McArdle Blog L7 ~ 8/7/2014
Staying cool and stopping tumors: How the two may be linked
Around 130 species of mammals and over 280 species of birds (but not penguins!) can be found in the Arctic. The same area is home to fewer than 10 species of reptiles and amphibians combined. One important reason for this disparity is that mammals and birds can generate their own body heat. The ability to ‘defend’ a stable body temperature or thermoregulate sets apart birds and mammals like us from the vast majority of other organisms.
The exact molecular mechanisms by which we ‘warm-blooded' creatures maintain a stable body temperature aren’t completely understood, but scientists are slowly piecing the puzzle together.
In a paper published today in the journal PLOS Genetics researchers at the University of Wisconsin-Madison, led by Dr. Caroline Alexander at the McArdle Laboratory for Cancer Research, have identified a crucial protein, syndecan-1, that is essential for mice being able to adapt to cold temperatures.
The Sdc1-/- mouse
It has been known for some time that mice which do not have the syndecan-1 gene, and so are unable to make syndecan-1 protein, resist developing many different kinds of tumors including mammary, lung and liver tumors as well as lymphomas. These Sdc1-/- mice are somewhat smaller than wild type mice that do make syndecan-1 protein but otherwise appear to be normal.
“How on earth do these mice resist tumors?” Dr. Alexander has often found herself wondering. “That question has been a real driving force behind our study of these animals” she explains.
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”, says Dr. Alexander.
Various experiments confirmed that the Sdc1-/- mice were ‘chronically cold-stressed’, meaning they felt cold at temperatures comfortably tolerated by wild type mice. “Of course, we wondered why?” says Dr. Alexander, the gleam of a scientist facing an unanswered question appearing in her eyes.
The Clue in the Skin
At this point Dr. Alexander remembers going to a research talk given by Dr. James Ntambi, a professor in the Department of Biochemistry and chair of the Department of Nutritional Sciences at UW-Madison.
She remembers Dr. Ntambi talking about how deleting a single gene – the Δ9-desaturase-1 isoform or SCD1 gene – from only the skin cells of mice caused an increase in the total amount of energy being used by these mice.
“It made me think, WOW, the skin is a very important tissue metabolically”, says Dr. Alexander. So she and her colleagues started to take a shallower look at the Sdc1-/- mice and focused on its skin. Pretty soon they hit pay-dirt.
“Think of our skin as a modified layer of Gore-Tex fiber”, explains Dr. Alexander, and shows me a picture to prove her point.
The outer layer of our skin serves as a waterproof barrier, much like the outer layer of a waterproof jacket. 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 (and in humans may partly explain how we can ‘enjoy’ outdoor activities during the lovely Wisconsin winters).
When Dr. Alexander looked at the intradermal fat of the Sdc1-/- mice, which cannot make syndecan-1 protein, she found a far thinner layer compared to that in wild type mice. Moreover, while the layer of intradermal fat expanded when wild type syndecan-1 positive mice were moved to lower temperatures, it did not in the Sdc1-/- mice.
A lack of intradermal fat in Sdc1-/- mice
“It made us reconsider the importance of skin as an insulator”, says Dr. Alexander. “From the inside of our bodies to the outside there is often a big temperature difference and skin properties are modifiable by exposure to different conditions”. Mice literally add fat to their skin over time when ambient temperatures are lowered but apparently not if they are unable to make syndecan-1 protein.
Why would that be? To answer that question the Alexander lab turned to the published literature. “It was like a detective story”, says Dr. Alexander, “We were following clues in the literature”. 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 insulator functions properly. The end result is that a Sdc1-/- mouse feels cold at temperatures that don’t seem to bother wild type mice.
Now Dr. Alexander and her colleagues had a clue as to why Sdc1-/- mice feel cold at higher temperatures than wild type mice. But was this linked in any way to their capacity to resist tumors?
The p38α protein and tumor resistance
“We hypothesized that there was something metabolically different about these [Sdc1-/-] mice that made them tumor resistant”, says Dr. Alexander. The Alexander lab proceeded to ask an unbiased research question: Were there any differences in molecular signaling between the Sdc1-/- and wild type mice? They started by looking at checkpoint signaling.
“A molecular checkpoint is like a policing mechanism; it changes biological outcomes if there is damage present within or to a cell”, explains Dr. 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 and before the cell divides into progeny.
One checkpoint protein stood out in their search: mitogen activated protein kinase-14, commonly called MAPK14 or simply p38α. “This is a protein that is activated anytime mitochondria are misbehaving” quipps Dr. Alexander. Mitochondria are the energy-producing centers within our cells, and one way birds and mammals generate body heat closely involves these enigmatic intracellular organelles.
When the Alexander lab looked at whether p38α was activated in Sdc1-/- mice, they found it was “lit up all the time”, according to Dr. Alexander. The p38α protein was hyper-activated in the liver, lungs and some fat tissue of Sdc1-/- mice. Activated p38α can in turn lead to the activation of ‘anti-cancer’ checkpoint proteins like p53. Activated p38α 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”, asserts Dr. Alexander, “and you sitting at 72 degrees may be a very different you than you sitting outside in the cold or the heat!”
For example research from Dr. Elizabeth Repasky’s laboratory at the Roswell Park Cancer Institute in Buffalo, NY that showed tumor growth and the response of the immune system in mice was affected by what temperature these mice were housed at.
It’s possible that as we learn more about how surrounding temperature affects tumors we can 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 Dr. Alexander.
She is well aware of the serendipitous nature of these discoveries, but says that is often the nature of scientific progress. “The NIH [National Institutes for Health] would never have [funded] it”, she says while talking about this research project “but now thermoregulation is getting to be a ‘hot’ topic!”
Note: This article is based on the paper titled “Syndecan-1 is required to maintain intradermal fat and prevent cold stress” published in the journal PLOS Genetics. This paper can be accessed at: http://www.plosgenetics.org/doi/pgen.1004514