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Tracing the Steps of Metastasis, Cancer's Menacing Ballet

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Science  14 Feb 2003:
Vol. 299, Issue 5609, pp. 1002-1006
DOI: 10.1126/science.299.5609.1002

New studies are beginning to deconstruct this mysterious process, which is overwhelmingly the cause of cancer deaths

“We put the cancer cells in last Tuesday,” Weili Fu explains, as she slits open a mouse's chest. Speaking over the rapid hiss-click of a miniature ventilator, she threads a tiny catheter into the pulmonary artery and infuses a bolus of dye. Fu and her mentor at the University of Pennsylvania in Philadelphia, Ruth Muschel, keep the lung pressure high until the chemical runs through, highlighting the lungs' blood vessels to help trace the path of human cancer cells injected 8 days ago into the animal's tail. Under a microscope, the tumor cells show up in vivid shades of yellow within blood vessels dyed red—exposing a dynamic view of metastasis, the process by which cancer cells migrate from a primary tumor to other sites in the body.

When cancer cells metastasize, the fallout is devastating; indeed, it leads to death for most of the 282,000 people in the United States who succumb to four common cancers—of the breast, lung, prostate, and colon. But until very recently, many biologists were put off by the challenge of studying this process in the lab. The roadblocks are daunting. Because metastasis sweeps through various parts of the body, it must be studied mainly in whole animals rather than in cell and tissue cultures. Obtaining data from mice, which rarely have cancers that spread, remains difficult. Human tissue samples are scarce, too, because few cancer patients have secondary tumors surgically removed.

Although these challenges persist, the study of metastasis is undergoing a renaissance. Once the province of a small band, it is now drawing many scientists as one of the last great frontiers of cancer biology. Recent studies have found, unexpectedly, how little in metastasis occurs by chance. Instead, a constellation of molecular signals in cancer cells and the patient's own body steer tumor cells, bit by bit, from the primary site to a new, ideal home. Large-scale gene studies are suggesting fundamental differences between metastatic cells and other cancer cells. Researchers are also taking a deeper look at electrifying similarities between embryonic and metastatic cells.

Illuminating an enemy.

Cancer cells glow yellow inside the blood vessels of a mouse's lung.

CREDIT: WEILI FU AND RUTH MUSCHEL

Deciphering metastasis is a painstaking task. Like Muschel and Fu, growing numbers of researchers are tackling complex experiments and obtaining images of disease that could open new opportunities for treatment. The field's expansion has also brought growing pains. New entrants are challenging long-accepted theories, leading, many say, to sniping and quarrels, as each camp seeks to advance its worldview (see sidebar, p. 1005).

Although contentious at times, this work is providing insight into some fundamental puzzles. Among them: Are certain tumors predestined to be metastatic from their very beginning? What draws cancer cells to specific organs? Ultimately, for a cancer to progress, “something has to happen” to give tumor cells the capacity to thrive in new environments, says Bruce Zetter of Children's Hospital in Boston, and researchers are still trying to learn what that is.

A cunning enemy

Viewed in retrospect, the spread of cancer looks like an intricately choreographed ballet, linking dozens of steps in what's known as the metastatic cascade. Before they form a new tumor, cells must escape from the primary site, tumble into the bloodstream, and survive typhoonlike blood flow powerful enough to kill them. They must lodge in a spot conducive to growth (most are not) and colonize this outpost, recruiting blood vessels critical for nourishment.

This pattern—well established and orderly though it may seem—belies a number of peculiarities familiar to oncologists. Tumors that appear identical under the microscope display utterly divergent behaviors in the body, some spreading aggressively while others stay put. Cancers that appear cured may never stir again; or they may resurface as a metastasis 10 or 20 years later. This unpredictability frustrates physicians and patients.

One of the enduring goals of the field is to find a way to read a cancer's tea leaves. Yet even as sophisticated diagnostics push back the date when cancer first becomes visible, no universal signs of cell destiny have emerged. “When you try to ask the question of whether early detection by mammography predicts outcome,” says Muschel, “it's not very good. That could be because there are two categories of tumors, one of which has the metastasis phenotype.” If those phenotypes exist, identifying them could potentially guide treatment decisions.

Scientists have not unearthed a global signature that reads “metastasis” from the day of diagnosis, but they are picking up messages from all sorts of cancer cells that hint at their destiny. From one overexpressed enzyme marking metastatic colon cancer cells to a dizzying expression pattern of 70 genes in breast cancer linked to a poor prognosis, researchers are discerning individual, and sometimes divergent, signatures that are gradually pointing the way toward metastasis predictors.

What makes a metastasis?

In the early days of metastasis research in the 1970s, the focus was on dissecting the first step in the metastatic cascade, a cancer cell's escape from the primary tumor. At that time, scientists believed that if cancer cells had peeled off and infiltrated the bloodstream, “the horse is out of the barn and there's nothing you can do about it,” says cancer biologist Carrie Rinker-Schaeffer of the University of Chicago. Isaiah Fidler, a veterinary surgeon-turned-pathologist, proposed 3 decades ago that a cryptic minority of cancer cells harbor an inherent ability to spread. The rest are ill equipped to travel, said Fidler, now at the University of Texas M. D. Anderson Cancer Center in Houston. The proportion wasn't exact—guesses ranged from 1 in 10,000 to 1 in 1 million cells in a tumor—but regardless of their number, Fidler believed, something about these cells propelled them to launch a metastasis.

Tumbling down the metastatic cascade.

After breaking off from the primary tumor (far left), cancer cells travel through the blood vessels. Those that reach a secondary site such as the lung (right) may colonize it and form a metastasis.

ILLUSTRATION: C. SLAYDEN/SCIENCE

Fidler, widely considered the grandfather of metastasis research, inspired a core group of fewer than a dozen scientists to roll up their sleeves and try to identify what makes these cells different from others in the primary tumor. They focused on genes that are turned on or off only in cancer cells that have metastasized. Patricia Steeg of the National Cancer Institute in Bethesda, Maryland, and colleagues found the first gene, nm23, in 1988; at least seven more have been identified since then. When turned on, these genes appear to inhibit cancer's spread; when shut down, they are often associated with metastases, but apparently they do not affect primary tumor growth. Researchers dubbed them metastasis-suppressor genes, although their precise functions remain fuzzy. At a meeting in the late 1990s, Steeg and her colleagues, pooling their information, discovered that metastasis-suppressor genes are less relevant to the first stage of the metastatic cascade than to one of the last, a cancer cell's ability to colonize a new site.

This realization came as other researchers, eager to find out what enables a small fraction of malignant cells to thrive, began to focus on the later steps of the cascade. To their surprise, scientists are discovering that metastasis faces remarkably long odds. Although some tumors shed millions of cells into the blood, few reach an organ, and even fewer grow into full-blown secondary tumors. Recent imaging work in Ann Chambers's lab at the University of Western Ontario in London, Canada, has shown that only 1 in 40 skin cancer, or melanoma, cells that hit the liver will form what are called micrometastases: clumps of cells that remain small unless they develop blood vessels. Just 1% of those will acquire a blood-supply network and metamorphose into true metastases. “We ended up … seeing a totally different picture [from] what I assumed to be true,” says Chambers.

What enables a voyaging cancer cell to beat the odds and thrive? Metastasis researchers have more than one explanation. Some, such as Steeg and Rinker-Schaeffer, believe that metastasis-suppressor genes, which seem to come into play later in the cascade, are critical. They agree with Fidler's original theory that only a tiny portion of a primary tumor contains cells with metastatic potential. This suggests that the larger the tumor, the likelier it is to harbor metastatic cells and hence to spread.

Although Fidler's theories have been challenged in the past, it's only now, with the advent of gene microarrays, that they are being rigorously put to the test. Todd Golub, head of cancer genomics at the Whitehead Institute in Cambridge, Massachusetts, runs one of many cancer labs that are developing microarray technologies to monitor thousands of genes simultaneously. Studies analyzing tumor samples and correlating patient outcomes with gene activity are identifying literally dozens of genes whose expression appears to vary in tune with cancer's spread.

Researchers such as Golub and René Bernards of the Netherlands Cancer Institute in Amsterdam argue that certain primary tumors are, early in development, composed largely of cells with a genetic makeup that compels them to metastasize. Furthermore, they believe it may be possible to identify these deadly tumors early on by analyzing their gene-expression patterns.

Seeds and soils

As scientists skirmish over gene-expression studies, separate molecular biology work is spawning at least one principle on which almost everyone agrees: Metastasis appears to be partly controlled by messages embedded in the organs to which cancer spreads. Elements of the signals stimulating metastasis may come “not from the tumor cells themselves but from the microenvironment,” suggests Golub. The new tumor locale seems to include a key that cancer cells use to unlock the site and thrive.

Researchers have long puzzled over the ties that bind metastasized cancer to certain organs, knowing that specific cancers indisputably show a taste for specific sites. Whereas breast cancers favor the bone and lungs, for example, colon cancers prefer the liver. In 1889, a British surgeon named Stephen Paget spelled out in The Lancet his “seed and soil” theory, which argues that metastasis depends on matching certain types of “seeds,” or cancer cells, with “soils” in which they are likely to grow. Researchers now agree that although many ties between primary tumors and metastases are statistically predictable based on blood-flow patterns, about a third defy logic, among them breast and prostate cancers' frequent and deadly spread to bone.

As they decipher these affinities, biologists are finding that the choice of where to relocate isn't solely a cancer cell's to make: Distant organs also beckon them. The ensuing dialogue tugs the cells closer, or creates a welcoming second home in which they can freely multiply.

Albert Zlotnick, director of genomic medicine at Eos Biotechnology in South San Francisco, California, saw this pattern emerge 2 years ago while examining well-known proteins called chemokines. Chemokines, which recruit white blood cells to damaged tissue, landed in the spotlight in 1996 when HIV was found to use them to enter cells. Zlotnick eavesdropped on chemokine signals between metastatic breast cancer cells and two locales to which breast cancer spreads, lymph nodes and lungs. He was surprised to find that chemokines helped explain breast cancer's affinity for these organs: The cancer cells expressed specific chemokine receptors, and lymph nodes and lungs expressed the molecules that bind to them. In mice, he found, blocking this back-and-forth Morse code helped inhibit cancer's proliferation.

Joan Massagué, a new entrant to the metastasis field, is exploring what drives breast cancer to distant targets, particularly bone tissue. The question is especially intriguing because breast cancer cells strike bone more readily than anatomy would predict. In his lab at Memorial Sloan-Kettering Cancer Center in New York City, Massagué is studying how the cancer and target cells signal to one another; already, he's identified proteins that enable cancer cells to adhere tightly to bone and attack bone tissue.

Massagué is also finding that breast cancer cells corrupt a much-studied signaling pathway called transforming growth factor-β (TGF-β). Other researchers have found that TGF-β can function as a tumor suppressor, slowing the growth of some primary tumors. But in unpublished research, Massagué has observed that metastatic breast cancer cells appear to turn the tables on TGF-β; for them, it helps spur invasion and metastasis. Cancer cells must “acquire a number of abilities … to nest and thrive at appropriate sites,” says Massagué, and he thinks that subverting TGF-β is one of their successful dodges.

Some cutting-edge work also suggests that cancer cells master these tricks by turning back the clock. Last month, Denise Montell, a developmental biologist at the Johns Hopkins School of Medicine in Baltimore, Maryland, published an article in Nature Reviews: Molecular Cell Biology pointing out a possible connection between embryo development and metastasis that she stumbled on by accident. Montell was analyzing how cells in an adult fruit fly ovary migrate from one place to another—similar to the cell migration that occurs during embryo development and during metastasis, when cells move from one organ to another.

Montell found that two critical cell-signaling pathways, known to help cells proliferate in embryos and, in some cases, in cancers, also confer mobility. One of these, governed by steroid hormones and a fruit fly gene called taiman, controls the timing of cell migration in certain ovarian and embryonic cells. A closely related mammalian protein is highly expressed in metastatic breast cancer. Although scientists have long linked hormonal effects with cancer, they have not coupled hormones with migratory abilities. Startled by these associations, 2 years ago, Montell shifted some of her 10-person lab into metastasis studies and collaborations with cancer biologists.

Others are seeing tantalizing parallels between early development and cancer cells that have completed the metastatic cascade. “If you look at the molecular profile of these cells” in gene-expression studies, “they look like stem cells,” says Mary Hendrix of the University of Iowa in Iowa City. Stem cells carry built-in blueprints that enable them to morph into various tissue types. This, she explains, would clarify how breast cancer cells can live perfectly comfortably in strange environments.

All these advances, though, are years from being translated into therapies. Adding to the uncertainty is the erratic performance of one treatment that targets metastases as well as primary tumors: antiangiogenic drugs, which inhibit new blood vessel growth (Science, 22 March 2002, p. 2198).

But if old treatment approaches are struggling, new ones are emerging. Researchers are increasingly interested in designing drugs to focus on the final step in the metastatic cascade. Tumors have often spread insidiously through the body by the time they are diagnosed, but as surgeon Judah Folkman of Children's Hospital in Boston has shown, micrometastases may linger for anywhere from a few months to more than a decade before suddenly becoming metastases proper. This suspended state has recently captured scientists' attention; many believe that it's a pause that offers hope, and prolonging it may be the best short-term strategy for halting metastasis.

Delaying disease may defeat it. “That, I think, is a newly appreciated goal of cancer treatment,” says Zetter of Children's Hospital. He hopes that someday metastasis, if not curable, will be treatable as a chronic disease—and that more than just a lucky few will be able to live with it.

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