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Sapping Cancer's Energy

Craig Thompson didn't set out to be a spokesman for the importance of bioenergetics in determining cell fate.

Karen Hopkin(khopkin@the-scientist.com)
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Craig Thompson didn't set out to be a spokesman for the importance of bioenergetics in determining cell fate. Now a professor of medicine and chair of cancer biology at the University of Pennsylvania School of Medicine, he trained as a physician and became interested in research when he realized that "we really didn't understand quite as much as we needed to about basic biology to develop effective therapies for patients," he says. To pay for medical school, Thompson accepted a scholarship from the Navy and, following his training, he turned his attention to medical procedures that were of interest to the military – for example, bone marrow transplantation. The Navy planned to be prepared should such treatments become necessary to combat radiation injury on US soil.

In the early days, physicians were using bone marrow transplantation to treat patients, mostly with leukemias, who'd done poorly on standard cancer therapies. "The...

MYC IN THE BURSA

While at the Fred Hutchinson Cancer Research Center, Thompson had become interested in studying cancer and immunity in chickens. Working with Paul Neiman, Thompson found that the oncogene myc promotes proliferation of chicken lymphocytes, but only when the cells are safely ensconced in the bursa of Fabricius, the organ in which the bird's B cells mature. When he removed the cells from the bursa, "they died like stones," says Thompson.

"We thought, gee, if that's true, there must be something in the bursal environment that keeps cells from undergoing apoptosis as long as they're there," he explains. "So we went looking for genes that would keep bursal cells alive." And they found bcl-X, a relative of the bcl-2 gene that keeps programmed cell death in check. The discovery of this cell-death inhibitor "rocketed him to fame," says Raff. "It made an especially big splash because cell death was just in the beginning of its exponential rise. So that made him one of the heroes in the field."

Thompson then connected these two major discoveries, showing that CD28 stimulates production of bcl-X in mouse and human T cells, suggesting that the costimulatory pathway works by regulating cell survival during an immune response. Linking an extracellular signaling pathway with cell survival was not a major leap of imagination; most biologists now believe that animal cells are programmed to kill themselves if they don't receive the proper signals from their neighbors, says Raff. These survival signals, acting through proteins such as bcl-2, keep the cell death program shut down. But Thompson then tossed metabolism into the mix.

"Craig argues that the bcl-2 family mainly regulates metabolism. So that what survival signals are doing is not regulating cell death directly, but regulating death indirectly by regulating metabolism – for example, the transport of glucose and amino acids across the plasma membrane," says Raff. "That's where he's unique."

Indeed, Thompson hypothesizes that the function of extracellular signaling molecules is to give cells permission to take up sufficient nutrients to grow, maintain themselves, or reproduce. "We believe that in mammals, there's a constant supply of nutrients – glucose and amino acids – but that cells need specific transporters and specific metabolic enzymes to utilize those resources," says Thompson. "And those genes are under absolutely exquisite control by extracellular signal transduction." In other words, cells need permission from other cells in the organism to be able to access the nutrients they need to live.

FUELING CANCER

Derailment of the cell's system, Thompson finds, can lead to cancer. The oncogene akt, for example, boosts glucose uptake in transformed cells by driving the recruitment of glucose transporters to the cell surface. The added fuel could power the cancer cell's penchant for proliferation, and might explain something called the "Warburg effect." In 1930, German biochemist Otto Warburg observed that most cancer cells undergo a shift in metabolism: they tend to scarf up and burn through loads of glucose because they rely more heavily than do normal cells on glycolysis to produce their ATP. Warburg believed that this reliance on glucose came about because cancer cells somehow lost the ability to carry out the more efficient ATP-generating process of oxidative phosphorylation, which coupled with glycolysis produces on the order of 30 ATP molecules per molecule of glucose, compared to the two ATPs produced by glycolysis alone.

But Thompson and others think that the shift occurs not because tumor cells can't carry out oxidative phosphorylation, but because they gain the ability to take up and process as much glucose as they can – allowing them to make all the energy and the components they need to survive and proliferate. Although glycolysis alone produces less energy than oxidative phosphorylation, cancer cells crank up the activity of the pathway enough to more than compensate for the loss of efficiency. The theory makes sense according to oncologist Chi Dang of the Johns Hopkins University School of Medicine, who finds that myc also boosts the activity of enzymes involved in glycolysis. "In the paradigm we have now, oncogenes are like the accelerator and tumor suppressors are like the brakes. But basically what people forget about is the fuel source for the car." And like any cells, tumor cells need fuel to grow.

What's more, by favoring glycolysis over oxidative phosphorylation, cancer cells can spare their pyruvate – the glycolytic product that gets carried into the mitochondria to produce ATP. Instead of burning its pyruvate, a cancer cell can save it to make the fatty acids needed to build new membranes, "which you have to do in order to make another cell," says Lewis Cantley of Harvard Medical School.

Although the idea that this metabolic derangement is a necessary step in cancer formation is still somewhat controversial, more researchers are warming up to the idea. "We arrived at similar conclusions that the regulation of metabolism is going to be a major mechanism by which the PI3 kinase/Akt pathway is transforming cells," says Cantley. Whether the conversion will be strictly required for all cancers remains to be seen. "But, yes, I think that it's going to be very frequent in tumors and that one way or another something has to happen to turn on this pathway in order to get a tumor," he adds.

"One by one, all of our favorite oncogenes are going to tie into this story," Cantley predicts. "I think it's going to turn out to be incredibly important." Thompson and Dang hope to take advantage of cancer's metabolic Achilles' heel to design novel therapeutics.

REWRITING THE TEXTBOOKS

The good news for students, says Dang, is that when metabolism becomes integrated into the cancer story, "all this stuff that you memorize will start to click together biologically. It'll be more than just a bunch of diagrams." The bad news for established scientists: "Everybody's going to have to pull their biochemistry texts back out and relearn everything."

"We're at best halfway through our exploration of this idea. Actually, halfway is probably a gross exaggeration," says Thompson. "But we're going to see it through."

Thompson adds, "No one knows the answer right now. But we're having a wonderful time as a community discussing it. And we'll all learn something because – face it – none of us invented this system. We're just trying to figure it out."

In the meantime, Thompson will continue to go to meetings to spread the word and share his ideas. Attend one of his sessions and you'll likely be intrigued. But if you want to chat with him afterward, you might have to wait. "At meetings people form a line to talk to him," says Wei-Xing Zong, a postdoc who recently accepted a position at SUNY Stony Brook. And the same is true in lab, he points out. "You often see two or three people waiting in line outside Craig's office." Why? Because, Zong says, "he's fun to talk to."

And he's not afraid to be provocative. "Craig is definitely very insightful, but he can also be inciting," says Dang. "He'll say dogmatic things just to stir people up and get them to really think."

Which is part of what makes him so engaging. "He brings energy and enthusiasm and intelligence and a broad view to scientific questions, which is what you want in a scientist," says Raff. "He really is a breath of fresh air. It's always a treat to talk to him."

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