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TAMPA, Florida – Cells need energy to survive and thrive. In general, if oxygen is available, the cells will oxidize glucose to carbon dioxide, which is very efficient, just like burning gasoline in your car. However, even in the presence of adequate oxygen, many malignant cells instead choose to ferment glucose into lactic acid, which is a much less efficient process. This metabolic adaptation is called the Warburg effect, as it was first described by Otto Warburg almost a century ago. Since then, the conditions that would evolutionarily select for cells to exhibit a Warburg effect have been the subject of debate, as they are much less efficient and produce toxic waste.
“The Warburg effect is poorly understood because it makes no sense for a cell to ferment glucose when it could get a lot more energy by oxidizing it. Our current study gets to the heart of this problem by defining the micro-environmental conditions that exist in early cancers. which would select for a Warburg phenotype. This is important because these cells are much more aggressive and likely to lead to fatal cancers, “said Mehdi Damaghi, Ph.D., lead author of the study and researcher in the Department of Cancer Physiology at the Moffitt Cancer Center.
To better understand the conditions that select the Warburg effect and the mechanisms by which cells can express this metabolic adaptation, Moffitt researchers subjected non-malignant cells to the severe tumor microenvironment present at the onset of carcinogenesis, known as Ductal carcinoma in situ (DCIS). DCIS is an uncontrolled growth of cells in the breast ducts. This is the earliest stage at which breast cancer can be diagnosed. Although it is considered non-invasive, it can lead to invasive cancer in a fraction of the cases. In a new research article published in the Proceedings of the National Academy of Sciences, Moffitt’s team shows that these conditions select cells to express a Warburg effect.
The researchers hypothesized that the complex interplay of factors in the severe tumor microenvironment of DCIS, such as low nutrient content, low oxygen content, and high acidity, may lead pre-malignant cells to express a Warburg phenotype in order to survive and thrive in these harsh conditions. To test their theory, the research team subjected low glycolytic breast cancer cells to these different microenvironmental selection pressures (low oxygen, high acidity, low glucose, and starvation) for 12 to 18 months. Following this selection, individual clones of cancer cells were isolated and characterized for their metabolic and transcriptomic profiles.
Their results indicate that the poor metabolic conditions in the tumor microenvironment of DCIS lead these pre-malignant cells to select a Warburg phenotype by transcriptional reprogramming. In particular, the researchers found that activating and stabilizing the transcription factor, KLF4, allows cancer cells to adapt to a phenotype capable of surviving a harsh environment. “Although KLF4 is clearly responsible for this phenotype in this particular system, we expect that different cell lines will come up with their own approaches to address this need for metabolic adaptation. We call this “functional equivalence,” said Robert Gillies, PhD, senior author and chair of the Department of Cancer Physiology. “We have clearly shown that this phenotype is selected by difficult micro-environmental conditions.”
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This research was supported by the National Cancer Institute (U54CA193489, U01CA232382, R01CA077575, P30-CA076292) and the Moffitt Center of Excellence for Evolutionary Therapy.
About the Moffitt Cancer Center
Moffitt is dedicated to one vital mission: to help prevent and cure cancer. The Tampa-based facility is one of 51 comprehensive cancer centers designated by the National Cancer Institute, an honor that recognizes Moffitt’s scientific excellence, multidisciplinary research, and strong training and education. Moffitt is the # 11 cancer hospital and has been nationally listed by US News & World Report since 1999. Moffitt’s expert nurses are recognized by the American Nurses Credentialing Center with Magnet® status, its highest honor. . With more than 7,000 team members, Moffitt has an economic impact in the order of $ 2.4 billion. For more information, call 1-888-MOFFITT (1-888-663-3488), visit MOFFITT.org and follow the momentum on Facebook, Twitter, Instagram and YouTube.
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