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Corona et al. Adenosine A2B receptor in cancer

Phylogenetically, both the anti-inflammatory and microenvironment has been associated with increased
the pro-inflammatory actions of adenosine have proliferation of prostate cancer cells in vitro [20] .
a protective function, the first keeping in check the
cascade of events typical of inflammation and thus Lastly, the A2B receptor has been shown to activate
avoiding tissue damage, the second facilitating the downstream oncogenic pathways frequently
reaction to and elimination of foreign pathogens. mutated in cancer such as mitogen-activated
protein kinase [18,19] , as well as phospholipase C,
Exactly as it is the case for other immune- cathelicidin antimicrobial peptide, NFkB1 and
checkpoints, tumour cells can exploit these defence arachidonic acid signalling. Moreover, A2B is also
mechanisms to induce immune suppression and a downstream target of the transcription factor Fos-
cancer-tolerance. In this context, the expression of related Antigen-1 (Fra-1), a gene involved in the
A2B in immune cells has attracted a lot of attention, development of metastasis [16] . A2B pharmacological
as the receptor seems to drive the expansion of blockade in Fra-1 positive breast cancer cells
immunosuppressive, pro-angiogenic and cancer inhibited metastasis to the lungs in a mouse model
tolerant cells . For these reasons, adenosine of metastatic breast cancer. In the near future, it is
[9]
may be considered itself an immune-modulatory possible that identification of Fra-1 positive tumours
checkpoint molecule [10] . This hypothesis is further will guide the stratification of patients that are most
strengthened by evidence of a synergic anti-tumour likely to respond to A2B inhibitors.
effect elicited combining anti-PD-1 (or CTLA-4) and
adenosine signalling inhibitors [11-14] . This synergism Notwithstanding the mounting evidence in favour
requires CD73 (one of the nucleotidases involved of an oncogenic role for A2B, most of the data
in adenosine generation) expression on tumour supporting this hypothesis come from pre-clinical
cells, suggesting that the adenosine produced in the studies in vitro. Whilst A2A small molecule inhibitors
context of the tumour could interfere with the effect are already in clinical development (NCT02403193
of targeted immunotherapies [13] . The addition of and NCT02655822), the same cannot be said
A2A- or A2B-receptor inhibitors to current targeted for A2B receptor inhibitors. All the A2B receptor
immunotherapies could therefore represent a means inhibitors have been tested in vitro and in vivo, but
to overcome acquired resistance to such treatments. their pharmacokinetic characteristics are still mostly
unknown.
It is worth noting that, besides the effects of adenosine
and A2B on the immune system, the expression of A2B has the potential to become a therapeutic
this receptor on the surface of cancer cells seems to target, at least in tumours overexpressing the
mediate important oncogenic effects in a variety of protein. However, more studies are needed to
cancers. Pharmacological inhibition or knockdown of explore all the functions of the A2B receptor and
A2B decreases proliferation of tumour cells [15-17] and its ligand, particularly with the aim of gaining a
a role for A2B in tumour progression and metastasis better understanding of the multiple A2B receptor-
is supported by multiple studies in bladder, breast, independent metabolic effects of adenosine [22] .
colon, prostate and other cancers [14,15,18-20] .
Moreover, due to the extensive cross-talk and
In particular in triple negative breast cancer, the number of molecular targets involved with the
expression of CD73 is associated with poor prognosis adenosine signalling pathway, and considering the
and pharmacological resistance to doxorubicin [21] . ubiquitousness of the receptors, it is conceivable that
Similarly, high expression of A2B in cancer cells side effects of the inhibition of CD73, A2A and A2B
increases invasiveness and metastasis and is a could represent an issue in the clinical setting.
predictor of poor prognosis and shorter survival in
triple negative breast cancer (TNBC) [19] . On the other Finding strategies to specifically target receptors
hand, presence of A2B in the host immune cells expressed on tumour cells could help mitigate the
does not impact the metastatic potential of TNBC toxicity of these agents. Also, using these drugs
tumour cells in the same metastatic mouse models in combination with other targeted agents, as it is
of breast carcinoma, as demonstrated by the fact already the case with A2A-inhibitors, will hopefully
that blockade of tumour-expressed A2B receptor, in further decrease toxicities by exploiting the synergism
A2B receptor-deficient mice, reduces the metastatic shown in combination therapy.
burden from TNBC cell lines xenografts.
Finally, pharmacologically modulating metabolic
Moreover, constitutive activation of the conditions such as hypoxia should likely increase the
adenosine receptor A2B in response to a hypoxic effectiveness of these molecules.
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ September 27, 2017 207