Mittra Indraneel, Samant Urmila, Sharma Suvarna, Raghuram Gorantla V, Saha Tannistha, Tidke Pritishkumar, Pancholi Namrata, Gupta Deepika, Prasannan Preeti, Gaikwad Ashwini, Gardi Nilesh, Chaubal Rohan, Upadhyay Pawan, Pal Kavita, Rane Bhagyeshri, Shaikh Alfina, Salunkhe Sameer, Dutt Shilpee, Mishra Pradyumna K, Khare Naveen K, Nair Naveen K, Dutt Amit
Translational Research Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Mumbai 410210, India.
Division of Laboratory Medicine, Tata Memorial Hospital, Tata Memorial Centre, Mumbai 400012, India.
Cell Death Discov. 2017 May 29;3:17015. doi: 10.1038/cddiscovery.2017.15. eCollection 2017.
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 NFB, IL-6, TNF and IFN. 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. H2AX and NFB 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.
肿瘤微环境中的旁观者细胞表现出DNA损伤和炎症迹象，这可能导致它们发生致癌转化。导致这些促癌病理的细胞间通讯介质尚未确定。我们在此表明，垂死癌细胞释放的游离染色质（cfCh）是触发周围健康细胞DNA损伤和炎症的关键介质。当将垂死的人类癌细胞与NIH3T3小鼠成纤维细胞一起培养时，它们会产生大量cfCh，并迅速进入旁观者NIH3T3细胞的细胞核并整合到其基因组中。这导致H2AX以及炎性细胞因子NFB、IL-6、TNF和IFN的激活。cfCh的基因组整合引发了转录的全局失调以及与吞噬作用、DNA损伤和炎症相关途径的上调。当活癌细胞与NIH3T3细胞共培养时，未观察到这些活性。然而，静脉注射到小鼠体内后，发现死细胞和活细胞均具有活性。已知活癌细胞静脉注射后会发生广泛的细胞死亡，并且我们观察到这两种类型细胞产生的cfCh都整合到远处器官细胞的基因组中，并诱导DNA损伤和炎症。H2AX和NFB经常在同一细胞中共表达，这表明DNA损伤和炎症是密切相关的病理状态。由于同时发生的DNA损伤和炎症是致癌转化的有力刺激因素，我们的结果表明，垂死癌细胞释放的cfCh可以在局部和远处器官中转化微环境中的细胞，从而提供一种肿瘤侵袭和转移的新机制。上述促癌病理状态可以通过同时使用染色质中和/降解剂来消除，这提示了治疗的可能性。
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