"We have known for more than 50 years that low-oxygen, or hypoxic, cells cause resistance to radiation therapy," said senior co-author Mark Dewhirst, DVM, Ph.D., professor of radiation oncology and pathology at Duke. "Over the past 10 years, scientists have found that hypoxic cells are also more aggressive and hard to treat with chemotherapy. The work we have done presents an entirely new way for us to go after them."
Many tumors have cells that burn fuel for activities in different ways. Tumor cells near blood vessels have adequate oxygen sources and can either burn glucose like normal cells, or lactic acid (lactate). Tumor cells further from vessels are hypoxic and inefficiently burn a lot of glucose to keep going. In turn, they produce lactate as a waste product.
Tumor cells with good oxygen supply actually prefer to burn lactate, which frees up glucose to be used by the less-oxygenated cells. But when the researchers cut off the cells' ability to use lactate, the hypoxic cells didn't get as much glucose.
For the dangerous hypoxic cells, "it is glucose or death," said Pierre Sonveaux, professor in the UCL Unit of Pharmacology & Therapeutics and lead author of the study, published in the Nov. 20 online edition of the Journal of Clinical Investigation. He formerly worked with Dr. Dewhirst at Duke.
The next challenge was to discover how lactate moved into tumor cells. Because lactate recycling exists in exercising muscle to prevent cramps, the researchers imagined that the same molecular machinery could be used by tumor cells.
"We discovered that a transporter protein of muscle origin, MCT1, was also present in respiring tumor cells," said Dewhirst. The team used chemical inhibitors of MCT1 and cell models in which MCT1 had been deleted to learn its role in delivering lactate.
"We not only proved that MCT1 was important, we formally demonstrated that MCT1 was unique for mediating lactate uptake," said Professor Olivier Feron of the UCL Unit of Pharmacology & Therapeutics.
Blocking MCT1 did not kill the oxygenated cells, but it nudged their metabolism toward inefficiently burning glucose. Because the glucose was used more abundantly by the better-oxygenated cells, they used up most of the glucose before it could reach the hypoxic cells, which starved while waiting in vain for glucose to arrive.
"This finding is really exciting," Dewhirst said. "The idea of starving hypoxic cells to death is completely novel."
Even though hypoxic tumor cells have been identified as a cause of treatment resistance for decades, there has not been a reliable method to kill them. "They are the population of cells that can cause tumor relapse," said Professor Feron.
A significant advantage of the new strategy is that a new drug does not need to reach hypoxic cells far from blood vessels and it does not need to enter into cells at all – it merely needs to block the transporter molecule that moves the lactose, which is outside of the cells. "This finding will be really important for drug development," said Sonveaux.
The researchers also showed in mice that radiation therapy along with MCT1 inhibition was effective for killing the remaining tumor cells, those nearest the blood vessels. This proved to be a substantial antitumor approach.
Mary Jane Gore | EurekAlert!
3D images of cancer cells in the body: Medical physicists from Halle present new method
16.05.2018 | Martin-Luther-Universität Halle-Wittenberg
Better equipped in the fight against lung cancer
16.05.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...
A team led by Austrian experimental physicist Rainer Blatt has succeeded in characterizing the quantum entanglement of two spatially separated atoms by observing their light emission. This fundamental demonstration could lead to the development of highly sensitive optical gradiometers for the precise measurement of the gravitational field or the earth's magnetic field.
The age of quantum technology has long been heralded. Decades of research into the quantum world have led to the development of methods that make it possible...
Cardiovascular tissue engineering aims to treat heart disease with prostheses that grow and regenerate. Now, researchers from the University of Zurich, the Technical University Eindhoven and the Charité Berlin have successfully implanted regenerative heart valves, designed with the aid of computer simulations, into sheep for the first time.
Producing living tissue or organs based on human cells is one of the main research fields in regenerative medicine. Tissue engineering, which involves growing...
A team of scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg investigated optically-induced superconductivity in the alkali-doped fulleride K3C60under high external pressures. This study allowed, on one hand, to uniquely assess the nature of the transient state as a superconducting phase. In addition, it unveiled the possibility to induce superconductivity in K3C60 at temperatures far above the -170 degrees Celsius hypothesized previously, and rather all the way to room temperature. The paper by Cantaluppi et al has been published in Nature Physics.
Unlike ordinary metals, superconductors have the unique capability of transporting electrical currents without any loss. Nowadays, their technological...
02.05.2018 | Event News
13.04.2018 | Event News
12.04.2018 | Event News
18.05.2018 | Power and Electrical Engineering
18.05.2018 | Information Technology
18.05.2018 | Information Technology