For years, scientists have observed that cancer cells from certain breast cancer patients (with aggressive forms of the disease) contained low levels of mitochondrial DNA. No one could explain how this characteristic influenced disease progression. Until now.
The Science: Mitochondria, the “powerhouses” of mammalian cells, are also a signaling 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.
In mammals, each cell contains between 100 and 1,000 copies of mitochondrial DNA, but previous research had found that as many as 80 percent of people with breast cancer have low mitochondrial DNA, or mtDNA, content.
What The Researchers Did: To gain an understanding of the mechanism that connects low mtDNA levels with a cellular change that leads to cancer and metastasis, the investigators 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-tumor-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.
“Reducing mitochondrial DNA makes mammary cells look like cancerous stem cells,” Avadhani said. “These cells acquire the characteristics of stem cells, that is the ability to propagate and migrate, in order to begin the process of metastasis and move to distal sites in the body.”
“Most patients who had low copy numbers of mitochondrial DNA have a poordisease prognosis,” Guha said. “We’ve shown a causal role for this mitochondrial defect and identified a candidate biomarker for aggressive forms of the disease. In the future, mtDNA and the factors involved in mitochondrial signaling may serve as markers of metastatic potential and novel points for therapeutic intervention of cancer stem cells. Since the specific inducers of cancer stem cells, which are key drivers of metastasis, remain elusive, our current findings are a significant advancement in this area.”
No two breast cancers are exactly alike, so having a way to recognize patients who are at high-risk for developing particularly invasive and rapidly metastasizing cancers could help physicians customize treatments. In addition, researchers are currently filling in the unknown components of the signaling pathway linking a cell’s mitochondrial DNA levels and its involvement in metastatic disease.
Researchers will move to mouse models, and to ways of finding how we can use this seemingly key information for humans. I’m Dr. Michael Hunter.
The small print: The material presented herein is informational only, and is not designed to provide specific guidance for an individual. Please check with a valued health care provider with any questions or concerns. As for me, I am a Harvard- , Yale- and UPenn-educated radiation oncologist, and I practice in the Seattle, WA (USA) area. I feel genuinely privileged to be able to share with you. If you enjoyed today’s offering, please consider clicking the follow button at the bottom of this page.
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References: 1. http://www.sciencedaily.com/releases/2013/11/131108124850.htm; 2. M Guha, S Srinivasan, G Ruthel, A K Kashina, R P Carstens, A Mendoza, C Khanna, T Van Winkle, N G Avadhani. Mitochondrial retrograde signaling induces epithelial–mesenchymal transition and generates breast cancer stem cells. Oncogene, 2013; DOI: 10.1038/onc.2013.467