Differential Regulation of Methylation-Regulating Enzymes by Senescent Stromal Cells Drives Colorectal Cancer Cell Response to DNA-Demethylating Epi-Drugs.
Differential Regulation of Methylation-Regulating Enzymes by Senescent Stromal Cells Drives Colorectal Cancer Cell Response to DNA-Demethylating Epi-Drugs.
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DOI：
10.1155/2018/6013728
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发表时间：
2018
影响因子：
4.3
通讯作者：
Hajdúch M
中科院分区：
文献类型：
--
作者：
Agrawal K;Das V;Táborská N;Gurský J;Džubák P;Hajdúch M
晚期结肠癌从原发肿瘤部位扩散到远处器官，在远处器官中结肠不相关的基质群体为肿瘤细胞的生长提供了有利的生态位。结肠癌细胞和结肠非相关成纤维细胞之间的异质细胞相互作用在远处转移部位是重要的，但这些细胞-细胞相互作用的治疗策略转移性结肠癌仍然被低估。最近的研究表明，DNA去甲基化表观药物5-氮杂胞苷（AZA）和5-氮杂-2 ′-脱氧胞苷（DAC）在实体瘤治疗中具有潜在的应用价值。虽然这些表观药物单独或与其他抗癌疗法组合的作用已得到充分描述，但基质细胞及其分泌组对癌细胞对这些药物的反应的影响仍然难以捉摸。在这项研究中，我们确定了正常和衰老的结肠不相关的成纤维细胞及其条件培养基对结直肠癌（CRC）细胞的AZA和DAC的反应，使用基于细胞的DNA去甲基化报告系统的影响。我们的数据表明，成纤维细胞加速细胞增殖，差异调节DNA甲基化调节酶的表达，增强DAC诱导的CRC细胞去甲基化。相反，来自衰老成纤维细胞的上调NF-κB活性的条件培养基改变了未经药物处理的CRC细胞中的脱氧胞苷激酶水平，并消除了DAC对DNA甲基转移酶1降解的影响。与2D培养物类似，衰老成纤维细胞除了增加CRC细胞的干细胞性之外，还增加了共培养球体中CRC细胞的DNA去甲基化。本研究首次证明了正常和衰老的基质细胞及其条件培养基对DAC引起的DNA去甲基化的影响。数据显示，在高基质细胞共培养物中DAC的活性增加，并表明肿瘤-基质比在预测DNA去甲基化表观遗传癌症治疗的结果中的潜力。
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-κB 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 stemness 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.
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影响因子：
5.2
作者：
Conti J;Thomas G
通讯作者：
Thomas G
影响因子：
3.7
作者：
Hagemann S;Heil O;Lyko F;Brueckner B
通讯作者：
Brueckner B
影响因子：
--
作者：
Li H;Chiappinelli KB;Guzzetta AA;Easwaran H;Yen RW;Vatapalli R;Topper MJ;Luo J;Connolly RM;Azad NS;Stearns V;Pardoll DM;Davidson N;Jones PA;Slamon DJ;Baylin SB;Zahnow CA;Ahuja N
通讯作者：
Ahuja N
影响因子：
1.2
作者：
Das, Viswanath;Furst, Tomas;Hajduch, Marian
通讯作者：
Hajduch, Marian
影响因子：
4.3
作者：
Fabre, Claire;Grosjean, Jennifer;Kroemer, Guido
通讯作者：
Kroemer, Guido