H. Lee Moffitt Cancer Center & Research Institute
Robert Gatenby is Chair of the Department of Radiology at the Moffitt Cancer Center in Florida and also the Principle Investigator of the Moffitt Cancer Center PS-OC. He describes the content of the talk he was about to give.
Robert Gatenby: I personally am speaking about glucose metabolism and how glucose is used by cells to make energy, ATP, which it needs for its functioning. And it really goes back to a paradigm that's well over 150 years old. Louis Pasteur, most noted for pasteurization, discovered in the mid-19th century that when cells are exposed to oxygen they no longer make alcohol or lactic acid, they just convert glucose to CO2 and water. And this is a good thing because under those circumstances, when glucose is metabolized with oxygen, it makes a lot of ATP. So this is the most efficient way to convert glucose into energy. Since that time, it’s been universally viewed that glucose metabolism is controlled by the presence of oxygen. If oxygen is present glucose is metabolized to CO2 and water. The other pathway that metabolizes glucose to lactic acid (and is what makes your muscles sore when you're exercising) is really just an emergency backup. It’s just there when oxygen is depleted as it is in the in the muscles of an athlete. The reason this is of interest in cancer is that since Warburg’s time, which is now almost 100 years ago, it’s been known that cancer cells are unusual because they use these glycolytic pathways that convert glucose to lactic acid even in the presence of oxygen. That has always been viewed with puzzlement and it's always been assumed that there must be some defect in the oxidative phosphorylation pathways or something about the cell that's disrupted, but this has really never been shown. So what we've done is actually taken a different view of things and what we said is that instead of being driven by the amount of oxygen present and the amount of ATP, that can be produced; metabolism is based on the demand. The reason that's different is that the glycolytic pathways, the ones that produce lactic acid, although the not very efficient they are very fast. So they can respond very quickly, about a hundred fold faster to reductions in ATP than can the mitochondria, which are more efficient. So in this is very much like a power grid. Our power grids are full of unusual variable demands but also a standard amount of energy that’s necessary. So what typically happens is that we use our nuclear power plants or steam power plants to cover the base energy needs that’s there all the time. And then we use gas turbines, which are less efficient but much faster, to allow you to be sure that if you flip the light on that it comes on, to supply for various needs that are unpredictable. So what we said then is that glycolysis actually is extremely important even in the presence of oxygen because it allows the cell membrane to respond to unexpected changes which may be fatal to the cell, and by rapidly producing ATP, it allows the pumps on the cell membrane to respond to anything that perturbs it and so is it is a really important part of the way cells function.
Pauline Davies: So this seems to suggest to me that if he could somehow knock out this glycolytic pathway, that maybe the cancer cells wouldn't do so well: they’d would slow down.
Robert Gatenby: It may be that because cancer environments are so heterogeneous and they’re so variable. So there's lots of fluxes in blood flow and oxygen and acids, so their membranes are constantly being perturbed and the cells themselves are constantly moving, potentially being attacked by the immune system. And so the membrane is very active which means that the glycolytic pathways are very active, so it would suggest that attacking glycolytic metabolic pathways, while you are doing something else to the cell - you know, increase the demands, do things are that are going to perturb the membrane, perhaps change glucose concentrations or oxygen concentrations or even give chemotherapy. A lot of chemotherapies are pumped out by membrane pumps, so if you were to do that, for example, so you're maximally stressing the membrane and then do something that might turn off the glycolytic pathways, you may stress the cells beyond their capability of responding and cause cell death. It probably isn't by itself going to work, but if you are tricky, if you use combinations of therapies that on one hand increase the demand, and then when you’ve increased the demand try to cut it off, I think you may have some a strategy that may be effective.
Pauline Davies: Why do you think that that old paradigm stuck around for so long untested?
Robert Gatenby: Well I think it's not totally wrong and in the sense that it's certainly true that if we don't have oxygen, our cells turn to this alternative metabolic pathway and so that's correct. Oddly though the biological community, although it’s had evidence that this may not be entirely correct, has never really challenged this basic paradigm, I guess in part because so old; it's been around for almost 2 centuries and is just so well-established that I think we haven't really thought it through carefully. I think this is an opportunity and it's been interesting to do that.
Pauline Davies: And so what did you think of doing that?
Robert Gatenby: The fundamental explanation never appealed to be very much; it just intuitively didn't seem right. I think the idea of one whole metabolic pathway simply as an emergency backup seemed just too simple. I think that evolution is just too good for that, it's such a wonderful optimization process that it's going to use every possible advantage. And I think the fact that the glycolytic metabolism, although it's not efficient, is so fast, it seemed clear to me that that was going to be a significant advantage and evolution would use it.
Pauline Davies: Why then don’t ordinary cells use that pathway if it’s so good? You might say that it’s because they don’t need it!
Robert Gatenby: That's correct. What we’ve proposed is that this is not based on the availability of oxygen or the efficiency of glucose metabolism of ATP, it’s based on demand. If you take normal cells and you increase the demand in the cell membrane by stimulating the membrane pumps, then they would use the glycolytic metabolism and that's what we've shown, actually. The theoretical work that was done with math modeling and was then followed by experiments where we did exactly that sort of thing; we stimulated membrane pumps or we inhibited membrane pumps and what we showed was that that didn't really affect the oxidative metabolism pathways at all but it greatly affected glycolysis. Alternatively, if you do things like alter the protein synthesis or if you if you shut that off, we think that's primarily supported by the mitochondria, by the oxidative metabolism. And in fact we’ve shown that if you reduce proteins synthesis, the oxidative metabolism goes down but glycolysis does not. So I think what we're seeing then is just that normal cells, because our bodies are really fairly uniform, they don't really see rapid changes and so at baseline there is probably not a lot of glycolysis going on, but cancer cells are very different; they are subject into a extremely variable environment, constant changes and so by the need to be able respond quickly, cancer cells up regulate this glycolytic pathway. Normal cells would too, and do, when they need to.
Pauline Davies: Such as in embryogenesis?
Robert Gatenby: It could be and there has been some evidence that cells in embryos are much more glycolytic. We know that when an immune cell becomes activated that it becomes far more glycolytic; we know that's fibroblasts, if they become activated, become more glycolytic. So we know that this happens in normal cells, so it is not that it just doesn't happen, it’s simply that nature always optimizes things. In this case it doesn't optimize the efficiency of ATP production, it optimizes the ability of ATP to get where it’s needed.
Pauline Davies: Well I think that it sounds like a very significant piece of research that you have done.
Robert Gatenby: Thank you, I think it's been very interesting, it's a little geeky!