Page 140 - Read Online

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

infiltrating myeloid cells CD11b high /Gr-1 high , suggesting and selective antagonist of A adenosine receptors
2B
that A receptor suppresses immune surveillance. or silencing A receptors blocked the proliferative
[72]
2B
2B
Later, Cekic et al. [104] showed that the selective blockade effects induced by a non-selective adenosine analog
of A receptor inhibits bladder and breast tumor NECA. [107,108] Other studies indicate that A adenosine
2B
2B
growth in mice, by inducing a T-cell mediated response receptor is highly expressed also in oral squamous
in a CXCR3-dependent manner. In a mouse model of carcinoma cell lines, as well as in human oral
melanoma, selective blockade of A receptor inhibits carcinoma tissues, where its expression is correlated
2B
tumor growth. [105] This effect was associated with lower with those of HIF-1. [109] Studies by Gessi et al. [110]
levels of IL-10 and MCP-1 in the tumor tissue and demonstrate that in colon cancer cells, although at the
reduced accumulation of tumor-infiltrating MDSCs. [105] mRNA levels A receptor is more expressed than A ,
1
2B
Notably, the levels of MDSCs in secondary lymphoid A and A , the density of A receptors is the highest
2A
3
3
organs remained unchanged in mice treated with the among the adenosine receptor subtypes. Later,
selective A receptor antagonist, consistent with a other studies have demonstrated that the adenosine
2B
selective activity of the antagonist on the recruitment A receptor is up-regulated in colorectal carcinoma
2B
of MDSCs to tumor lesions rather than with a putative tissues and colon cancer cell lines compared with
systemic effects. [105] Blockade of A receptor within normal colorectal mucosa under hypoxic conditions. [111]
2B
the tumor microenvironment modulates the intra- Antagonists of A receptors inhibit cancer cell
2B
tumoral levels of various inflammatory mediators and proliferation, suggesting that this receptor may be a
growth factors that could in turn influence the features potential therapeutic target for colorectal cancer. [111]
of tumor-infiltrating immune cells, promoting the
recruitment/accumulation of MDSC. [106] Accordingly, the In contrast, in gastric cancer cells A adenosine
2B
percentage of tumor-infiltrating CD8+ T cells upon A receptor has been identified as target of miR-
2B
receptor blockade enhanced in the tumor lesions. [105] 128b, a proto-oncogene miRNA down-regulated in
Furthermore, treatment of mice with the A receptor gastric cancer tissues. [112] In this work, the authors
2B
antagonist PSB1115 in combination with dacarbazine, demonstrate that the down-regulation of miR-128b
a chemotherapeutic agent commonly employed in gastric cancer cell is associated with an over-
in melanoma patients, reduces tumor growth and expression of A adenosine receptor and decreased
2B
significantly increases the number of CD8 T cells in cell apoptosis rate. [112] In osteosarcoma cells it
+
the melanoma lesions demonstrating the high potential has been demonstrated that p73 upregulates A
2B
of combining A receptor blockade and chemotherapy adenosine receptor and A 2B receptor agonists can
2B
for cancer treatment. [105,106] enhance p73-dependent cell death in response
to chemotherapy. [113] Moreover, stimulation of A
2B
In conclusion, the experimental evidence in some tumor receptor with a non-selective adenosine analog
mouse models suggest that the selective blockade NECA induces apoptosis in ovarian cancer cells. [114]
of A 2B receptor may ameliorate T cell-mediated Nonetheless,while a number of studies demonstrate
immune surveillance by impairing the accumulation that stimulation of A adenosine receptor in some
2B
of suppressive cells and the levels of inflammatory cancer cell types promotes proliferation, whereby
factors in the tumor microenvironment. [72,104-106] knockdown or pharmacological inhibition of this
However, despite the relevance of these observations, receptor reduces tumor cell growth and promotes
more studies are needed to provide a detailed apoptosis, [107-111] opposite results have been also
understanding of the role of A receptor in modulating described. [112,113] The discrepancy might likely depend
2B
the immune responses in tumor environments. on the cancer cell types, the expression levels of this
receptor on tumor cells and the selectivity and/or
A RECEPTOR AND TUMOR STROMA concentrations of pharmacological tools used in the
2B
experimental settings.
A number of studies indicate that A receptor can
2B
directly affect the proliferation/migration of tumor It has been demonstrated that agonists of A
2B
cells and the function of other stroma cells that receptor induce anti-proliferative and pro-apoptotic
populate the tumor niche, including endothelial cells effects on glioblastoma cancer stem cells (CSCs). [115]
and fibroblasts. Furthermore, stimulation of A receptors as well
2B
as A receptors sensitize glioblastoma CSCs to
1
A critical role for A adenosine receptor in mediating chemotherapy. [115]
2B
proliferation and/or apoptosis in different cancer cell
lines has been delineated. A adenosine receptor A role of A receptor in promoting the migration
2B
2B
is highly expressed in prostate cancer cell lines of tumor cells in vitro and in vivo has been clearly
132 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ July 17, 2017