Metabolism was lost in the shadows of cancer research for decades but has recently been reclaiming some of the spotlight.
Now, Mina Bissell, Distinguished Scientist with Berkeley Lab’s Life Sciences Division and a leading authority on breast cancer, has shown that aerobic glycolysis – glucose metabolism in the presence of oxygen – is not the consequence of the cancerous activity of malignant cells but is itself a cancerous event.
“A dramatic increase in sugar uptake could be a cause of oncogenesis,” Bissell says. “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.”
These phase contrast and confocal immunofluorescence images (inset)show 3D cultures of non-malignant (S1) and malignant (T4-2) human breast cells in which glucose metabolism is inhibited by the addition of 2-deoxy-D-glucose (2DG). Suppressing glucose uptake leads to a phenotypic reversion of malignant cells (they look normal) while not affecting the non-malignant cells. (Click to enlarge)
Working with Bissell, Yasuhito Onodera, a Japanese postdoctoral fellow in her research group who is now an assistant professor in Japan, examined the expression of glucose transporter proteins in human breast cells. The focus was on the glucose transporter known as GLUT3, the concentrations of which Onodera and Bissell showed are 400 times greater in malignant than in non-malignant breast cells. The study was carried out using a 3D culture assay developed earlier by Bissell and her group for mouse mammary cells and later with her collaborator, Ole Petersen, for human breast cells. The assay enables actual reproduction of breast cells to form structural units and for malignant cells to form tumor-like colonies.
“We found that overexpression of GLUT3 in the non-malignant human breast cells activated known oncogenic signaling pathways and led to the loss of tissue polarity and the onset of cancerous growth,” Bissell says. “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 non-malignant 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 ATP 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.Mina Bissell is a leading authority on breast cancer who holds the title of Distinguished Scientist at Berkeley Lab. (Photo by Roy Kaltschmidt)
Mina Bissell is a leading authority on breast cancer who holds the title of Distinguished Scientist at Berkeley Lab. (Photo by Roy Kaltschmidt)
“In a series of papers published in the early 1970s, using fibroblasts from chick embryos and their malignant counterparts, we showed that if the microenvironmental context was equalized, the rate of aerobic glycolysis was indeed higher in cancer cells under all conditions tested,” Bissell says. “Clearly Warburg was correct in saying that cancer cells always had increased aerobic glycolysis; however, he was not necessarily correct in saying that the defect had to be in respiratory pathways. We found these pathways to be similarly active in normal and malignant fibroblasts, as we find also now in our breast cancer cell studies in 3D assays.”
Bissell would go on to discover that the cause of increased aerobic glycolysis was a dramatic increase in glucose uptake by cancer cells, but at that time did not determine whether this increase was the cause of malignant transformation. In this new study with Onodera and Jin-Min Nam of Japan’s Hokkaido University, 3D laminin-rich extracellular matrix cultures of non-malignant human breast epithelial cells from a reduction mammoplasty were compared to malignant cells derived from the study’s non-malignant cells.
Bissell says 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 non-malignant breast cells behave in a manner that is phenotypically analogous to their corresponding architecture in living tissue.
“In our 3D culture assay, glucose uptake and metabolism determined the signaling activity and the morphology of both malignant and non-malignant mammary epithelial cells,” Bissell says. “Our ability to revert the malignant phenotype in our 3D cultures shed new light on the importance of glucose uptake and metabolism in inducing oncogenic signaling.”
Bissell and her Japanese collaborators believe their 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 anti-diabetic drugs, such as metformin, which lower blood glucose levels, have been linked to lower cancer risks and mortality.
“Our work highlights the importance of the context in studying pathways involved in tissue-specificity and disease, and sheds additional light on the relationship between metabolic diseases and cancer” Onodera explains.
The results of this study have been reported by Onodera, Nam and Bissell, in the Journal of Clinical Investigation (JCI). The paper is titled “Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways.” Bissell and Onodera are both corresponding authors.
This research was primarily supported by the National Cancer Institute, the Department of Defense (DOD) Breast Cancer program, the Breast Cancer Research Foundation (BCRF) and in part by a fellowship and a grant to Yasuhito Onodera from Uehara Memorial Foundation (Tokyo, Japan) and The Japan Society for the Promotion of Science.
Lawrence Berkeley National Laboratory addresses the world’s most urgent scientific challenges by advancing sustainable energy, protecting human health, creating new materials, and revealing the origin and fate of the universe. Founded in 1931, Berkeley Lab’s scientific expertise has been recognized with 13 Nobel prizes. The University of California manages Berkeley Lab for the U.S. Department of Energy’s Office of Science.
Lynn Yarris | EurekAlert!
The genes are not to blame
20.07.2018 | Technische Universität München
Targeting headaches and tumors with nano-submarines
20.07.2018 | Universitätsmedizin der Johannes Gutenberg-Universität Mainz
A new manufacturing technique uses a process similar to newspaper printing to form smoother and more flexible metals for making ultrafast electronic devices.
The low-cost process, developed by Purdue University researchers, combines tools already used in industry for manufacturing metals on a large scale, but uses...
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
20.07.2018 | Power and Electrical Engineering
20.07.2018 | Information Technology
20.07.2018 | Materials Sciences