Washington: Researchers have revealed how a reduction in mitochondrial DNA content leads human breast cancer cells to take on aggressive, metastatic properties.
The work has broken new ground in understanding why some cancers progress and spread faster than others and may offer clinicians a biomarker that would distinguish patients with particularly aggressive forms of disease, helping personalize treatment approaches.
Mitochondria, the "powerhouses" of mammalian cells, are also a signalling hub.
They are heavily involved in cellular metabolism as well as in apoptosis, the process of programmed cell death by which potentially cancerous cells can be killed before they multiply and spread. In addition, mitochondria contain their own genomes, which code for specific proteins and are expressed in coordination with nuclear DNA to regulate the provision of energy to cells.
To gain an understanding of the mechanism that connects low mtDNA levels with a cellular change that leads to cancer and metastasis, Penn School of Veterinary Medicine's Manti Guha, a senior research investigator, and Narayan Avadhani ,and their colleagues set up two systems by which they could purposefully reduce the amount of mtDNA in a cell.
One used a chemical to deplete the DNA content, and another altered mtDNA levels genetically. They compared normal, non-cancer-forming human breast tissue cells with cancerous breast cells using both of these treatments, contrasting them with cells with unmanipulated mtDNA.
The differences between cells with unmodified and reduced mtDNA levels were striking, the researchers found. The cells in which mtDNA was reduced had altered metabolism and their structure appeared disorganized, more like that of a metastatic cancer cell.
Even the non-tumour-forming breast cells became invasive and more closely resembled cancer cells. Significantly, cells with reduced mtDNA became self-renewing and expressed specific cell surface markers characteristic of breast cancer stem cells.
The study has been published in the journal Oncogene.
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