Adenosine Stimulate Proliferation and Migration in Triple Negative Breast Cancer Cells

Fernandez-Gallardo, Miriam; González‐Ramírez, Ricardo; Sandoval, Alejandro; Felix, Ricardo; Monjaraz, Eduardo

doi:10.1371/journal.pone.0167445

Cited by 45 publications

(44 citation statements)

References 32 publications

(34 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…e adenosine pathway is one of the major inhibitory pathways operating in the TME [28]. Previous studies have indicated that large amounts of adenosine accumulated in the hypoxic TME contribute to suppressing the immune response and promoting tumor progression [29][30][31]. According toÖztürk et al [32], aqueous extracts from S. marianum can inhibit ADA in gastric cancerous tissues and may have an important role in the immune regulation of GC.…”

Section: Discussionmentioning

confidence: 99%

Adenosine Generated by Regulatory T Cells Induces CD8⁺T Cell Exhaustion in Gastric Cancer through A2aR Pathway

Shi

Feng

et al. 2019

BioMed Research International

View full text Add to dashboard Cite

Background. Adenosine, derived from the degradation of ATP via ectonucleotidases CD39 and CD73, is a critical immunosuppressive metabolite in the hypoxic microenvironment of tumor tissue. Adenosine signaling via A2aR can inhibit the antitumor immune response of CD8+ T cells. CD39 and CD73 high-expressing Tregs play a critical role in tumor immune evasion of gastric cancer (GC). The present study investigated the underlying mechanism by which Tregs suppress antitumor immune responses in GC. Materials and Methods. Fifty-two GC samples were collected, and the frequency of FoxP3+ Tregs and CD8+ T cells and density ratios of A2aR+/CD8+ T cells, CD39+/FoxP3+ Tregs, and CD73+/FoxP3+ Tregs in GC were assessed with multiplex immunofluorescence. The expression of FoxP3 and A2aR in GC tissues was also detected by the immunoblotting assay. We next investigated the relationship between density of FoxP3+ Tregs, ratio of A2aR+/CD8+ T cells, and clinicopathological parameters. At the same time, Tregs and CD8+ T cells were isolated from peripheral blood of five GC patients, and the antagonists of CD39 and CD73 were used to assess the ability of Tregs to decompose ATP into adenosine. In addition, we cocultured CD8+ T cells and Tregs with antagonists of A2aR and A2bR in order to examine the alterations in immune function of CD8+ T cells. Results. The density of both FoxP3+ Tregs and A2aR+/CD8+ T cells was higher in GC tissue compared to peritumoral normal tissue and significantly correlated with the TNM stage, lymph node metastasis, and distant metastasis of GC. The process of Treg hydrolysis of ATP into adenosine was blocked by the antagonists of CD39 and CD73. In addition, Tregs could induce apoptosis and inhibit proliferation of CD8+ T cells, while this effect could be obviously reduced by applying the antagonist of A2aR or A2aR+A2bR. Moreover, IFN-γ, TNF-α, and perforin generated by CD8+ T cells could also be inhibited through the adenosine A2aR pathway. Conclusions. The FoxP3+ Tregs and A2aR+/CD8+ T cells were excessively infiltrated in GC tissue. Tregs from GC can decompose ATP to adenosine and in turn induce apoptosis and inhibit the proliferation of CD8+ T cells through the A2aR pathway, further leading to immune escape of GC.

show abstract

Section: Discussionmentioning

confidence: 99%

Adenosine Generated by Regulatory T Cells Induces CD8⁺T Cell Exhaustion in Gastric Cancer through A2aR Pathway

Shi

Feng

et al. 2019

BioMed Research International

View full text Add to dashboard Cite

show abstract

“…A number of studies have shown that A2BR activation can enhance tumor growth [84,85,[106][107][108] and that targeting A2BR at the genetic level can reverse this effect [84,106,108]. A2BR activation has also been shown to play a role in the migration and metastasis of tumor cells [19,[108][109][110][111], due to the ability of A2BR to induce the epithelialmesenchymal transition (EMT) through activation of the ERK1/2 pathway [112,113]. Interestingly, Giacomelli et al [113] demonstrated that the activation of cAMP (mediated through A2BR activation) inhibited the EMT and that effects were more pronounced in the presence of a PKA inhibitor.…”

Section: Expression Of Adenosine Receptors and Signaling Pathways In mentioning

confidence: 99%

Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

Sek¹,

Mølck²,

Stewart³

et al. 2018

Preprint

View full text Add to dashboard Cite

The immune system plays a major role in the surveillance and control of malignant cells, with the presence of tumor infiltrating lymphocytes (TILs) correlating with better patient prognosis in multiple tumor types. The development of ‘checkpoint blockade’ and adoptive cellular therapy has revolutionized the landscape of cancer treatment and highlights the potential of utilizing the patient’s own immune system to eradicate cancer. One mechanism of tumor-mediated immunosuppression that has gained attention as a potential therapeutic target is the purinergic signaling axis, whereby the production of the purine nucleoside adenosine in the tumor microenvironment can potently suppress T and NK cell function. The production of extracellular adenosine is mediated by the cell surface ectoenzymes CD73, CD39 and CD38 and therapeutic agents have been developed to target these as well as the downstream adenosine receptors (A1R, A2AR, A2BR, A3R) to enhance anti-tumor immune responses. This review will discuss the role of adenosine and adenosine receptor signaling in tumor and immune cells with a focus on their cell-specific function and their potential as targets in cancer immunotherapy.

show abstract

“…In breast cancer, for instance, A2b receptor expression is associated with poor survival in the triple negative (TNBC) subset 51 . Using A2b selective agonist (BAY 60‐6583) and antagonist (GS‐6201), A2b activation was shown to stimulated in vitro proliferation and migration of MDA‐MB‐231 cells 52 . A2b stimulation also increased expression of Na V 1.5 channels, 52 and was also described to promote breast tumor growth and metastasis 53 …”

Section: A2b Receptor In Cancermentioning

confidence: 99%

Targeting A2 adenosine receptors in cancer

2017

View full text Add to dashboard Cite

Tumor cells use various ways to evade anti-tumor immune responses. Adenosine, a potent immunosuppressive metabolite, is often found elevated in the extracellular tumor microenvironment. Therefore, targeting adenosine-generating enzymes (CD39 and CD73) or adenosine receptors has emerged as a novel means to stimulate anti-tumor immunity. In particular, the A2 (A2a and A2b) adenosine receptors exhibit similar immunosuppressive and pro-angiogenic functions, yet have distinct biological roles in cancer. In this review, we describe the common and distinct biological consequences of A2a and A2b adenosine receptor signaling in cancer. We discuss recent pre-clinical studies and summarize the different mechanisms-of-action of adenosine-targeting drugs. We also review the rationale for combining inhibitors of the adenosine pathway with other anticancer therapies such immune checkpoint inhibitors, tumor vaccines, chemotherapy and adoptive T cell therapy.

show abstract

Adenosine Stimulate Proliferation and Migration in Triple Negative Breast Cancer Cells

Cited by 45 publications

References 32 publications

Adenosine Generated by Regulatory T Cells Induces CD8⁺T Cell Exhaustion in Gastric Cancer through A2aR Pathway

Adenosine Generated by Regulatory T Cells Induces CD8⁺T Cell Exhaustion in Gastric Cancer through A2aR Pathway

Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

Targeting A2 adenosine receptors in cancer

Contact Info

Product

Resources

About

Adenosine Stimulate Proliferation and Migration in Triple Negative Breast Cancer Cells

Cited by 45 publications

References 32 publications

Adenosine Generated by Regulatory T Cells Induces CD8+T Cell Exhaustion in Gastric Cancer through A2aR Pathway

Adenosine Generated by Regulatory T Cells Induces CD8+T Cell Exhaustion in Gastric Cancer through A2aR Pathway

Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

Targeting A2 adenosine receptors in cancer

Contact Info

Product

Resources

About

Adenosine Generated by Regulatory T Cells Induces CD8⁺T Cell Exhaustion in Gastric Cancer through A2aR Pathway

Adenosine Generated by Regulatory T Cells Induces CD8⁺T Cell Exhaustion in Gastric Cancer through A2aR Pathway