Bad Neighbors

A tumor's surroundings may reveal the answers to how cancer grows and spreads. 

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.”

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