Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

A Role of Sugar Uptake in Breast Cancer Revealed

19.12.2013
Berkeley Lab Researchers Show that Aerobic Glycolysis is a Cause of Malignancy

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.

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!
Further information:
http://www.lbl.gov

More articles from Health and Medicine:

nachricht Routing gene therapy directly into the brain
07.12.2017 | Boston Children's Hospital

nachricht New Hope for Cancer Therapies: Targeted Monitoring may help Improve Tumor Treatment
01.12.2017 | Berliner Institut für Gesundheitsforschung / Berlin Institute of Health (BIH)

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Long-lived storage of a photonic qubit for worldwide teleportation

MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.

Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...

Im Focus: Electromagnetic water cloak eliminates drag and wake

Detailed calculations show water cloaks are feasible with today's technology

Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...

Im Focus: Scientists channel graphene to understand filtration and ion transport into cells

Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.

To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...

Im Focus: Towards data storage at the single molecule level

The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.

Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...

Im Focus: Successful Mechanical Testing of Nanowires

With innovative experiments, researchers at the Helmholtz-Zentrums Geesthacht and the Technical University Hamburg unravel why tiny metallic structures are extremely strong

Light-weight and simultaneously strong – porous metallic nanomaterials promise interesting applications as, for instance, for future aeroplanes with enhanced...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

AKL’18: The opportunities and challenges of digitalization in the laser industry

07.12.2017 | Event News

 
Latest News

Long-lived storage of a photonic qubit for worldwide teleportation

12.12.2017 | Physics and Astronomy

Multi-year submarine-canyon study challenges textbook theories about turbidity currents

12.12.2017 | Earth Sciences

Electromagnetic water cloak eliminates drag and wake

12.12.2017 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>