Metabolism was lost in the shadows of cancer research for decades but has recently been reclaiming some of the spotlight. Now, aerobic glycolysis, which is glucose metabolism in the presence of oxygen, has been shown to be a cancerous event, rather than a consequence of the cancerous activity of malignant cells.
“A dramatic increase in sugar uptake could be a cause of oncogenesis,” said Mina Bissell, PhD, of Lawrence Berkeley National Laboratory in Berkeley, California. She is a leading authority on breast cancer. “Furthermore, through a series of painstaking analysis, we have discovered two new pathways through which increased uptake of glucose could itself activate other oncogenic pathways. This discovery provides possible new targets for diagnosis and therapeutics.”
The research team examined the expression of glucose transporter proteins in human breast cells. The focus was on the glucose transporter known as glucose transporter 3 (GLUT3), the concentrations of which were found to be 400 times greater in malignant than in nonmalignant breast cells. The study was carried out using a 3D culture assay that enables actual reproduction of breast cells to form structural units and for malignant cells to form tumor-like colonies. The study was published in the Journal of Clinical Investigation (2013; doi:10.1172/JCI63146).
“We found that overexpression of GLUT3 in the nonmalignant human breast cells activated known oncogenic signaling pathways and led to the loss of tissue polarity and the onset of cancerous growth,” Bissell said. “Conversely, the reduction of GLUT3 in the malignant cells led to a phenotypic reversion, in which the oncogenic signaling pathways were suppressed and the cells behaved as if they were nonmalignant even though they still contained the malignant genome.”
Bissell began exploring the relationship between aerobic glycolysis and malignant cells more than 40 years ago. She was intrigued with a hypothesis proposed in 1924 by biochemist and future Nobel laureate Otto Heinrich Warburg, which held that increased aerobic glycolysis at the expense of respiration and higher adenosine triphosphate production is a cause and not a symptom of cancer. This hypothesis became controversial because many researchers could find aerobic glycolysis in normal cells. Even now, the majority view holds that increased sugar uptake in cells is the result of the intense metabolic demands of tumor cells and not a cause of malignant transformation.
Bissell said this demonstration of an active role in breast cancer development for glucose uptake could only have been revealed through a 3D culture assay in which both malignant and nonmalignant breast cells behave in a manner that is phenotypically analogous to their corresponding architecture in living tissue.
These findings help explain why hyperglycemia in diseases such as obesity and diabetes can raise the risk of breast and other cancers. In addition, these results may also help explain why antidiabetic drugs, such as metformin, which lower blood glucose levels, have been linked to lower cancer risks and mortality.