrp within the tumour environment, such
[32]
that the ratio between flAcrp:Acrp is higher than in the surrounding normal tissue . Local conversion to
[33]
Acrp could help create a more beneficial tumour environment by functioning in an autocrine manner .
Thus, not only do CRC patients often have lower circulating levels of APN, but also a different proportion of
APN subtypes that benefit tumour progression.

Gastric cancer
APN levels have been shown to have an inverse correlation to gastric cancer (GC) [Table 1]. One study found
that GC cells lacking AdipoR1 had higher peritoneal dissemination and lymphatic metastases than AdipoR1