Tightening the body’s cancer-catching net

Cancer-Catching Net

At CU Cancer Center, researchers, discover how dinosaurs, diabetes, Star Trek extras and Keith Richards combine to keep the body cancer-free.

Interstate 70 is bad enough on a normal Monday evening, let alone when an accident makes the freeway look more like long-term parking at Denver International Airport. And so it’s easy to sit there, stewing, scanning radio stations, and thinking about what could possibly have caused the accident in front of you and why the highway patrol can’t move the wreck to the median. I mean—sheesh—you could be home by now sitting comfortably on the couch and grumbling about Peyton Manning’s arm!

That is, if it weren’t for that darn accident.

But look at it another way: most nights the freeway is packed with 4,000-pound chunks of fire-propelled metal, hurtling across the pavement at 70 mph while their pilots shove their heads in Cheetos bags or fidget with their supposedly hands-free smart phone systems. Some of these people you wouldn’t trust with a popcorn maker let alone a Hummer. Really, it’s pretty astounding there aren’t more accidents.

The same is true of cancer.

Cancer research centers tend to focus on what to do once the body is sick, once an accident is already on the road. For example, at University of Colorado Cancer Center when a patient walks in the door the physician asks what went wrong and how to fix it.

“But maybe a better question is, for all the people we don’t see, what goes right,” says Andrew Thorburn, PhD, deputy director of CU Cancer Center.

He points out that there are about 10 to 100 trillion cells in the human body, with 50 to 60 billion cells replaced every day. That’s 50 to 60 billion chances per day that a cell can accidentally accumulate a mutation or combination of mutations that cause cancer. Like cars on a fast freeway, “You look at those odds and it’s surprising that cancer isn’t more prevalent,” Thorburn says.

Andrew Thorborn, PhD, CU Cancer CenterOr maybe it’s not that surprising after all.

It’s no random accident—no game of Russian roulette—that keeps the body cancer free. Instead it’s a handful of precise mechanisms that Thorburn calls “prerequisites of multicellular life” that have evolved to ensure we stay healthy long enough to pass on our genes. Researchers at CU Cancer Center and elsewhere are broadening their focus to explore not only what goes wrong when we get cancer, but what goes right when we don’t.

Place Original Face Down on Glass

First, “the body has an astoundingly precise copy machine,” Thorburn says. When a cell divides, it copies the full expanse of its DNA, giving away a copy to its daughter cell and keeping a copy for itself. The code of life is made up of only four bits of information, called nucleotides, which when strung together can look something like this: ATGACGGAGCTTCGG.

If you were sitting at a keyboard, could you look at this code and reproduce it? What would be your error rate? The body’s error rate is only about one mistake in every 100,000 nucleotides. That’s pretty darn good.

Now imagine the 30,000-ish genes included in every human cell’s DNA—the blueprints for all the construction and workings of your body. Each gene is made up of about 3,000 nucleotide base pairs. That’s not all: functional genes make up only about 2 percent of your DNA and so in all you have around 6 billion nucleotide base pairs in each cell’s DNA. This means that despite the body’s careful copy machine, each new cell is likely to have about 120,000 mutations. Now multiply that by 50 to 60 billion cells and you get…well, you get a really big number that you certainly don’t want to see printed here.

Jill Slansky, PhDSo in addition to an accurate copy machine, the body also has an accurate proofreader. Instead of accepting these mutations, the body tries to identify and fix them.

A cell builds DNA by stacking it one nucleotide at a time. And as it stacks nucleotides, the cell has enzymes that crawl along the original DNA, comparing it to the copy. When an enzyme finds an error—say a G that should be an A—it pulls the mistake and inserts a correction. The cell’s proofreading mechanism catches and fixes about 99 percent of errors this way—good but not nearly good enough to keep mutations out of
your genome.

The more cells you need to replace (for example, because you kill cells with a sunburn), and the higher a cell’s mutation rate (say, because the sun’s UV rays slice and dice DNA like Dan Aykroyd’s Super Bassomatic on “Saturday Night Live”), the more mutations make their way past the copy machine and proofreader. Now the body’s job switches from fixing errors to eliminating them.

Copy Correctly or Kill

As you’d expect, one recognizer-and-killer is the immune system. But it’s tricky: cancer cells are your own cells gone bad. Your immune system is supposed to kill foreign cells like bacteria and viruses, not your own cells, and so it has difficulty turning its firepower on more domestic terrorists.

Interestingly, there’s one kind of person whose immune system does kill cancer cells and that’s people with autoimmune diseases like Type 1 diabetes, in which the immune system’s T-cells erroneously attack the pancreas’s insulin-producing cells. Patients with Type 1 diabetes almost never get pancreatic cancer. And patients with the autoimmune condition vitiligo, in which T-cells attack the skin’s pigment-producing cells, are dramatically protected against skin cancer. It seems that an over-sensitive immune system kills cancer cells first. On the flip side, people who are immunocompromised, as are those with HIV, have higher rates of many cancers.

“When you develop a cancer, by definition soft tissue has gone haywire. And when you develop an autoimmune condition like Type 1 diabetes, by definition your T-cells have gone haywire,” says David Wagner, PhD, CU Cancer Center investigator and associate professor of medicine at the CU School of Medicine. “Perhaps we could push T-cells to just beneath this threshold of ‘haywire’ to combat the cancer cells that have already gone past this tipping point.”

James Degregori, PhD, CU Cancer CenterIt’s like your email spam filter: one form of cancer immunology seeks to dial up the sensitivity of your immune system’s spam filter in order to route cancer cells to the “kill” folder, perhaps destroying some healthy cells along the way.

Wagner is working to control T-cell sensitivity with a protein called CD40. Tweaking CD40 in one direction makes T-cells more aggressive and tweaking it in another direction makes T-cells more docile. Other CU Cancer Center immunologists are working with vaccines to sensitize T-cells against cancer.

According to Jill Slansky, PhD, co-leader of the Immunology and Immunotherapy Program at CU Cancer Center and National Jewish Health, here’s one way it works: “The immune system is designed to recognize abnormal proteins and kill the cells that present these proteins. Due to mutations, cancer cells make abnormal proteins, but because cancer cells also share so much similarity with the body’s own, healthy cells,
the immune response may not be very strong.

“We’re working to boost the sensitivity of T-cells to these tumor-specific antigens. Like any vaccine, if you can give T-cells a preview of these foreign proteins, you can sensitize T-cells to recognizing these proteins on actual cells,” Slansky says.

Sacrificing Cells for the Greater Good

In fact, cells containing cancer-causing mutations might not even need the intervention of the immune system to end up dead.

“Cells are hardwired to kill themselves if there’s something wrong with them,” says Thorburn, whose research focuses on this programmed cell suicide called apoptosis. “If a cell’s in the wrong place or growing at the wrong time, healthy cells have this natural default to just kill themselves.”

Like an unnamed character tagging along with the “Star Trek” crew on an unexplored planet, cells are expendable. So the body errs on the side of caution—one teeny-tiny false move in the way a cell goes about its business can show that it harbors a dangerous mutation, and the body would rather throw the cell under the bus than risk it spawning a dangerous tumor.

For example, if you’ve taken high school biology, you probably still have that dream where you’re sitting at a desk, pencil in hand, no clothes, staring at an unexpected test on the stages of the cell cycle. Messing up the steps of the cell cycle won’t help your biology grade and it doesn’t help most cancer cells, either. That’s because the body places customs agents at the boundary of each step. If a cell rushes through or tries to skip a stage of cell division, tumor suppressor genes (customs agents) recognize the cell and mark it for apoptosis.

Likewise, these regulators look for broken DNA, unnatural bulging or misarranged chromosomes—any one of these can mark a cancerous cell and any one can get a cell marked for apoptosis.

DandelionSo in addition to a mutation that allows an early cancer cell to act cancerous, cancer cells also include mutations to these anti-tumor or tumor suppressor genes, making them toothless.

In fact, “Simply disabling some of those anti-cancer genes is sufficient to create cancer,” says Thorburn, “and ironically, cancer cells are often easier to push into apoptosis than healthy cells—it’s as if they were trying to kill themselves and just didn’t quite manage it.”

Dinosaurs, Keith Richards and the Body’s Changing Tissue Landscape

Then in addition to accurate copying, the immune system and apoptosis, there’s the role of the tissue surrounding mutated cells.

Sure, the older you are, the higher likelihood that one of your 50 to 60 billion cell duplications per day will result in a sneaky mutation that avoids control, but Cancer Center researcher James DeGregori, PhD, shows that it’s not only the increasing chance of a mutation with time that leads to higher cancer rates in older adults.

“You put an early cancer cell in healthy tissue and that cancer cell is unlikely to survive,” says DeGregori, professor of molecular biology at the CU School of Medicine. “It’s like what happened to the dinosaurs 65 million years ago. Dinosaurs were great and they weren’t changing that fast; they were well adapted to their landscape. Until that darn meteor. Suddenly dinosaurs weren’t a good fit for the new landscape. The species didn’t have to change their mutation rate; it was the new landscape that drove speciation.

“Similarly, what primarily drives cancer rates higher as we age is the changed landscape,” he says.

Our healthy cells are optimized for the conditions of our healthy, younger tissue. In fact, they’re so perfectly optimized for young tissue that changing anything about a cell makes it less fit for its surroundings. That’s the case of cancer cells—they’re different and thus less fit, and so healthy cells simply out compete them. The young body uses basic survival-of-the-fittest to keep cancer in check.

But, “when tissue is old, healthy cells are no longer a perfect fit for the landscape, and mutations might help a cancer cell adapt in ways a healthy cell can’t,” DeGregori says.

Blot out the sun with a meteor’s cloud of dust and mammals will eventually outcompete thunder lizards. Age or transform tissue until it’s far enough from its healthy norm and cancer cells can outcompete their healthy peers.

DeGregori’s work supports the conclusions of CU Cancer Center investigators Pepper Schedin, PhD, and Ginger Borges, MD, who work with the tissue landscapes that give rise to breast cancers.

“We see that breasts with higher rates of inflammation—as those undergoing the process of involution during which milk-producing cells are replaced by fat cells—have higher rates of both initial cancer and metastasis,” Schedin says.

Inflammation and a dramatically changing tissue landscape leave healthy cells looking for their footing, while cancer cells, like dandelions, take advantage of the disturbed earth. Borges and Schedin’s work explores the use of non-steroidal anti-inflammatory drugs like ibuprofen to reduce inflammation in these tissues, hopefully bringing it in line with the conditions for which healthy cells are optimized.

Obesity and the Challenge of Proving Prevention

The influence of tissue on cancer is also important on a more global scale. The process of breast involution, sunburn and smoking are not the only ways to create inflammation. Obesity can also create cancer risk. (Read “Battle of the Bulge” in the previous edition of C3).

In fact, Tim Byers, MD, MPH, professor of epidemiology at the Colorado School of Public Health and associate director for prevention and control at CU Cancer Center, believes that in many cases an intentional 10 percent weight loss after surgery for breast cancer can be as effective as adjuvant chemotherapy in preventing relapse.

Knowing these mechanisms the body uses to stay cancer free, you’d think we could design and test interventions to help the body with its work and artificially boost its defenses.

Unfortunately, “the real difficulty in exploring any of these preventative strategies is the logistical and ethical difficulty of prescribing any intervention for people who aren’t yet sick,” Thorburn says.

For example, you can’t give 1,000 women ibuprofen and compare their breast cancer rates to 1,000 women given sugar pills. Likewise, you can’t experimentally introduce cancer proteins in a vaccine to people who don’t yet have the disease. Thus, prevention strategies are tricky to prove.

But the times they are a-changing.

Like CU Cancer Center, other cancer centers are starting to prioritize their departments of prevention and control. And cancer vaccines, including the drug Yervoy for metastatic melanoma and Gardasil for HPV that causes genitourinary cancers in men and women, have gone from fringe science to FDA approval.

Next time you’re stuck in an I-70 traffic jam, instead of fretting in a way that’s really not good for your blood pressure, try being thankful that accidents are rare.

In addition to being courageous as you face cancer, offering your compassion to others affected, and helping support organizations looking for tomorrow’s best fixes, take a minute to marvel at the body’s ability to get it right so often.

We are machines made to resist cancer. By understanding how these machines work, we may find ways to help them resist cancer just a little bit better.

Decoding Cancer Fall 2012

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About the author: Garth Sundem

In addition to writing for the University of Colorado Cancer Center, Garth is the author of the books The Geeks' Guide to World Domination, Brain Candy, and Geek Logik. Contact him at garth.sundem [at] ucdenver.edu.

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