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Potential role of cell-free chromatin in cancer metastasis

Divya Vishwanath

Circulating tumor DNA (ctDNA) is found in serum and plasma fractions from blood
Circulating tumor DNA (ctDNA) is found in serum and plasma fractions from blood   (Photo: By Racheljunewong, via Wikimedia Commons)

Chromatin from dying cancer cells causes DNA damage and inflammation in healthy, non-cancerous cells in their vicinity, says a recent study published in Cell Death Discovery. Circulating cell-free chromatin (cfCh) may thus play a role in metastasis and spread of cancer, both locally and in a systemic manner. 

The study, conducted by researchers from   Advanced Centre for Treatment, Research and Education in Cancer (ACTREC) at Tata Memorial Centre, Mumbai and Homi Bhabha National Institute, Mumbai reiterates findings of their previous study, which demonstrated that fragmented DNA and chromatin are biologically active molecules. Chromatin from cells of cancer patients as well as healthy volunteers was shown to damage surrounding healthy cells by integrating into their genomes causing double-stranded breaks and apoptosis. 

The researchers used dead cells from a cancer cell line (called Jurkat), which had its chromatin labelled with a fluorescent molecule-Bromodeoxyuridine (BrdU). They incubated these cells with an actively growing cell line (NIH3T3). BrdU is used to study cell proliferation since it is incorporated into the newly synthesised DNA of replicating cells. In this study, the authors detected fluorescence in the actively growing cells after 6 hours. This indicated that nuclear material (chromatin) from the dead, cancerous cells was taken up by the live cells. When the same cells were treated with chromatin degrading agents no chromatin uptake by actively growing cells was detected. The live cells also showed evidence of DNA damage response, inflammation, and apoptosis.

The next series of experiments consisted of injecting fluorescently-labeled dying cancer cells intravenously into mice to see if a similar response is elicited in vivo. Fluorescent signals were detected in brain, lung, and liver cell nuclei of the injected mice, thus showing the presence of cfCh in the cells of these distant organs. Evidences of DNA damage and inflammation were also detected in these organs. 

The researchers were eventually able to show through both in vivo and in vitro experiments that CfCh enters healthy cells and integrates into their DNA.

What does this mean for cancer therapy? Indraneel Mittra, cancer surgeon and the principal investigator of this study says, “this suggests that metastasis may be caused by circulating dead tumour cells via the medium of chromatin fragments. This challenges the well-established theory of cancer metastasis that living circulating tumour cells (CTCs) get lodged in distant organs and grow to form secondary tumours.” He further clarifies, “most CTCs are apoptotic and patients whose CTCs are enriched in apoptotic cells have poor prognosis and have a greater tendency to develop liver metastasis.”

Does this mean that assaying levels of cfCh in a cancer patient can help assess the degree of metastasis? It is a long way off but it may be a possibility in the future. It will require us to “design a method, which can distinguish DNA from cancer cells from those released by normal cells, perhaps by making use of an epigenetic marker that distinguishes transformed cells from normal ones”, says Vaijayanti Gupta, Vice-President, Clinical R&D, Strand Life Sciences. “Once this is established, one has to figure out if one has to look for them in the CTCs, or pockets where cancer cells are known to hide, like the thymus, or just free-floating fragments in the plasma”, she adds.

“Our paper suggests a re-thinking of ‘kill cancer cells at any cost’ approach”, says Mittra. “It may be that the more we kill, the more we may be helping it spread. Therefore, future research should be focused on destroying the chromatin fragments that emerge from dead cancer cells thereby preventing further spread,” he concludes.