Adenosine Kinase Deficiency Increases Susceptibility to a Carcinogen

El-Kharrag, Rkia; Owen, Randy; Boison, Detlev

doi:10.1089/caff.2018.0019

Cited by 9 publications

(10 citation statements)

References 39 publications

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“…The role of ADK in cancers varies in different cancer types. Although previous studies showed that ADK was overexpressed in tumor tissues in patients with breast cancer and glioma ( 42 , 43 ), it was shown in patients with HCC that ADK was down-regulated, consistent with what we have observed ( 44 ). ENT4 was reported to be up-regulated in desmoplastic small round cell tumor (DSRCT) ( 45 ).…”

Section: Discussionsupporting

confidence: 92%

Hypoxia-inducible factor orchestrates adenosine metabolism to promote liver cancer development

et al. 2023

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Hypoxia-induced adenosine creates an immunosuppressive tumor microenvironment (TME) and dampens the efficacy of immune checkpoint inhibitors (ICIs). We found that hypoxia-inducible factor 1 (HIF-1) orchestrates adenosine efflux through two steps in hepatocellular carcinoma (HCC). First, HIF-1 activates transcriptional repressor MXI1, which inhibits adenosine kinase (ADK), resulting in the failure of adenosine phosphorylation to adenosine monophosphate. This leads to adenosine accumulation in hypoxic cancer cells. Second, HIF-1 transcriptionally activates equilibrative nucleoside transporter 4, pumping adenosine into the interstitial space of HCC, elevating extracellular adenosine levels. Multiple in vitro assays demonstrated the immunosuppressive role of adenosine on T cells and myeloid cells. Knockout of ADK in vivo skewed intratumoral immune cells to protumorigenic and promoted tumor progression. Therapeutically, combination treatment of adenosine receptor antagonists and anti–PD-1 prolonged survival of HCC-bearing mice. We illustrated the dual role of hypoxia in establishing an adenosine-mediated immunosuppressive TME and offered a potential therapeutic approach that synergizes with ICIs in HCC.

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Section: Discussionsupporting

confidence: 92%

Hypoxia-inducible factor orchestrates adenosine metabolism to promote liver cancer development

et al. 2023

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“…The expression of this enzyme is likely also decreased in inflammatory lesions, which often are highly hypoxic [ 72 ]. In line with this, expression of ADK has been found to be decreased in human liver cancer [ 73 ]. Accordingly, increased intracellular adenosine levels and decrease in the expression of ADK during pathological conditions may lead to markedly decreased phosphorylation of adenosine analogs.…”

Section: Intracellular Adenosine Levelsmentioning

confidence: 75%

Cellular Uptake and Intracellular Phosphorylation of GS-441524: Implications for Its Effectiveness against COVID-19

Rasmussen

Jürgens

Thomsen

et al. 2021

Viruses

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GS-441524 is an adenosine analog and the parent nucleoside of the prodrug remdesivir, which has received emergency approval for treatment of COVID-19. Recently, GS-441524 has been proposed to be effective in the treatment of COVID-19, perhaps even being superior to remdesivir for treatment of this disease. Evaluation of the clinical effectiveness of GS-441524 requires understanding of its uptake and intracellular conversion to GS-441524 triphosphate, the active antiviral substance. We here discuss the potential impact of these pharmacokinetic steps of GS-441524 on the formation of its active antiviral substance and effectiveness for treatment of COVID-19. Available protein expression data suggest that several adenosine transporters are expressed at only low levels in the epithelial cells lining the alveoli in the lungs, i.e., the alveolar cells or pneumocytes from healthy lungs. This may limit uptake of GS-441524. Importantly, cellular uptake of GS-441524 may be reduced during hypoxia and inflammation due to decreased expression of adenosine transporters. Similarly, hypoxia and inflammation may lead to reduced expression of adenosine kinase, which is believed to convert GS-441524 to GS-441524 monophosphate, the perceived rate-limiting step in the intracellular formation of GS-441524 triphosphate. Moreover, increases in extracellular and intracellular levels of adenosine, which may occur during critical illnesses, has the potential to competitively decrease cellular uptake and phosphorylation of GS-441524. Taken together, tissue hypoxia and severe inflammation in COVID-19 may lead to reduced uptake and phosphorylation of GS-441524 with lowered therapeutic effectiveness as a potential outcome. Hypoxia may be particularly critical to the ability of GS-441524 to eliminate SARS-CoV-2 from tissues with low basal expression of adenosine transporters, such as alveolar cells. This knowledge may also be relevant to treatments with other antiviral adenosine analogs and anticancer adenosine analogs as well.

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“…Samples from animals with unclear/insufficient extent of genetic knockdown were excluded from this study. A total of 25 formalin-fixed paraffin-embedded (FFPE) blocks from KRAS [ 28 ], KRAS/adenosine kinase (Adk) [ 32 ] and KRAS/ nuclear factor IA (Nfia) [ 33 ] genetically engineered mice (GEMM) were included in this study. These mice have previously been extensively characterized and chosen for this study due to a high tumor burden including a high percentage of FCA and HCC tumor nodules [ 28 ].…”

Section: Methodsmentioning

confidence: 99%

Vascular Remodeling Is a Crucial Event in the Early Phase of Hepatocarcinogenesis in Rodent Models for Liver Tumorigenesis

Tulessin

Sarker²,

Griger³

et al. 2022

Cells

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The investigation of hepatocarcinogenesis is a major field of interest in oncology research and rodent models are commonly used to unravel the pathophysiology of onset and progression of hepatocellular carcinoma. HCC is a highly vascularized tumor and vascular remodeling is one of the hallmarks of tumor progression. To date, only a few detailed data exist about the vasculature and vascular remodeling in rodent models used for hepatocarcinogenesis. In this study, the vasculature of HCC and the preneoplastic foci of alteration (FCA) of different mouse models with varying genetic backgrounds were comprehensively characterized by using immunohistochemistry (CD31, Collagen IV, αSMA, Desmin and LYVE1) and RNA in situ hybridization (VEGF-A). Computational image analysis was performed to evaluate selected parameters including microvessel density, pericyte coverage, vessel size, intratumoral vessel distribution and architecture using the Aperio ImageScope and Definiens software programs. HCC presented with a significantly lower number of vessels, but larger vessel size and increased coverage, leading to a higher degree of maturation, whereas FCA lesions presented with a higher microvessel density and a higher amount of smaller but more immature vessels. Our results clearly demonstrate that vascular remodeling is present and crucial in early stages of experimental hepatocarcinogenesis. In addition, our detailed characterization provides a strong basis for further angiogenesis studies in these experimental models.

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Adenosine Kinase Deficiency Increases Susceptibility to a Carcinogen

Cited by 9 publications

References 39 publications

Hypoxia-inducible factor orchestrates adenosine metabolism to promote liver cancer development

Hypoxia-inducible factor orchestrates adenosine metabolism to promote liver cancer development

Cellular Uptake and Intracellular Phosphorylation of GS-441524: Implications for Its Effectiveness against COVID-19

Vascular Remodeling Is a Crucial Event in the Early Phase of Hepatocarcinogenesis in Rodent Models for Liver Tumorigenesis

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