Targeting A2 adenosine receptors in cancer

Allard, David; Turcotte, Martin; Stagg, John

doi:10.1038/icb.2017.8

Cited by 92 publications

(62 citation statements)

References 94 publications

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“…8 Accumulating evidences have revealed that A2A receptors respond to the adenosine stimulation and thus modulate multiple physiological and pathophysiological processes including memory formation, emotionstate alteration, inflammatory reaction, immune regulation, braininjury repair, and aging process. 9,10 Recent researches have revealed that elevated adenosine levels in extracellular tumor Abbreviations: BBB, blood-brain barrier; LDH, lactate dehydrogenase; SDF-1, Stromal cell-derived factor-1. microenvironment and the activation of A2A receptors contribute to the immune escape and promote the progression and metastasis of tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Adenosine A2A receptor activation reduces brain metastasis via SDF‐1/CXCR4 axis and protecting blood‐brain barrier

Chen

Zhou

et al. 2020

Molecular Carcinogenesis

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Brain metastasis is a leading cause of death worldwide, but the mechanism involved remains unclear. Stromal cell‐derived factor‐1 (SDF‐1)/C‐X‐C motif chemokine receptor 4 (CXCR4) signaling has been reported to induce the directed metastasis of cancers, and adenosine A2A receptor activation suppresses the SDF‐1/CXCR4 interaction. However, whether A2A receptor activation implicates the SDF‐1/CXCR4 signaling pathway and thus modulates brain metastasis remains unclear. In this study, Western blot was performed to evaluate the protein levels. Cell invasion and migration assays were used to estimate the metastasis ability of PC‐9 cells. The viability of cells was demonstrated by lactate dehydrogenase and cell proliferation assays. And the findings in vitro were further identified in nude mice. Notably, adenosine A2A receptor activation inhibited the proliferation and viability of PC‐9 cells and thus suppressed the brain metastasis. A2A receptor stimulation protected the function of blood‐brain barrier (BBB). The suppression of brain metastasis and the protection of BBB by A2A receptor relied on SDF‐1/CXCR4 signaling, and treatment using A2A receptor agonist and CXCR4 antagonist protected the nude mice from malignancy metastasis in vivo. Adenosine A2A receptor activation suppressed the brain metastasis by implicating the SDF‐1/CXCR4 axis and protecting the BBB.

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Section: Introductionmentioning

confidence: 99%

Adenosine A2A receptor activation reduces brain metastasis via SDF‐1/CXCR4 axis and protecting blood‐brain barrier

Chen

Zhou

et al. 2020

Molecular Carcinogenesis

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“…The ecto-5 0 -nucleotidase CD73 causes accumulation of extracellular adenosine in the tumor microenvironment (TME), thereby promoting tumor immune escape, metastasis, and resistance to immune checkpoint inhibitors (1). Extracellular adenosine mediates its immunosuppressive activity essentially by activating the high-affinity A2A and low-affinity A2B receptors.…”

Section: Introductionmentioning

confidence: 99%

CD73 Promotes Resistance to HER2/ErbB2 Antibody Therapy

et al. 2017

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Expression of the ectonucleotidase CD73 by tumor cells, stromal cells, and immune cells is associated in cancer with immune suppression. In this study, we investigated the role of CD73 on the activity of the anti-HER2/ErbB2 monoclonal antibody (mAb) trastuzumab. In a prospective, randomized phase III clinical trial evaluating the activity of trastuzumab, high levels of CD73 gene expression were associated significantly with poor clinical outcome. In contrast, high levels of PD-1 and PD-L1 were associated with improved clinical outcome. In immunocompetent mouse models of HER2/ErbB2-driven breast cancer, CD73 expression by tumor cells and host cells significantly suppressed immune-mediated responses mediated by anti-ErbB2 mAb. Furthermore, anti-CD73 mAb therapy enhanced the activity of anti-ErbB2 mAb to treat engrafted or spontaneous tumors as well as lung metastases. Gene ontology enrichment analysis from gene-expression data revealed a positive association of CD73 expression with extracellular matrix organization, TGFβ genes, epithelial-to-mesenchymal transition (EMT) transcription factors and hypoxia-inducible-factor (HIF)-1 gene signature. Human mammary cells treated with TGFβ or undergoing EMT upregulated CD73 cell-surface expression, confirming roles for these pathways. In conclusion, our findings establish CD73 in mediating resistance to trastuzumab and provide new insights into how CD73 is regulated in breast cancer. .

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“…As a result, high quantities of adenosine are released into the extracellular space. Then this small molecule activates A2a receptors on effector T cells and increases intracellular cAMP to inhibit TCR-mediated signaling by preventing zeta-chain-associated protein kinase 70 (ZAP70) phosphorylation and activator protein-1 activation ( 36 ). The subsequently decreased TCR signaling leads to impaired CD25 expression and IL-2 production which are detrimental to effector T cells proliferation and activation.…”

Section: Soluble Mediators Derived From Tregmentioning

confidence: 99%

Tregs: Where We Are and What Comes Next?

2017

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Regulatory T cells are usually recognized as a specialized subset of CD4+ T cells functioning in establishment and maintenance of immune tolerance. Meanwhile, there is emerging evidence that regulatory T cells (Tregs) are also present in various non-lymphoid tissues, and that they have unique phenotypes credited with activities distinct from regulatory function. Their development and function have been described in plenty of manuscripts in the past two decades. However, with the deepening of research in recent years, emerging evidence revealed some novel mechanisms about how Tregs exert their activities. First, we discuss the expanding family of regulatory lymphocytes briefly and then, try to interpret how fork-head box P3 (Foxp3), a master regulator of the regulatory pathway in the development and function of regulatory T cells, functions. Subsequently, another part of our focus is varieties of tissue Tregs. Next, we primarily discuss recent research on how Tregs work and their faceted functions in terms of soluble mediators, functional proteins, and inhibitory receptors. In particular, unless otherwise noted, the term “Treg” is used here to refer specially to the “CD4+CD25+Foxp3+” regulatory cells.

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Targeting A2 adenosine receptors in cancer

Cited by 92 publications

References 94 publications

Adenosine A2A receptor activation reduces brain metastasis via SDF‐1/CXCR4 axis and protecting blood‐brain barrier

Adenosine A2A receptor activation reduces brain metastasis via SDF‐1/CXCR4 axis and protecting blood‐brain barrier

CD73 Promotes Resistance to HER2/ErbB2 Antibody Therapy

Tregs: Where We Are and What Comes Next?

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