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In the Way Cancer Cells Work Together, a Possible Tool for Their Demise
New York Times, January 29, 2015

A tumor, as strange as it may sound, is a little society. The cancer cells that make it up cooperate with one another, and together they thrive.

Scientists are only starting to decipher the rules of these communities. But if they can understand how these cells work together, then they may be able to stop the tumor. “You can drive it to collapse,” said Marco Archetti, a biologist at the University of East Anglia and at the Icahn School of Medicine at Mount Sinai.

Cancer starts when healthy cells mutate and lose the safeguards that normally keep their growth in check. The cells start to multiply quickly, and their descendants gain new mutations, some of which make the cells even better at multiplying.

As tumors rapidly develop, they outgrow their blood supply, and stores of nutrients and growth-stimulating chemicals, known as growth factors, run low. As it turns out, cancer cells survive this harsh new environment by helping one another.

New mutations can cause cancer cells to start making their own growth factors, and they don’t keep these essential chemicals to themselves. Growth factors seep throughout the tumor, affecting all the cells. “It’s one of the hallmarks of cancer,” Dr. Archetti said.

This kind of cellular cooperation can get complicated, as Dr. Edward J. Gunther, an oncologist at Penn State College of Medicine, and his colleagues discovered while studying breast cancer tumors in mice.

The tumors were made of two types of cancer cells, and neither type could grow in the lab without the other. Each type of cancer cell was providing the other with some kind of essential aid.

Last year, Dr. Gunther and his colleagues discovered a compound produced by one type of cancer cell that stimulates the growth of the other. He suspects that the other cells produce a growth factor of their own, creating “a reciprocal cross-talk,” as he put it.

The cooperation among tumor cells is strikingly similar to what goes on in an ant colony or other animal societies. Ants divide up the work, with individuals specializing in different jobs.

Cooperative societies can be very successful, but they also have a vulnerability that can be devastating: They can be destroyed by cheaters who mooch off the labors of others without donating any of their own. If cheaters become too common, the few remaining cooperators can’t carry out all the work the society needs to survive.

Dr. Archetti and his colleagues have found evidence that cancer cells cheat one another, too. They reported their research this week in Proceedings of the National Academy of Sciences.

The cheating they discovered takes place in pancreas tumors. Scientists have long known that some of these cancer cells gain a mutation that causes them to make a growth-stimulating chemical called IGF-II. In many cases, these tumors contain other cells that don’t produce IGF-II. Dr. Archetti and his colleagues wondered if the nonproducers were taking advantage of the producers.

To find out, the researchers mixed together the two types of cells in the lab and observed their growth. The scientists found that nonproducer cells thrived on the IGF-II made by the producer cells, growing faster than they would on their own.

Yet the producer cells got no advantage from being in the mixture, suggesting that the nonproducers really do cheat.

To see how harmful this relationship could be, the scientists reared the mixed cells under different conditions. Sometimes, the cheaters wiped out the IGF-II producers, the scientists found.

One way to let the cheaters win was to rear the cells in a rich broth of nutrients and growth factors. The cheating cells grew quickly. The IGF-II producing cells, by contrast, lagged behind. They were using up energy to make unnecessary growth factors, which they could have used to grow fast. Over time, the cheating cells completely took over the population, the scientists found.

Dr. Gunther, who was not involved in the new study, said the study raised some intriguing possibilities about how cancers develop in real life.

When tumors start to grow, they enjoy a rich blood supply. If cheating cells emerge at this early stage, they can grow quickly, engulfing the IGF-II producers. With so many cheaters and so few IGF-II producers, the tumor can’t sustain its growth for long.

“It might naturally act to prevent cancer progression by causing tumors to stall at an early stage,” Dr. Gunther said.

If tumors can survive this early threat, Dr. Archetti’s research suggests, they can grow and even tolerate a substantial number of cheaters.

To mimic the harsh conditions inside a large tumor, Dr. Archetti and his colleagues fed their cancer cells a meager diet with a scarce supply of growth factors. Now the cheaters depended much more on the IGF-II producers.

If the cheaters became too numerous, they ran low on the donated growth factors and their growth became sluggish. Eventually, the cheaters and the IGF-II producers reached an equilibrium in their microscopic community.

But the cancer cells can fall out of balance with a push, Dr. Archetti and his colleagues also found.

The scientists found that if they started off the experiment with a high level of cheaters, they grew so quickly that the IGF-II producers didn’t have a chance to rebound. Instead, they disappeared from the mixture of cancer cells.

This finding may point to a new strategy for fighting cancer — one that Dr. Archetti and his colleagues are now testing out. In effect, they want to create a tumor within a tumor.

The researchers are taking IGF-II producing cells out of tumors in mice and shutting down the genes they use to make growth-stimulating chemicals. The scientists are then letting these newly created cheaters multiply and putting them back into the tumors.

The team hopes these extra cheaters will disrupt the tumor so badly that it will collapse.

“I certainly buy it — this kind of free-rider behavior has long been predicted,” said Carlo Maley, a biologist at the University of California, San Francisco, who was not involved in the study.

But he cautioned that the experiment didn’t involve a real case of cancer but just artificial mixtures of cancer cells. Scientists have yet to document cheating in real tumors in animals or humans.

“However, I’m sure it happens,” Dr. Maley added.

Copyright 2015 The New York Times Company. Reproduced with permission.
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