Tiny Fish Reveals Cancer Secrets

Scientists have found a way to watch in real time as human cancer cells produce tumors that spread throughout the body of a living organism. It's as though the body has suddenly become transparent, letting researchers watch the entire drama of how cancer spreads. The spread, or metastasis, is what usually kills cancer victims.

The human body isn't transparent, of course, but researchers have come up with a remarkable substitute. The tiny zebra fish has taken center stage in labs around the world because it is very similar genetically to humans, and its skin is so transparent that scientists can watch as dramatic changes take place.

The zebra fish has made it possible for researchers at the University of California, San Diego, School of Medicine, to watch human cancer cells produce tumors that spread throughout the fish. By examining each step along the way they have come up with an important discovery. It takes two proteins, acting together, to allow the cancer cells to pierce through the wall of blood vessels, a critical step in the spread of cancer.

If they, or someone else, can figure out a way to disrupt that process, it might "block the spread of cancer in the body," said lead researcher Richard Klemke, professor of pathology at the university.

One Step Closer

Klemke emphasized that such a development may be years away, but he's convinced that he and his colleagues have moved cancer research "one step closer to understanding the process at the very basic level."

Thus, a handful of resourceful scientists, working with a fish that few thought important just a few years ago, are able to see for themselves just what takes place when something goes terribly wrong inside a living organism. It would be better, of course, if they could do that with humans, but the zebra fish is a worthy partner.

Geneticist Mary Ellen Lane of Rice University has been studying this freshwater fish for years. She said that humans and the zebra fish share at least 80 percent of the same genes. It is so similar that we might as well call it cousin.

"The vascular system of the zebra fish has been well characterized, and the components that regulate blood vessel formation and angiogenesis (the creation of new blood vessels) in the zebra fish have been found to be very, very similar to mammals and humans," Klemke said. "That to me is absolutely amazing."

That's one of several reasons Klemke and his colleagues decided to use the fish in their research. Cancer spreads though the generation of new blood vessels, or angiogenesis, and to do that the cells must somehow pierce through the walls of existing vessels. They found that two proteins that have been long suspected of making that possible are indeed involved, but neither can do it alone. They need each other to carry out their nefarious deed.

One of the proteins, called vascular endothelial growth factor, is secreted by cancerous cells to stimulate new blood vessel formation. The second, called RhoC, is involved in cell migration.

Fish Tales

The San Diego researchers injected zebra fish with cells from inflammatory breast cancer, the deadliest form of human breast cancer. Some of the cells carried the cell migration protein, and some did not. The cells were tagged with fluorescent proteins that emit different colors so the researchers could identify the cells they were seeing through their microscope and determine if the migration protein is important.

Only those cells with the migration protein were able to break through the walls of the blood vessels.

"That's very, very valuable to be able to watch both your control and your cancer cell lines in the same environment and see how they behave as they interact with the blood system," Klemke said.

After several weeks of observation, the scientists were able to determine that the cancer cells grew something they call "false feet," thus making them more mobile, but they also needed the protein that stimulates new blood vessel formation to break through the blood vessel wall.

So it required both proteins -- one for mobility and one for generating new blood vessels -- to "complete the most critical step of metastasis, entering the blood vessels," said the university's Konstantin Stoletov, lead author of a paper on the research in a recent online edition of the Proceedings of the National Academy of Science.

Keeping Proteins Apart

If some way can be found to keep those two proteins from cooperating, the cancer could be stopped in its tracks, the researchers said.

"That would be huge because the vast majority of cancer patients succumb to the spread of the disease to other organs," Klemke said.

And once again, the zebra fish will be called into the battle. Researchers will actually be able to see how various therapeutic agents function.

"We can grow human tumor cells in an optically transparent animal so we can visualize the process in high resolution detail," Klemke said. "Then we can test the pharmaceutical agents and determine how they impact the process of tumor formation and metastasis. It's a win-win situation."

So the zebra fish, common in aquariums around the world, is likely to be on center stage for a long, long time.

Lee Dye is a former science writer for the Los Angeles Times. He now lives in Juneau, Alaska.

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