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Page 14 of 23 Monks et al. J Cancer Metastasis Treat 2019;5:24 I http://dx.doi.org/10.20517/2394-4722.2018.79

opposite effect occurred [188] . Therefore, the concentration of APN used for conditioning may greatly change
the outcome of a study.

Many of the studies showing APN having pro-inflammatory effects used concentrations of ~10 µg/mL [160,186] .
A recent study demonstrated that approximately a plasma APN concentration of 40 µg/mL was needed to
induce IL-10 production and an anti-inflammatory response [117] . Furthermore, physical exercise can increase
APN by 260% off baseline [189] . Therefore, it may be unlikely that using a physiological level of APN would
result in the desired anti-inflammatory effects due to sub-optimal signalling.

Interpreting APNs role on immune cells is further complicated as the kinetics of AdipoR1/R2 differ
depending on the specific immune cell and stage of differentiation. Expression of AdipoR1/R2 occurs in
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80%-90% of CD14 , compared to 10% of T-cells [156] . As monocytes differentiate into macrophages AdipoR1
expression decreases, whereas AdipoR2 expression is constant [190] . Likewise, the presence of various APN
oligomers and the multitude of signalling differences make it hard to pinpoint APNs exact role. For example,
differences are observed between HMW APN and gAcrp inhibition of the NF-κB pathway [191] . HMW
APN required shorted incubation period to inhibit NF-κB compared with gAcrp. While gAcrp produces a
transient activation and requires a longer incubation period to inhibit the pathway [191] .

In the adaptive immune system APN has been shown to act as a negative regulator for T-cells [156] and affect
the migration of T-cells towards diseased tissue [141,149] . Although only 10% of T-cells express AdipoR1/R2 on
their surface, the majority of T-cells store these receptors within intracellular clathrin-coated vesicles. After
stimulation, T-cells upregulate these receptors on the surface and APN interaction subsequently enhances
apoptosis and inhibits proliferation. In APN-deficient mice, infection lead to a significantly higher number
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of CD137 T cells [156] . Furthermore, culturing APN-DCs with allogenic T-cells decreased T-cell proliferation
and pro-inflammatory cytokine production [146] . A rise in regulatory T-cells was also identified, providing
an alternative mechanism that APN can regulate the immune system [146] . With regard to migration, APN
can inhibit expression of chemokines that act as T-cell chemoattractants in atherogenesis [141] . Therefore,
when APN levels are low in cancer, this could favour T-cell recruitment, and contribute towards adaptive
immune response. Lastly, one study suggested that rather than affecting proliferation, APN directly activates
CD4 T-cells and increases secretion of interferon-g and IL-6 [160] . It is thought that this inflammatory
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activation likely desensitises the cells to further pro-inflammatory stimuli. That said, this study uses a low
concentration of APN which may influence our interpretation of the results.

FUTURE IMPLICATIONS OF INTERFERING WITH THE APN PATHWAY ON CANCER
TREATMENT
It is clear that APN has the ability to alter cancer outcomes, biology, and anti-cancer immunity. Therefore,
APN has been identified as a therapeutic and preventive target for cancer therapy. The pleiotropic nature
of various APN isoforms has caused trouble initially engineering an APN analogue, consequently groups
decided to screen for endogenous agonists or enhancing existing APN levels.

The first APN receptor agonist screened for and produced was ADP355 [192] . ADP355 binds both AdipoR1/
R2, with a greater affinity to AdipoR1 [192] . In vivo, this agonist inhibited orthotopic human BC xenograft
growth by 31%, with an acceptable safety profile. Similar to gAcrp, ADP355 regulated signalling pathways
AMPK, STAT3, PIK3/Akt, and ERK1/2. The group was able to improve agonistic activity by 5-10 fold by
substituting Gly4 and Tyr7 residues with Pro and Hyp respectively [193] . High-throughput screening identified
several endogenous adiponectin ligands: AdipoR1 agonists included matairesinol, arctiin, (-)-arctigenin and
gramine, while AdipoR2 agonists included parthenolide, taxifoliol, deoxyschizandrin, and syringing [194] .
Further studies identified AdipoRon as a strong AdipoR1/R2 agonist at low micromolar concentrations,
signalling through AMPK and PPAR-α pathways [195] .