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Page 8 of 23 Monks et al. J Cancer Metastasis Treat 2019;5:24 I http://dx.doi.org/10.20517/2394-4722.2018.79

Figure 2. Direct effects of APN on epithelial ells and summary of APNs anti-cancer signalling pathways. In normal epithelial cells, APN
is bound by T-cadherin and presented directly or indirectly to AdipoR1/R2 to inhibit signaling pathways activated in neoplasia. APN-
activates AMPK, and inhibits PI3K/AKT, mTOR, MAPK and JAK/Stat pathways, or directly affects GSK3β to suppress cancer promoting
pathways. Cancer cells down-regulate T-cadherin while AdipoR1/R2 expression persists and cancer-promoting pathways prevail. One
model is that ceramidase activity associated with AdipoR1/R2 weighs the balance in favor of cancer cell survival. T-cadherin expressed
in the tumor vasculature promotes cancer as a pro-angiogenic factor in cooperation with APN (not shown). Green arrows represent
activating pathways. Red lines represent inhibitory pathways. gAcrp: globular adiponectin; flAcrp: full length adiponectin; RTK: receptor
tyrosine kinase; JAK: Janus kinases; Stat: signal transducer and activator of transcription proteins; PI3K: PI3-kinases; Akt: protein kinase B;
mTOR: mammalian target of rapamycin; AMPK: 5’ APM activated protein kinase; GSK3β: glycogen synthase kinase-3 beta

[32]
its activation . Several factors related to obesity have been shown to induce this pathway and potentially
result in carcinogenesis, thus making it a good target for obesity related GI cancer. APN can directly [111] and
indirectly [112] inhibit the PI3K/AKt signalling pathway.

APN also interacts with several other pathways that are involved in carcinogenesis and the maintenance
of tumour survival including: the Wnt/GSK3B/B-catenin-signalling pathway [113] , signal transducer and
activator of transcription-3 (STAT-3), and mitogen activated protein kinase (MAPK). APN inhibits STAT-
3 which has a role in cancer cell proliferation, invasion, and survival [114] . STAT-3 promotes pro-oncogenic
inflammatory pathways, including NF-κB and IL-6-Janus tyrosine kinase, and inhibits the STAT-1 and
NF-κB mediated T helper 1 anti-tumour immune response [114] . Both gAcrp and flAcrp have the ability to
suppress STAT-3 and the associated JNK pathways in HC and PrC [115] . APN also interacts with the MAPK
which signals through cJNK, MAPKp38, and extracellular signal-regulated kinases (ERK)1/2 [40,116,117] .

Multiple studies have found that AdipoR1/R2 are over-expressed in cancers. In the setting of hypoadiponectinemia
it makes sense to have a compensatory upregulation of the receptors. However, this seems counter-intuitive
as the cancer cells are over-expressing receptors that act to hinder their growth and proliferation. It is
[17]
suggested that in a metabolically deprived tumour environment the cells metabolic needs take priority .
That said, it has been shown that APN can also have proliferative effects on cancer cells [118] . Further studies
looking into how the expression of APNs receptors changes throughout tumorigenesis are important as the
[32]
biological effects of APN depend on the tissue-specific expression of these receptor subtypes .