Extracellular ATP and adenosine in tumor microenvironment: Roles in epithelial–mesenchymal transition, cell migration, and invasion

Álvarez, Cecilia; Troncoso, María F.; Espelt, María V.

doi:10.1002/jcp.30580

Cited by 23 publications

(13 citation statements)

References 83 publications

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“…Consistent with our findings in the feces, Hernández-Muñoz et al revealed the altered adenine nucleotides in the liver of mice with early and late liver fibrosis (Hernández-Muñoz et al, 1990). Adenine was a key purine nucleobase in nucleic acids, and its derivatives regulated various physiological processes such as energy metabolism (Frenguelli and Dale, 2020), tumor microenvironment (Alvarez et al, 2021), brain injury (Frenguelli and Dale, 2020), and insulin secretion of β cells and adipogenesis (Nicholls, 2016). Moreover, the purine metabolites also severed as extracellular signaling molecules to modulate matrix deposition during fibrosis (Ferrari et al, 2016).…”

Section: Discussionsupporting

confidence: 90%

“…The concentration of extracellular nucleotides remains low under physiological conditions and turns out to be high in pathological status (Alvarez et al, 2021), indicating that the persistent increase of purine metabolites like adenine in our model mice might be the key event in the development of liver cirrhosis. Consistent with our findings in the feces, Hernández-Muñoz et al revealed the altered adenine nucleotides in the liver of mice with early and late liver fibrosis (Hernández-Muñoz et al, 1990).…”

Section: Discussionmentioning

confidence: 88%

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Dynamic Alterations of the Gut Microbial Pyrimidine and Purine Metabolism in the Development of Liver Cirrhosis

Xiong

Shao

et al. 2022

Front. Mol. Biosci.

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Background: Liver cirrhosis is the common end-stage of liver disease which lacks effective treatment, thus studies to determine prevention targets are an urgent need. The intestinal microbiota (IM) play important roles in modulating liver diseases which are mediated by microbial metabolites. Despite decades of growing microbial studies, whether IM contribute to the development of cirrhosis and the intimate metabolic link remain obscure. Here, we aimed to reveal the dynamic alterations of microbial composition and metabolic signatures in carbon tetrachloride (CCl4)-induced liver cirrhosis mice.Methods: CCl4-treated mice or normal control (NC) were sacrificed (n = 10 per group) after 5 and 15 weeks of intervention. The disease severity was confirmed by Masson’s trichrome or Sirius red staining. Metagenomics sequencing and fecal untargeted metabolomics were performed to evaluate the composition and metabolic function of IM in parallel with the development of cirrhosis.Results: The CCl4-treated mice presented liver fibrosis at 5 weeks and liver cirrhosis at 15 weeks indicated by collagen deposition and pseudo-lobule formation, respectively. Mice with liver cirrhosis showed distinct microbial composition from NC, even in the earlier fibrosis stage. Importantly, both of the liver fibrosis and cirrhosis mice were characterized with the depletion of Deltaproteobacteria (p < 0.05) and enrichment of Akkermansia (p < 0.05). Furthermore, fecal metabolomics revealed distinguished metabolomics profiles of mice with liver fibrosis and cirrhosis from the NC. Notably, pathway enrichment analysis pointed to remarkable disturbance of purine (p < 0.001 at 5 weeks, p = 0.034 at 15 weeks) and pyrimidine metabolic pathways (p = 0.005 at 5 weeks, p = 0.006 at 15 weeks) during the development of liver cirrhosis. Interestingly, the disorders of pyrimidine and purine metabolites like the known microbial metabolites thymidine and 2′-deoxyuridine had already occurred in liver fibrosis and continued in cirrhosis.Conclusion: These novel findings indicated the crucial role of IM-modulated pyrimidine and purine metabolites in the development of liver cirrhosis, which provides microbial targets for disease prevention.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 88%

Dynamic Alterations of the Gut Microbial Pyrimidine and Purine Metabolism in the Development of Liver Cirrhosis

Xiong

Shao

et al. 2022

Front. Mol. Biosci.

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“…The second signal required for inflammasome formation in the colon is the release of ADP by injured cells (Zhang et al 2020a, b). Additionally, ATP is commonly thought of as an activator and extracellular levels of ATP are also commonly elevated in the tumor microenvironment (Di Virgilio and Adinolfi 2017;Alvarez et al 2021). It has been noted that this signal results in an increase of IL-1β with marginal effect on TNF-α and IL-6.…”

Section: Discussionmentioning

confidence: 99%

Inflammation suppresses DLG2 expression decreasing inflammasome formation

Keane

Herring

Rolny

et al. 2022

J Cancer Res Clin Oncol

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Purpose Loss of expression of DLG2 has been identified in a number of cancers to contribute to the disease by resulting in increased tumor cell proliferation and poor survival. In light of the previous evidence that DLG2 alters the cell cycle and affects proliferation, combined with indications that DLG2 is involved in NLRP3 inflammasome axis we speculated that DLG2 has an immune function. So far, there is no data that clearly elucidates this role, and this study was designed to investigate DLG2 in inflammatory colon disease and in colon cancer as well as its impact on inflammasome induction. Methods The DLG2 expression levels were established in publicly available inflammation, colon cancer and mouse model datasets. The overexpression and silencing of DLG2 in colon cancer cells were used to determine the effect of DLG2 expression on the activation of the inflammasome and subsequent cytokine release. Results The expression of DLG2 is repressed in inflammatory colon diseases IBD and Ulcerative colitis as well as colorectal cancer tissue compared to healthy individuals. We subsequently show that induction with inflammatory agents in cell and animal models results in a biphasic alteration of DLG2 with an initial increase followed by an ensuing decrease. DLG2 overexpression leads to a significant increase in expression of IL1B, IκBζ and BAX, components that result in inflammasome formation. DLG2 silencing in THP1 cells resulted in increased release of IL-6 into the microenvironment which once used to treat bystander COLO205 cells resulted in an increase in STAT3 phosphorylation and an increase proliferating cells and more cells in the G2/M phase. Restoration of DLG2 to the colon resulted in reduced AKT and S6 signaling. Conclusion DLG2 expression is altered in response to inflammation in the gut as well as colon cancer, resulting in altered ability to form inflammasomes. Trial registration NCT03072641.

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“…Since mitochondria ATP synthases are rapidly translocated to cell surface lipid rafts under tumor-like hypoxic and acidic environments [ 465 , 466 , 467 ], cancer cells can also rely on the internalization of extracellular ATP (eATP) to significantly elevate intracellular ATP (iATP) to enhance drug resistance by maintaining the energy requirement of drug efflux by ATP-binding cassette (ABC) transporters [ 468 , 469 , 470 ]. eATP has been associated with cancer cell migration and invasion [ 471 , 472 ], induction of epithelial-mesenchymal transition (EMT) to promote metastasis in lung cancer [ 473 ], and activation of cancer stem cell-like changes to promote metastasis in non-small-cell lung cancer [ 474 ].…”

Section: Melatonin May Promote Prp Physiological Functions and Inhibi...mentioning

confidence: 99%

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

Loh¹,

Reíter

2022

Molecules

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The unique ability to adapt and thrive in inhospitable, stressful tumor microenvironments (TME) also renders cancer cells resistant to traditional chemotherapeutic treatments and/or novel pharmaceuticals. Cancer cells exhibit extensive metabolic alterations involving hypoxia, accelerated glycolysis, oxidative stress, and increased extracellular ATP that may activate ancient, conserved prion adaptive response strategies that exacerbate multidrug resistance (MDR) by exploiting cellular stress to increase cancer metastatic potential and stemness, balance proliferation and differentiation, and amplify resistance to apoptosis. The regulation of prions in MDR is further complicated by important, putative physiological functions of ligand-binding and signal transduction. Melatonin is capable of both enhancing physiological functions and inhibiting oncogenic properties of prion proteins. Through regulation of phase separation of the prion N-terminal domain which targets and interacts with lipid rafts, melatonin may prevent conformational changes that can result in aggregation and/or conversion to pathological, infectious isoforms. As a cancer therapy adjuvant, melatonin could modulate TME oxidative stress levels and hypoxia, reverse pH gradient changes, reduce lipid peroxidation, and protect lipid raft compositions to suppress prion-mediated, non-Mendelian, heritable, but often reversible epigenetic adaptations that facilitate cancer heterogeneity, stemness, metastasis, and drug resistance. This review examines some of the mechanisms that may balance physiological and pathological effects of prions and prion-like proteins achieved through the synergistic use of melatonin to ameliorate MDR, which remains a challenge in cancer treatment.

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Extracellular ATP and adenosine in tumor microenvironment: Roles in epithelial–mesenchymal transition, cell migration, and invasion

Cited by 23 publications

References 83 publications

Dynamic Alterations of the Gut Microbial Pyrimidine and Purine Metabolism in the Development of Liver Cirrhosis

Dynamic Alterations of the Gut Microbial Pyrimidine and Purine Metabolism in the Development of Liver Cirrhosis

Inflammation suppresses DLG2 expression decreasing inflammasome formation

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

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