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Sorrentino et al. Role of A 2B receptor in cancer

demonstrated. Indeed, a number of studies show pro-angiogenic factors, including VEGF, IL-8 and basic
that adenosine may directly influence the migration/ fibroblast growth factor (bFGF). [118] Importantly, under
invasion of tumor cells via A adenosine receptor. hypoxic conditions the expression of A receptor in
2B
2B
Stagg et al. [42] have demonstrated that targeting endothelial and smooth muscle cells increased and
the adenosine-generating enzyme CD73 inhibits the stimulation of these receptors further enhance
tumor growth in mice and significantly delays the VEGF release. [119] Hypoxia is a common feature of
development of spontaneous lung metastasis.While tumor and can induce angiogenesis. At the same time,
the effect of anti-CD73 monoclonal antibody therapy adenosine, whose levels became elevated during
on primary tumor growth relays on its capacity to hypoxia, further enhances angiogenesis by stimulating
improve immune surveillance, the anti-metastatic A receptors, creating a positive feedback between
2B
effects to the lungs is rather dependent on a direct hypoxia, adenosine and VEGF.
effect of CD73-generating adenosine on breast
tumor-cell migration via A adenosine receptors Other studies also indicate that adenosine promotes
2B
stimulation. [42] Consistent with the role of A receptor the release of angiogenic factors, namely VEGF
2B
in promoting metastasis of breast cancer cells to the and IL-8, in some cancer cells lines, via A receptor
2B
lung, administration of selective or non-selective A including human melanoma cells [120] and glioblastoma
2B
receptor antagonists into mice significantly reduced cells, which express high levels of A receptor under
2B
metastasis burden. [42,104] Furthermore, antagonists hypoxic conditions. [121]
of A receptor preferentially inhibits the invasive
2B
[72]
capacity of breast cancer cells expressing Fos-related Using A receptor deficient mice, Ryzhov et al.
2B
antigen-1 (Fra-1), a transcription factor overexpressed firstly demonstrated the critical role of A receptor
2B
in human metastatic breast cancers. [116] Therefore, in modulating the VEGF levels in tumor tissues.
the authors suggest that Fra-1 activity is a prognostic Importantly, vascularization and tumor tissue VEGF
indicator of both breast cancer metastasis and levels were significantly reduced in A receptor
2B
[72]
responsiveness to pharmacological inhibitors, such deficient mice compared with WT mice. This effect
as A receptor antagonists. [116] was associated with reduced tumor infiltration of
2B
VEGF-producing myeloid cells, suggesting that A 2B
In a recent paper it has been demonstrated that receptor can modulate the release of VEGF either
high expression of A receptor is associated with from tumor cells and from host tumor-infiltrating
2B
[72]
poor survival in triple negative breast cancer (TNBC) immune cells, that can contribute to promote tumor
patients. As mentioned above, these authors angiogenesis. [123] As mentioned above, adenosine
[57]
demonstrate that A receptor antagonist prevents promotes the differentiation of dendritic cells precursors
2B
metastasis of A receptor-expressing tumor cells and into a subset of DC that produce angiogenic factors,
2B
improves survival when administered in combination including VEGF, and other immunosuppressive factors
[80]
with chemotherapeutic agents and immune checkpoints via A adenosine receptor. Notably, A -stimulated
2B
2B
inhibitors monoclonal antibodies in both experimental dendritic cells are able to promote tumor growth when
[80]
and spontaneous murine models of metastasis. injected into mice. These observations strongly
[57]
The anti-metastatic effects of A receptor antagonists suggest that adenosine sustains tumor angiogenesis
2B
is independent on lymphocytes and myeloid cells, during tumor growth by stimulating the release of
whilst tumor A receptor is critical. These evidence VEGF from endothelial cells, tumor cells and immune
[57]
2B
highlight that A receptor may be an attractive target cells. Accordingly, targeting CD73 in mice impairs
2B
for treatment of breast metastasis. tumor angiogenesis and decreases VEGF levels,
at least in part by lowering adenosine generation in
A adenosine receptor can also contribute to the pro- tumor environment that activates A receptors. [124]
2B
2B
angiogenic effects of adenosine in the tumor milieu. Therefore, targeting CD73 and/or A receptor may
2B
Vascular endothelial growth factor (VEGF) is a well- represent a potential therapeutic strategy to block
known mediator critically involved in tumor progression angiogenesis. In support of this, the pharmacological
and angiogenesis. [117] A number of studies linked blockade of A receptor with a selective antagonist in
2B
VEGF production to adenosine A receptor in human mice significantly reduces the tumor levels of VEGF
2B
endothelial cells, [118,119] in some tumor cell lines [120,121] and CD31 positive cells within tumor lesions. [122]
and in host immune cells, including dendritic cells and Moreover, the anti-angiogenic effect of A receptor
2B
myeloid-derived suppressor cells. [72,80,122] antagonists is, at least in part, dependent on the lower
frequency of tumor-infiltrating suppressive myeloid
A receptor is expressed on human endothelial cells cells (MDSCs), [72,122] breaking the positive feedback
2B
and its stimulation promotes the expression of several loop that promotes angiogenesis and MDSC-mediated
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ July 17, 2017 133