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Cell-free chromatin from dying cancer cells integrate into genomes of bystander healthy cells to induce DNA damage and inflammation.

ABSTRACT: 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 NF?B, 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 NF?B 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.

SUBMITTER: Mittra I

PROVIDER: S-EPMC5447133 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Cell-free chromatin from dying cancer cells integrate into genomes of bystander healthy cells to induce DNA damage and inflammation.

Mittra Indraneel I Samant Urmila U Sharma Suvarna S Raghuram Gorantla V GV Saha Tannistha T Tidke Pritishkumar P Pancholi Namrata N Gupta Deepika D Prasannan Preeti P Gaikwad Ashwini A Gardi Nilesh N Chaubal Rohan R Upadhyay Pawan P Pal Kavita K Rane Bhagyeshri B Shaikh Alfina A Salunkhe Sameer S Dutt Shilpee S Mishra Pradyumna K PK Khare Naveen K NK Nair Naveen K NK Dutt Amit A

Cell death discovery 20170529

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 mous ...[more]

PMID: 28580170

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Project description:Bystanders who drown during a rescue attempt in aquatic waterways are becoming an increasingly important issue within drowning prevention. In the Australian context, the majority of these incidents occur in coastal water ways. This study documents and characterizes bystander rescuer fatalities within Australian coastal waterways that occurred between 1 July 2004 and 30 June 2019 in order to provide suggestions for future public safety interventions involving bystander rescuers. Data was sourced through Surf Life Saving Australia's (SLSA) Coastal Fatality Database, which collates information from multiple sources. Sixty-seven bystander rescuer fatalities in coastal waterways were reported during the 15-year period, an average of 4.5 per year, which is a significant proportion of the five fatalities previously reported across all Australian waterways. The majority of coastal bystander rescuer fatality incidents occurred in the state of New South Wales (49%), at beaches (64%), in regional or remote areas (71%), more than 1 km from the nearest lifesaving service (78%), during summer (45%), in the afternoon (72%), in the presence of rip currents (73%), and did not involve the use of flotation devices to assist rescue (97%). The majority of coastal bystander rescuer victims were Australian residents (88%) born in Australia/Oceania (68%), males (81%), aged between 30-44 years old (36%), visitors to the location (55%), either family (69%) or friends (15%) of the rescuee(s), and were attempting to rescue someone younger than 18 years old (64%). Our results suggest future safety intervention approaches should target males, parents and carers visiting beach locations in regional locations during holiday times and should focus on the importance of flotation devices when enacting a rescue and further educating visitors about the rip current hazard. Future research should examine the psychology of bystander rescue situations and evaluate the effectiveness of different safety intervention approaches.

Dataset Information

Cell-free chromatin from dying cancer cells integrate into genomes of bystander healthy cells to induce DNA damage and inflammation.

Publications

Cell-free chromatin from dying cancer cells integrate into genomes of bystander healthy cells to induce DNA damage and inflammation.

Similar Datasets

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