The mystery of metastasis
Scientists seek new techniques for arresting cancer's spread
By Robert Levy
Metastatic cancer cells spread to other parts of the body by passing through the walls of blood or lymph vessels, riding the circulatory system, and then exiting downstream, where they form secondary tumors. Only about one in a million metastatic cells survive the journey.
Among its other villainous roles — intruder, saboteur, usurper, and traitor — cancer is also an imperialist.
Obeying the commands of misguided genes, advanced tumors sometimes extend their influence by launching bits of themselves to far regions of the body, where they take hold and form additional, secondary tumors. This process, known as metastasis, is cancer's final and most obstinate challenge to therapy. Tumors confined to a single area can often be entirely removed; those dispersed throughout the body represent a hardier, more elusive opponent.
While survival rates have climbed markedly over the past 30
years for patients whose cancer hasn't spread (top chart). the
rates for people with metastatic tumors have barely risen
(bottom).
Source: National Cancer Institute's SEER
Program
It is a measure of cancer's menace that tumors embark on their colonization scheme only when they are fully malignant. Cells with a few minor genetic glitches generally don't venture from their birthplace to cause trouble elsewhere. It isn't until multiple genes have failed—opening the throttle on cell growth, disguising cancer cells from the immune system, letting them leech off the body's blood supply—that the cells gain their grim mobility. Think of sea mines that are armed and activated before being released into the water; metastatic cells, too, represent an accumulation of dangers.
The process begins unassumingly enough. A single tumor cell dissolves the bonds that anchor it to surrounding tissue. It unfurls a few filaments from its surface, using them as direction finders as it creeps around and across other cells. When it encounters a blood or lymph vessel, it releases a chemical that enables it to slip between cells in the vessel wall and into the bloodstream or lymphatic system. Bobbing along, it lands a short time later in a distant part of the body, where it makes itself at home and quickly starts intruding on its neighbors' space and source of nourishment. Dividing relentlessly, it spawns a new outpost of the original tumor.
Such a description makes it all too easy to see the cell's actions as signs of conscious cunning. But cancer's malevolence is purely mechanical. The genes that enable metastatic cells to ensconce themselves in new locations are all defective or out-of-sync versions of normal genes. Defeating such cells requires understanding the molecular errors at the heart of their wanderlust.
Preventing metastasis—or halting it, slowing it, or somehow rendering it less harmful—is especially important because 90 percent of cancer deaths result from metastatic rather than isolated tumors. Even as five-year survival rates have gradually risen for patients with tumors confined to a single area, the numbers have barely budged for patients whose cancer has spread. For the four most common types of cancer—breast, colorectal, lung, and prostat—the odds facing patients with metastatic disease today are essentially the same as they were 30 years ago.
Even so, metastasis has never really been a mainstay of cancer research. With limited resources available, investigators have focused on catching and killing cancer at its earliest stages, when chances of a cure are highest. There has been a sense that the best way to deal with cancer is to destroy it outright—to devise treatments that aim for tumors' core malfunctions, rather than its ability to spread.
As medical advances turn cancer into more of a chronic disease—one that more people live with than die from—matastasis research is gaining new favor among scientist and those who fund their work.
But as medical advances turn cancer into more of a chronic diseas—one that more people live with than die from—metastasis research is gaining new favor among scientists and those who fund their work. Techniques that have laid bare so many of cancer cells' fundamental secrets are now being applied to the problem of metastasis. Prominent among these technologies is "gene expression profiling," which enables investigators to scan the activity of thousands of genes at a time. The grid-like patterns produced by such profiles serve as ID tags for different kinds of cells, allowing scientists to pinpoint specific malfunctions in metastatic cells and, potentially, defeat them.
Last year, Dana-Farber scientists Sridhar Ramaswamy, MD, (now at Massachusetts General Hospital) and Todd Golub, MD, used expression profiling to find a gene "signature" of tumors that are likely to spread. Their work, which may help identify patients at greatest risk of metastatic disease, offers a preview of the kind of advances the new research is making possible. Here, Paths of Progress offers a look at the leads some of their Dana-Farber colleagues are pursuing.
- Next: Calling off the invasion
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