Cell-free chromatin from dying cancer cells integrate into genomes of bystander healthy cells to induce DNA damage and inflammation.
Cell-free chromatin from dying cancer cells integrate into genomes of bystander healthy cells to induce DNA damage and inflammation.
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DOI：
10.1038/cddiscovery.2017.15
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发表时间：
2017
影响因子：
7
通讯作者：
Dutt A
中科院分区：
文献类型：
--
作者：
Mittra I;Samant U;Sharma S;Raghuram GV;Saha T;Tidke P;Pancholi N;Gupta D;Prasannan P;Gaikwad A;Gardi N;Chaubal R;Upadhyay P;Pal K;Rane B;Shaikh A;Salunkhe S;Dutt S;Mishra PK;Khare NK;Nair NK;Dutt A
肿瘤微环境的旁观者细胞显示出DNA损伤和炎症的证据，这些损伤和炎症可导致其致癌转化。引起这些原癌病理的细胞-细胞通讯的介体尚未鉴定。我们在这里表明，从垂死的癌细胞释放的无细胞染色质（cfCh）是触发周围健康细胞中DNA损伤和炎症的关键介质。当垂死的人类癌细胞与NIH 3 T3小鼠成纤维细胞一起沿着培养时，大量cfCh从它们中出现并迅速进入旁观者NIH 3 T3细胞的细胞核以整合到它们的基因组中。这导致H2 AX和炎性细胞因子NFκB、IL-6、TNFα和IFNγ的活化。cfCh的基因组整合触发了与吞噬作用、DNA损伤和炎症相关的转录的全面失调和途径的上调。当活的癌细胞与NIH 3 T3细胞共培养时，没有观察到这些活性。然而，在静脉注射到小鼠中时，发现死细胞和活细胞都是活性的。已知活的癌细胞在静脉注射时经历广泛的细胞死亡，并且我们观察到从两种类型的细胞中出现的cfCh整合到远处器官细胞的基因组中并诱导DNA损伤和炎症。γ H2 AX和NFκB在同一细胞中频繁共表达，表明DNA损伤和炎症是密切相关的病理学。由于同时发生的DNA损伤和炎症是致癌转化的有力刺激，我们的研究结果表明，来自垂死癌细胞的cfCh可以在局部和远处器官中转化微环境的细胞，从而提供肿瘤侵袭和转移的新机制。通过同时使用染色质中和/降解剂治疗，可以消除上述促癌病理，这表明了治疗的可能性。
Bystander cells of the tumor microenvironment show evidence of DNA damage and inflammation that can lead to their oncogenic transformation. Mediator(s) of cell–cell communication that brings about these pro-oncogenic pathologies has not been identified. We show here that cell-free chromatin (cfCh) released from dying cancer cells are the key mediators that trigger both DNA damage and inflammation in the surrounding healthy cells. When dying human cancer cells were cultured along with NIH3T3 mouse fibroblast cells, numerous cfCh emerged from them and rapidly entered into nuclei of bystander NIH3T3 cells to integrate into their genomes. This led to activation of H2AX and inflammatory cytokines NFκB, IL-6, TNFα and IFNγ. Genomic integration of cfCh triggered global deregulation of transcription and upregulation of pathways related to phagocytosis, DNA damage and inflammation. None of these activities were observed when living cancer cells were co-cultivated with NIH3T3 cells. However, upon intravenous injection into mice, both dead and live cells were found to be active. Living cancer cells are known to undergo extensive cell death when injected intravenously, and we observed that cfCh emerging from both types of cells integrated into genomes of cells of distant organs and induced DNA damage and inflammation. γH2AX and NFκB were frequently co-expressed in the same cells suggesting that DNA damage and inflammation are closely linked pathologies. As concurrent DNA damage and inflammation is a potent stimulus for oncogenic transformation, our results suggest that cfCh from dying cancer cells can transform cells of the microenvironment both locally and in distant organs providing a novel mechanism of tumor invasion and metastasis. The afore-described pro-oncogenic pathologies could be abrogated by concurrent treatment with chromatin neutralizing/degrading agents suggesting therapeutic possibilities.