When we think of ways to prevent or treat cancer, temperature control usually isn’t high on the list. But, researchers at the University of Wisconsin-Madison, led by Dr. Caroline Alexander at the McArdle Laboratory for Cancer Research, have made crucial progress in understanding a link between ambient temperature and how it may affect our ability to resist tumors.
It all started with some mice that are known to be resistant to a wide variety of tumors. These Sdc1-/- mice, which are unable to make a protein called Syndecan-1, are slightly smaller than wild-type mice, which do make Syndecan-1, but otherwise appear normal.
While working to understand how Sdc1-/- mice resist tumors, researchers in the Alexander laboratory noticed something odd. “They seemed to be cold all the time,” said Alexander.
Various experiments confirmed that the Sdc1-/- mice were ‘chronically cold-stressed,’ meaning they felt cold at temperatures comfortably tolerated by wild-type mice.
The researchers found that when wild-type mice are exposed to low temperatures they thicken a layer of fat in their skin over time. The Sdc1-/- mice, however, did not. Without any expansion in this layer of fat, the mice were always cold. “It made us reconsider the importance of skin as an insulator,” Alexander said.
The outer layer of our skin serves as a waterproof barrier, much like the outer layer of a waterproof jacket. This study is the first to conclusively show that within the layers of skin is an expandable layer of fat, called intradermal fat, that reduces the amount of heat escaping our bodies and helps us maintain a stable body temperature.
“It’s your little blanket against the outside world,” said Dr. Hannah Carey, professor at the UW-Madison School of Veterinary Medicine, who studies how hibernating mammals respond to extreme changes.
Carey, who wasn’t involved in this study, says “this new study shows that there is an important fat layer within your skin and the thickness of the fat layer affects the heat lost from your body.”
But why were the Sdc1-/- mice not expanding their layer of intradermal fat at low temperatures? It turns out that without Syndecan-1 the intradermal fat cells or adipocytes are unable to take up a specific kind of lipid or fat molecule called VLDL (Very Low Density Lipoproteins).
The inability to take in VLDL molecules prevents the intradermal fat cells from expanding and performing their insulating functions properly. The end result is that Sdc1-/- mice feelscold at temperatures that don’t seem to bother wild-type mice.
Identifying the molecular players crucial to maintaining skin fat when animals are challenged by the cold is an important accomplishment. “Knowing about those molecules could allow [the researchers] to develop ways to study this in humans,” said Carey.
Now Alexander and her colleagues have a clue as to why Sdc1-/- mice feel colder at higher temperatures than wild-type mice. But how was this linked to their capacity to resist tumors?
The UW researchers started looking at any differences in checkpoint signaling between the Sdc1-/- and wild-type mice. “A molecular checkpoint is like a policing mechanism; it changes biological outcomes if there is stress or damage present within or to a cell,” said Alexander.
Think of these checkpoints as building inspectors; if they detect cracks in the support beams or damage to the piping, construction is halted until the defects can be repaired. Checkpoint proteins keep an eye out for damages within a cell and try to make sure that any damage detected is repaired quickly before the cell divides into progeny.
One checkpoint protein stood out in their search: mitogen-activated protein kinase-14, commonly called MAPK14 or simply p38alpha. “This is a protein that is activated anytime mitochondria are misbehaving” said Alexander.
Mitochondria are the energy-producing centers within our cells, and one important way birds and mammals generate body heat closely involves these enigmatic intracellular organelles.
When the Alexander lab looked at whether p38alpha was activated in Sdc1-/- mice, they found it was “lit up all the time,” said Alexander. The p38alpha protein was hyper-activated in the liver, lungs and some fat tissue of Sdc1-/- mice. Activated p38alpha can in turn lead to the activation of ‘anti-cancer’ checkpoint proteins like p53. Activated p38alpha could be why Sdc1-/- mice are resistant to tumors.
Of course, we don’t yet know exactly how tumor development and progression are affected by ambient temperatures. “The main point is that they are affected,” said Alexander. As we learn more about how temperature affects tumors we may be able to come up with ways to prevent or treat them naturally. But we need to know a lot more before we can say that’s true”, acknowledges Alexander. At least, she says “thermoregulation is getting to be a ‘hot’ topic!”
