Adenosine 2B Receptor Expression on Cancer Cells Promotes Metastasis

Mittal, Deepak; Sinha, Debottam; Barkauskas, Deborah S.; Young, Arabella; Kalimutho, Murugan; Stannard, Kimberley; Caramia, Franco; Haibe‐Kains, Benjamin; Stagg, John; Khanna, Kum Kum; Loi, Sherene; Smyth, Mark J.

doi:10.1158/0008-5472.can-16-0544

Cited by 144 publications

(159 citation statements)

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“…[57] Here the authors show that blockade of A 2B receptor in A 2B receptor deficient mice is able to reduce the metastasis of human triple negative breast cancer (TNBC) xenografts, confirming the critical role of A 2B receptor on cancer cells rather than host cells. [57] Altogether these preclinical studies strongly support the therapeutic potential of targeting adenosine in cancer.…”

Section: Critical Roles Of Adenosine In Tumor Progressionmentioning

confidence: 66%

“…[116] In a recent paper it has been demonstrated that high expression of A 2B receptor is associated with poor survival in triple negative breast cancer (TNBC) patients. [57] As mentioned above, these authors demonstrate that A 2B receptor antagonist prevents metastasis of A 2B receptor-expressing tumor cells and improves survival when administered in combination with chemotherapeutic agents and immune checkpoints inhibitors monoclonal antibodies in both experimental and spontaneous murine models of metastasis. [57] The anti-metastatic effects of A 2B receptor antagonists is independent on lymphocytes and myeloid cells, whilst tumor A 2B receptor is critical.…”

Section: A 2b Receptor and Tumor Stromamentioning

confidence: 71%

“…[57] As mentioned above, these authors demonstrate that A 2B receptor antagonist prevents metastasis of A 2B receptor-expressing tumor cells and improves survival when administered in combination with chemotherapeutic agents and immune checkpoints inhibitors monoclonal antibodies in both experimental and spontaneous murine models of metastasis. [57] The anti-metastatic effects of A 2B receptor antagonists is independent on lymphocytes and myeloid cells, whilst tumor A 2B receptor is critical. [57] These evidence highlight that A 2B receptor may be an attractive target for treatment of breast metastasis.…”

Section: A 2b Receptor and Tumor Stromamentioning

confidence: 71%

“…[54] More recently, it has been demonstrated that blockade of A 2B adenosine receptor subtype with a selective antagonist improves survival and the anti-metastatic effects of anti-PD1 and anti-CTLA4 monoclonal antibodies in both melanoma and mammary cancer models of metastasis with cells expressing CD73. [57] The anti-metastatic effects of these combinations relies on the capacity of immune checkpoints inhibitors to boost immune responses and on direct effects of A 2B adenosine receptor inhibitor on cancer cell metastasis. [57] Here the authors show that blockade of A 2B receptor in A 2B receptor deficient mice is able to reduce the metastasis of human triple negative breast cancer (TNBC) xenografts, confirming the critical role of A 2B receptor on cancer cells rather than host cells.…”

Section: Critical Roles Of Adenosine In Tumor Progressionmentioning

confidence: 99%

“…[57] The anti-metastatic effects of these combinations relies on the capacity of immune checkpoints inhibitors to boost immune responses and on direct effects of A 2B adenosine receptor inhibitor on cancer cell metastasis. [57] Here the authors show that blockade of A 2B receptor in A 2B receptor deficient mice is able to reduce the metastasis of human triple negative breast cancer (TNBC) xenografts, confirming the critical role of A 2B receptor on cancer cells rather than host cells. [57] Altogether these preclinical studies strongly support the therapeutic potential of targeting adenosine in cancer.…”

Section: Critical Roles Of Adenosine In Tumor Progressionmentioning

confidence: 99%

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Role of adenosine in tumor progression: focus on A2B receptor as potential therapeutic target

Sissi¹,

Morello²

2017

JCMT

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Adenosine receptors are a family of G-coupled receptors which mediate the antiinflammatory and immune-suppressive effects of adenosine in a damaged tissue. A large number of evidence indicate that the accumulation of adenosine under hypoxic conditions favors tumor progression, helping cancer cells to evade immune responses. Tumor cells and/ or lymphoid and myeloid cells can express the adenosine-generating enzyme CD73 and/or A 2A receptor, which in turn strongly suppresses an effective T-cell-mediated response, while promotes the activity of suppressive cells such as Treg and myeloid-derived suppressor cells. CD73 inhibitors and A 2A antagonists, either as single agents, or in combination with immune-checkpoints inhibitors such as anti PD-1 monoclonal antibodies, are currently in Phase I clinical trial in cancer patients. Recent studies show that A 2B receptor plays an important role in mediating the pro-tumor effects of adenosine, since its selective blockade can inhibit tumor growth in some murine tumor models. Targeting A 2B receptor reduces immunosuppression induced by myeloid cells and inhibits the stromal cells activity within the tumor microenvironment, limiting tumor angiogenesis and metastatic processes. Here, the authors review the current data on involvement of A 2B receptor in regulating tumor progression and discuss the development of A 2B receptor inhibitors as potential therapeutic agents in cancer treatment. Key words:CD73/A 2 adenosine receptors axis, A 2B adenosine receptor, tumor immunity, tumor metastasis, tumor angiogenesis, cancer treatment ABSTRACTArticle history:

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Section: Critical Roles Of Adenosine In Tumor Progressionmentioning

confidence: 66%

Section: A 2b Receptor and Tumor Stromamentioning

confidence: 71%

Section: A 2b Receptor and Tumor Stromamentioning

confidence: 71%

Section: Critical Roles Of Adenosine In Tumor Progressionmentioning

confidence: 99%

Section: Critical Roles Of Adenosine In Tumor Progressionmentioning

confidence: 99%

See 3 more Smart Citations

Role of adenosine in tumor progression: focus on A2B receptor as potential therapeutic target

Sissi¹,

Morello²

2017

JCMT

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G Protein‐Coupled Receptors and Their Mutations in Cancer – A Focus on Adenosine Receptors

Wang¹,

Westen²,

IJzerman³

et al. 2022

GPCRs as Therapeutic Targets

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Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

Raninga

Lee

Sinha

et al. 2019

Intl Journal of Cancer

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Triple‐negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25–30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non‐TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA‐approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA‐MB‐231 xenograft and patient‐derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8+Ve T‐cell tumor infiltration in vivo and upregulated immune checkpoint PD‐L1 expression in an ERK1/2‐MYC‐dependent manner. Moreover, combination of AF with anti‐PD‐L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti‐PD‐L1 antibody that warrants further clinical investigation for TNBC patients.

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Adenosine 2B Receptor Expression on Cancer Cells Promotes Metastasis

Cited by 144 publications

References 50 publications

Role of adenosine in tumor progression: focus on A2B receptor as potential therapeutic target

Role of adenosine in tumor progression: focus on A2B receptor as potential therapeutic target

G Protein‐Coupled Receptors and Their Mutations in Cancer – A Focus on Adenosine Receptors

Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

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