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Bad Neighbors

BY LAURA BEIL
PUBLISHED TUESDAY, DECEMBER 22, 2009
Stephen Paget had a question: When cancer breaks free and starts to spread, where does it go and how does it get there?  As a surgeon at the West London hospital, he knew most people didn’t die from their original tumors, but from metastatic outposts in other parts of the body.

Paget’s numbers revealed a different story. After examining the records of 735 women who had died from breast cancer, he found that metastases occurred in the liver far more than any other organ. It wasn’t because of unlucky blood flow—the spleen, with similar circulation, rarely had malignancies. In the journal The Lancet, he proposed that cancer cells were like seeds, each one capable of sprouting: “When a plant goes to seed, its seeds are carried in all directions,” he wrote. “But they can only live and grow if they fall on congenial soil.”

That was  March 23, 1889. Revolutionary as Paget’s idea was, it remained in the shadows of cancer research for more than another century, as scientists concentrated their investigations on the rogue properties of tumors themselves. Finally, in 2006, 80 years after Paget’s death, the journal Nature Reviews Cancer recognized his “seed and soil” hypothesis as a milestone in our understanding of cancer.

To cancer, environment matters. Tumors aren’t just self-contained bursts of growth, but living, dynamic entities that alter—and are altered by—the location they find themselves in. When women examine their breasts for cancer, they look for lumps. So what’s a lump, exactly? “What you’re feeling for is the collagen, the extracellular matrix around the tumor,” says Zena Werb, PhD, professor of anatomy at the University of California, San Francisco. The tumor itself isn’t hard. “You’re feeling for something that responds to the tumor.”

In fact, cancer is so intertwined with its surroundings, research suggests that the nonmalignant tissue nestled around a tumor can, by itself, determine whether cancer lives, dies, or simply freezes in place.

Although Paget recognized the importance of the tumor environment 120 years ago, only relatively recently have scientists begun to understand the interplay between malignant and nonmalignant cells. Eventually, research may open new avenues for therapy. While traditional cancer therapy targets the cancer itself, future strategies might not just try to disable the tumors, but change the surrounding tissue to make it less accommodating. Studies might also lead to new means of cancer prevention by revealing genes or lifestyle choices that create a cancer-friendly environment. If you can’t remove the seed, reduce the soil to dust.

“You can buy the best tomato seeds in any nursery. If you put them in sand, you don’t get tomatoes. If you don’t fertilize them, you don’t get tomatoes,” says Isaiah J. Fidler, DVM, PhD, director of the Cancer Metastasis Research Center at M.D. Anderson Cancer Center in Houston. Back in 1980, Fidler performed a 20th-century version of Paget’s experiment, injecting melanoma cells into kidney, ovary, and lung tissue that had been grafted into mice. The cancer cells came from the same source, but grew only in the ovary and lung tissue, not the kidney. For cancer, he says, “You need the right seed in the right soil.”

A hospitable environment—researchers use the term “microenvironment”—appears to be necessary not only for metastases, but for the tumors they came from. Experiments going back to the 1970s have demonstrated that some cancer cells, when placed in a normal microenvironment—that is, surrounded by cells that have never touched cancer—stop growing and settle down to a quiet life. Like spoiled kids, cancer-prone cells may be more likely to run wild if their home rewards bad behavior. 

“Uncontrolled cell growth is not sufficient for cancer,” says Donald Ingber, MD, PhD, Judah Folkman Professor of Vascular Biology at Harvard Medical School and Children’s Hospital Boston. For a tumor to develop the muscle to thrive, invade surrounding organs, and dispatch cells to form still more cancers, “the tissue architecture has to break down.” 

Ingber envisions the day when treatment targets the microenvironment. “You would not be trying to kill the cancer,” he says. “You would be trying to revert it to normal tissue.”

To do that, though, researchers have to understand the difference between a normal environment and that of a tumor. This is not as simple as it may sound. The tumor microenvironment is so complex that entire textbooks are devoted to it. One major distinction is the thicket of blood vessels that supply the tumor with nutrients and oxygen.

Research into this aspect of the microenvironment has already led to drugs like Avastin (bevacizumab)—approved for metastatic breast, colon, and kidney cancers as well as non-small cell lung cancer and a type of brain tumor called glioblastoma multiforme—which work to strangle the tumor’s blood supply.

But what makes some environments more susceptible to corruption by cancer cells? No one yet knows for sure. Some differences may lie in the genes a person is born with.

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