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Chromatin from dead cancer cells integrates into genomes of living cells to induce DNA damage, inflammation, chromosomal instability and cancer.

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Following our observation that circulating Cfs are DNA damaging and oncogenic agents, we investigated whether application of dead cancerous cells (dcCfs) to NIH3T3 cells will bring about similar pathological changes. We found that numerous dcCfs exiting from the dead cells rapidly entered into the recipients, integrated into their genomes and triggered genome-wide de-regulation of transcription. Whole genome sequencing of NIH3T3 cells treated with dead human cancer cells detected several hundred thousand human reads in recipient mouse cells. Microarray analysis revealed up-regulation of multiple pathways related to phagocytosis, inflammation and cancer. Intracellular dcCfs induced dsDNA breaks, chromosomal instability, activation of apoptotic pathways and an intense up-regulation of inflammatory cytokines. Treatment with some types of dead cancerous cells induced rapid oncogenic transformation of NIH3T3 cells within 72hr - 96 hr; the transformed cells were tumourigenic in immune-deficient mice and FISH detected presence of human DNA signals in nuclei of tumour cells. Treatment with some of the other types of dead cancer cells led to senescence of the recipients. Intravenous injection of dead human cancer cells into mice activated H2AX, Caspase-3 and inflammation in cells of distant organs while FISH detected human DNA signals in their nuclei. Our results suggest that dead cancer cells may be responsible for local spread of cancer via the medium of dcCfs and may initiate new cancers in cells of distant organs if dead cancer cells were to enter into the blood stream.

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