Search for tag: "metabolism"

Interviewer: New insights into how cancer cells gain the deadly power to grow uncontrollably up next on The Scope.

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Interviewer: I'm talking with Dr. Jared Rutter Professor at The University of Utah. Dr. Rutter you've published a report, "Molecular Cell," describing what could be a key change that takes place in cancer cells that gives them an advantage over the normal cells in the body. I think what's fascinating about your discovery is that it relates to a hypothesis that was posed early last century. First of all, can you explain what this hypothesis is, The Warburg Effect?

Dr. Rutter: Dr. Warburg discovered that cancer cells do a different kind of metabolism than normal cells. That fundamental observation has been born out repeatedly in the years since and now has become a very active area of research both in discovery based research and academia, as well as more applied research going on in companies trying to treat cancer. The question will be whether that can now be exploited and in treatment.

Interviewer: You can tell me if I have this right, in a normal cell sugars or carbohydrates eventually go down a pathway where the cells powerhouse, mitochondria, makes energy, but in cancer cells it's different. What happens in cancer cells?

Dr. Rutter: So cancer cells go through about half of that pathway. They take the carbohydrates about halfway through that pathway but they don't take the carbohydrate into the mitochondria, the powerhouse of the cell, they do other things with it, and specifically they use that carbohydrate to create the building blocks that will enable them to make a new cell. So obviously cancer is a disease of overgrowth of cells dividing and duplicating themselves more rapidly than they should and that's what creates a tumor, or what creates the cancer.

Interviewer: I think your work really argues that there's a protein called MPC1 that is a key component of this shift in metabolism. What is MPC1?

Dr. Rutter: The MPC1 and MPC2 together make up a protein complex that enables carbohydrates in the form of a specific molecule called pyruvate to enter the mitochondria, again the powerhouse of the cell, and enable the mitochondria to then take that pyruvate and use it to create energy.

Interviewer: And what happens to this protein in cancer cells?

Dr. Rutter: We've shown that in a large number of cancers, most prevalently in ovarian cancer, that the part of the genome that encodes this protein is just lost. It's lost from the genome and therefore the gene is not expressed, the protein isn't made, and this MPC protein complex is just never formed. So what we did next was pretty simple in that is the hypothesis is that it being lost is actually important then what if we put it back in and force the cancer cells to make this protein, and what happens is they lose their ability to behave like cancer cells. Their metabolism reverts from the way that most cancer cells do in metabolism to be a much more normal type of metabolism and they lose the ability to form tumors in different situations, and so...

Interviewer: Wow, that's amazing.

Dr. Rutter: Yeah.

Interviewer: So you saw that effect both in a dish but also in the context of an animal too, correct?

Dr. Rutter: That's right. So yeah exactly, we saw it in a dish and then the gold standard for this type of experiment is to put tumor cells, cancer cells, into a mouse and ask whether they can form tumors, and what we found is that the cells that had this protein, this MPC protein, put back in were quite dramatically impaired in their ability to form tumors in mice and how fast those tumors grew.

Interviewer: What kind of difference are we talking about? I mean is it there's a tumor compared to no tumor, or is it a difference in size, or is it the number of tumors that form, or...?

Dr. Rutter: Yeah that's a good question. I would say the way that the experiment was done it really wasn't done in such a way that we could see a tumor versus no tumor. So what was done is to inject about 100,000 cells into the flank of a mouse and then so that you already have a fairly large number of cells there and then look at the ability of those cells to grow, form a tumor and how big that tumor becomes, but always they grew slower when this MPC protein was put back in.

Interviewer: When you're talking about the progression of cancer where do you think metabolism fits in the scheme of things? Do you think it might be one of the early changes that must take place in order for a cell to become invasive for example or...?

Dr. Rutter: Yeah we do, we actually know that. In some cases that there are certainly many cancers where one of the early steps is to manipulate the metabolic profile of those cells.

Interviewer: And what are you most excited about going forward?

Dr. Rutter: Well I think there are a few different things that I would say we're most excited about. I would say first is just trying to understand what is the cause of the failure of the cancer phenomenon when we force cancer cells to make that protein. We just really don't understand it and whatever the answer is it will be interesting, and then the second, like we've talked about, is to try and understand how to exploit this observation to make a difference in the context of the treatment or diagnosis of cancer, and we have some ideas that I think are quite good as to how to try and translate that into direct clinical application.

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Interviewer: Your fat tends to get a bad rap but there is good fat, it's called brown fat and not only does it help you stay thin it has amazing healing powers that you might not know about. Dr. A Patel, director of clinical regenerative medicine at the University of Utah, Tell me about brown fat and how fantastic it is.

Dr. Patel: It's a great question, everyone thinks fat is fat, and really there's two types of fat, there's white fat and there's brown fat. White fat is the big cells that make you gain weight give you heart disease, diabetes, metabolic syndrome, all these bad things. But if you think of little kids, they can eat thousands of calories and until they start getting older they don't lose that, everyone thinks their metabolism is slowing down but what it is, is they're losing their brown fat. When you're really young you have what's called brown fat and brown fat is very unique, it's very metabolically active so that's a fancy term that means it has a lot of horsepower in it,. It's having a little car with basically a big v8 engine, where white fat is a really big car with basically a 2 cylinder engine.

Interviewer: Yeah, it takes up a lot of space but moves real slowly.

Dr. Patel: And that's how most people feel when they get to fat, so what we've done is we've been able to identified a brown fat stem cell in actual patients. And everyone believes it's in kids but we found actually that you could find this even in patients who are 80 years old. The problem is as you get older you get fewer and fewer cells, these cells start dying off. So our goal was how do we one; identify these cells because then we can say can we look at this brown fat stem cell as a potential target for new drugs or new therapies where we can take grown ups who actually have diabetes, metabolic syndrome, all these bad things that can make you die from heart disease and look at a drug that could actually make you increase your own brown fat stem cells or can we grow these brown fat stem cells outside your own body and put them back into you and use them as a target for the diabetes, the weight gain.

Interviewer: So just to be clear, up until just recently it was believed that brown fat existed really in adult humans

Dr. Patel: Yeah, and that surprising, it's one of things that just because no one was able to identify it no one believed that you could actually find it or did it exist. This is incredible because this is something where obesity is an epidemic in the U.S. and there are millions of drugs, medications, fad diets and everything there but there's so little science to support it. This is where science is finally starting to catch up in saying what are we missing? Or what was there when we were younger; or what do bears have that lets them hibernate, and that's brown fat, that's what they have too? So, how do we harness the power of brown fat and not just say well we need more of it but how do we actually develop this in a safe reproducible manner that potentially may actually become not only a cell therapy but also a drug therapy to increase your body's own ability to produce more brown fat as you get older.

Interviewer: What's the biggest challenge that you're facing? You said this is in very early stages.

Dr. Patel: The biggest challenge with brown fat stem cell is that there's so few of them so how do you safely grow them in a large enough, make billions of these so we can study them better and actually make them potentially available for therapy because the goal would be you'd need trillions of cells to start looking at how could you use this as a therapeutic model or basically how would you treat patients with this. So growing them we've been able to identify them now how do you scale up to do the experiments to say does this really work in patients

Interviewer: So children have a lot of brown fat, as you grow older it decreases so your body is getting rid of it for some reason apparently.
Dr. Patel: Well one of the reasons the brown fat originally is what's called a thermal regulator, basically regulates heat, so when you have a shiver response when your young and you don't have a lot of fat, it generates heat. That's even in small animals and things like that. That's what brown fat is used for is to generate heat, regulate body temperature, and as you get older because you get more white fat you basically form your own insulation and you don't need , so it's a natural way of the body to say well if i don't need this cell I'm going to start getting rid of it. the problem is when your own body starts decreasing the amount of brown fat it's thinking I don't need it to produce heat, but we lose the ability to regulate a lot of other things such as fat, sugars, and all that so it's sort of a bad side effect of getting the white fat on board. So the more insulation you have the less metabolically functional or the less efficient you are. You become energy inefficient by having too much insulation.

Interviewer: So if I was to stay very lean and thin and keep the white fat off, would I be more likely to have more brown fat then?

Dr. Patel: You would be, the thinner you are the potential to more brown fat as you get older is much higher.

Interviewer: What's your final thought on this?

Dr. Patel: So brown fat has huge potential both for therapy, for diabetes but also just studying how the body works so we can find better ways to safely develop therapies to treat obesity, type II diabetes, and heart disease which is the number one killer of patients in the U.S.

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