Differential Regulation of Methylation-Regulating Enzymes by Senescent Stromal Cells DrivesColorectal Cancer Cell Response to DNA-Demethylating Epi-Drugs
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F18%3A73590725" target="_blank" >RIV/61989592:15110/18:73590725 - isvavai.cz</a>
Result on the web
<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Differential+Regulation+of+Methylation-Regulating+Enzymes+by+Senescent+Stromal+Cells+DrivesColorectal+Cancer+Cell+Response+to+DNA-Demethylating+Epi-Drugs" target="_blank" >https://www.ncbi.nlm.nih.gov/pubmed/?term=Differential+Regulation+of+Methylation-Regulating+Enzymes+by+Senescent+Stromal+Cells+DrivesColorectal+Cancer+Cell+Response+to+DNA-Demethylating+Epi-Drugs</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1155/2018/6013728" target="_blank" >10.1155/2018/6013728</a>
Alternative languages
Result language
angličtina
Original language name
Differential Regulation of Methylation-Regulating Enzymes by Senescent Stromal Cells DrivesColorectal Cancer Cell Response to DNA-Demethylating Epi-Drugs
Original language description
The advanced-stage colon cancer spreads from primary tumor site to distant organs where the colon-unassociated stromal population provides a favorable niche for the growth of tumor cells. The heterocellular interactions between colon cancer cells and colon-unassociated fibroblasts at distant metastatic sites are important, yet these cell-cell interactions for therapeutic strategies for metastatic colon cancer remain underestimated. Recent studies have shown the therapeutic potential of DNA-demethylating epi-drugs 5-azacytidine (AZA) and 5-aza-2'-deoxycytidine (DAC) for the treatment of solid tumors. While the effects of these epi-drugs alone or in combination with other anticancer therapies are well described, the influence of stromal cells and their secretome on cancer cell response to these agents remain elusive. In this study, we determined the effect of normal and senescent colon-unassociated fibroblasts and their conditioned medium on colorectal cancer (CRC) cell response to AZA and DAC using a cell-based DNA demethylation reporter system. Our data show that fibroblasts accelerate cell proliferation and differentially regulate the expression of DNA methylation-regulating enzymes, enhancing DAC-induced demethylation in CRC cells. In contrast, the conditioned medium from senescent fibroblasts that upregulated NF-KB activity altered deoxycytidine kinase levels in drug-untreated CRC cells and abrogated DAC effect on degradation of DNA methyltransferase 1. Similar to 2D cultures, senescent fibroblasts increased DNA demethylation of CRC cells in coculture spheroids, in addition to increasing the sternness of CRC cells. This study presents the first evidence of the effect of normal and senescent stromal cells and their conditioned medium on DNA demethylation by DAC. The data show an increased activity of DAC in high stromal cell cocultures and suggest the potential of the tumor-stroma ratio in predicting the outcome of DNA-demethylating epigenetic cancer therapy.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10601 - Cell biology
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>S - Specificky vyzkum na vysokych skolach
Others
Publication year
2018
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Stem Cells International
ISSN
1687-966X
e-ISSN
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Volume of the periodical
2018
Issue of the periodical within the volume
published 12 August 2018
Country of publishing house
US - UNITED STATES
Number of pages
11
Pages from-to
"nestránkováno"
UT code for WoS article
000442917200001
EID of the result in the Scopus database
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