"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!
Investigators may unlock mystery of how staph cells dodge the body's immune system
22.09.2017 | Cedars-Sinai Medical Center
Monitoring the heart's mitochondria to predict cardiac arrest?
21.09.2017 | Boston Children's Hospital
Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.
A warming planet
Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.
The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...
Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...
For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.
Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...
19.09.2017 | Event News
12.09.2017 | Event News
06.09.2017 | Event News
22.09.2017 | Life Sciences
22.09.2017 | Medical Engineering
22.09.2017 | Physics and Astronomy