Hypoxia-inducible factor 1-dependent expression of adenosine receptor 2B promotes breast cancer stem cell enrichment

Lan, Jie; Lu, Haiquan; Samanta, Debangshu; Salman, Shaima; Lü, You; Semenza, Gregg L.

doi:10.1073/pnas.1809695115

Cited by 115 publications

(95 citation statements)

References 67 publications

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“…Our results confirm that oxygen deprivation within 3D-O matrices can efficiently reiterate HIF-driven regulation in the resident BCa cells. It is well known that within the hypoxic tumor niche, a high level of HIF-driven adaptations is observed in terms of ECM modeling (Gilkes et al, 2014), expression of immune surface markers PD-L1 (Noman et al, 2014), MUC-1 (Chaika et al, 2012), CD73 (Lan et al, 2018) and hypoxia-induced extracellular vesicles (Ren et al, 2019). Under oxygen deprivation in 3D-O tumorous matrices while BCa cell proliferation was subsided, extracellular vesicle secretion and ECM expression by cultured BCa cells were increased corroborating previous published findings.…”

Section: Discussionsupporting

confidence: 88%

Bioengineering the Oxygen-Deprived Tumor Microenvironment Within a Three-Dimensional Platform for Studying Tumor-Immune Interactions

Bhattacharya

Calar

Evans

et al. 2020

Front. Bioeng. Biotechnol.

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Oxygen deprivation within tumors is one of the most prevalent causes of resilient cancer cell survival and increased immune evasion in breast cancer (BCa). Current in vitro models do not adequately mimic physiological oxygen levels relevant to breast tissue and its tumor-immune interactions. In this study, we propose an approach to engineer a three-dimensional (3D) model (named 3D engineered oxygen, 3D-O) that supports the growth of BCa cells and generates physio-and pathophysiological oxygen levels to understand the role of oxygen availability in tumor-immune interactions. BCa cells (MDA-MB-231 and MCF-7) were embedded into plasma-derived 3D-O scaffolds that reflected physio-and pathophysiological oxygen levels relevant to the healthy and cancerous breast tissue. BCa cells grown within 3D-O scaffolds were analyzed by flow cytometry, confocal imaging, immunohistochemistry/immunofluorescence for cell proliferation, extracellular matrix protein expression, and alterations in immune evasive outcomes. Exosome secretion from 3D-O scaffolds were evaluated using the NanoSight particle analyzer. Peripheral blood mononuclear cells were incorporated on the top of 3D-O scaffolds and the difference in tumor-infiltrating capabilities as a result of different oxygen content were assessed by flow cytometry and confocal imaging. Lastly, hypoxia and Programmed death-ligand 1 (PD-L1) inhibition were validated as targets to sensitize BCa cells in order to overcome immune evasion. Low oxygen-induced adaptations within 3D-O scaffolds validated known tumor hypoxia characteristics such as reduced BCa cell proliferation, increased extracellular matrix protein expression, increased extracellular vesicle secretion and enhanced immune surface marker expression on BCa cells. We further demonstrated that low oxygen in 3D-O scaffolds significantly influence immune infiltration. CD8+ T cell infiltration was impaired under pathophysiological oxygen levels and we were also able to establish that hypoxia and PD-L1 inhibition re-sensitized BCa cells to cytotoxic CD8+ T cells. Bioengineering the oxygen-deprived BCa tumor microenvironment in our engineered 3D-O physiological and tumorous

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Section: Discussionsupporting

confidence: 88%

Bioengineering the Oxygen-Deprived Tumor Microenvironment Within a Three-Dimensional Platform for Studying Tumor-Immune Interactions

Bhattacharya

Calar

Evans

et al. 2020

Front. Bioeng. Biotechnol.

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“…Pharmacological inhibitors of adenosinergic signaling in TME were well investigated for their functions in immunosuppression and linking membrane proteins like CD73 with intracellular signaling modulation 12,45,46 . Some of them showed significant therapeutic effects in mouse model or preclinical trials 45,[47][48][49] . We explored potential receptor assuming intracellular function of CD73 and identified A2AR as a critical receptor in modulating RICS function.…”

Section: Discussionmentioning

confidence: 99%

CD73 promotes tumor metastasis by modulating RICS/RhoA signaling and EMT in gastric cancer

Yao

et al. 2020

Cell Death Dis

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Tumor microenvironment plays vital roles in shaping cancer diversity, and CD73 (ecto-5′-nucleotidase; NT5E) is an emerging immune checkpoint in modulating cancer progression via conversion of immunostimulatory ATP into immunosuppressive adenosine. However, how the CD73 is regulated and how it functions in the progression of cancer are largely unknown. Here, we showed that CD73 was overexpressed and correlated with poor prognosis of gastric cancer. CD73 links adenosinergic signaling in microenvironment switching to induction of epithelial-tomesenchymal transition phenotype in gastric cancer during metastasis. Further pathway and gene set enrichment analysis of transcriptome data revealed the modulation role of CD73 in RICS/RhoA signaling by its extracellular function in adenosinergic pathway, which subsequently inhibited phosphorylation of LIMK/cofilin and promoted β-catenin activation. Pharmacological inhibition of CD73 adenosinergic signaling was found to induce RICS dysfunction. Dissemination and hematogenous metastasis model showed that targeting CD73 in gastric cancer could suppress experimental metastasis. To conclude, it substantiates CD73 as a target for treatment of gastric cancer metastasis and verifies RICS as an intracellular functional molecule linking CD73/adenosinergic signaling switching to RhoA/LIMK/cofilin pathway.

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“…HIF-1α increases A2BR expression in HCC cells and cancer cell proliferation (184). Recent studies by Lan and colleagues (185) show HIF-1α's induced expression of A2BR is essential in enriching breast cancer stem cells for the onset of recurrent disease (185). Studies linking A2BR to tumor progression include work in bladder (86), breast (186), colon (187), and prostate (188) cancer and involves A2BR activity on both immune and tumor cells.…”

Section: Liver Cancermentioning

confidence: 99%

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

et al. 2020

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CD73, a cell surface 5 ′ nucleotidase that generates adenosine, has emerged as an attractive therapeutic target for reprogramming cancer cells and the tumor microenvironment to dampen antitumor immune cell evasion. Decades of studies have paved the way for these findings, starting with the discovery of adenosine signaling, particularly adenosine A2A receptor (A2AR) signaling, as a potent suppressor of tissue-devastating immune cell responses, and evolving with studies focusing on CD73 in breast cancer, melanoma, and non-small cell lung cancer. Gastrointestinal (GI) cancers are a major cause of cancer-related deaths. Evidence is mounting that shows promise for improving patient outcomes through incorporation of immunomodulatory strategies as single agents or in combination with current treatment options. Recently, several immune checkpoint inhibitors received FDA approval for use in GI cancers; however, clinical benefit is limited. Investigating molecular mechanisms promoting immunosuppression, such as CD73, in GI cancers can aid in current efforts to extend the efficacy of immunotherapy to more patients. In this review, we discuss current clinical and basic research studies on CD73 in GI cancers, including gastric, liver, pancreatic, and colorectal cancer, with special focus on the potential of CD73 as an immunotherapy target in these cancers. We also present a summary of current clinical studies targeting CD73 and/or A2AR and combination of these therapies with immune checkpoint inhibitors.

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Hypoxia-inducible factor 1-dependent expression of adenosine receptor 2B promotes breast cancer stem cell enrichment

Cited by 115 publications

References 67 publications

Bioengineering the Oxygen-Deprived Tumor Microenvironment Within a Three-Dimensional Platform for Studying Tumor-Immune Interactions

Bioengineering the Oxygen-Deprived Tumor Microenvironment Within a Three-Dimensional Platform for Studying Tumor-Immune Interactions

CD73 promotes tumor metastasis by modulating RICS/RhoA signaling and EMT in gastric cancer

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

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