By Charlie Schmidt
When Tumor Cells Travel
What is metastasis-and what are researchers learning about it?
By Charlie Schmidt
Medical researchers have long struggled with how to best manage metastasis—the moment when cancer cells begin a mysterious migration toward distant sites in the body. Roving metastatic cells typically wind up in vital organs like the brain, lungs and liver, or in the bones, and spawn tumors that can be hard to treat.
Although metastases are still the leading cause of cancer death, with recent advances, five-year survival rates for patients with some metastatic cancers are on the rise. And promising new drugs are in the pipeline, raising hopes that a new and improved era of treatment might be under way. “We’re making tremendous gains,” says surgeon Steven K. Libutti, who heads the Tumor Angiogenesis Section of the National Cancer Institute’s Surgery Branch. “We think the next five to 10 years will generate more progress on [the scientific understanding of] metastasis than what we’ve been able to achieve during the last half century.”
Libutti’s optimism reflects a growing willingness among scientists to tackle metastasis research. Until recently, most scientists shied away from it, deterred by its daunting complexity. To spread through the body, metastatic cells have to separate from primary tumors, wrench themselves free of surrounding tissues, survive harrowing passages in blood or lymph fluid, evade attacks by the immune system, and somehow overcome rejection by their target organs. Why would metastatic cells strike out into the body and take such perilous risks? No one can say for sure. Each step in that process involves dozens of molecular interactions, all of them difficult to separate and investigate in detail.
But probing those interactions is getting easier. Empowered by new technologies—most of them arising from advances in molecular biology—scientists can screen thousands of genes for their potential roles in metastasis. “With new imaging tools, and better knowledge of cell behavior and the genes that underlie cancer, some groups are at last losing their fear of [metastasis research],” says cancer biologist and geneticist Joan Massagué, who heads the Cancer Biology and Genetics Program at Memorial Sloan-Kettering Cancer Center in New York City. “There’s still too few working on it directly, but more and more are dissecting metastasis like they’ve done with earlier stages of tumor growth and converting that knowledge to clinical applications. But this is a recent phenomenon, just two to three years old.”
Studies of metastasis have already paid off with some startling insights: For instance, scientists once thought that metastatic cells were nearly identical to ordinary cancer cells (or as articulated by tumor biologist Danny Welch of the University of Alabama at Birmingham, like “broken-off pieces from a primary tumor”). However, researchers have shown that metastases actually have additional genetic transformations that make them uniquely aggressive. Dermatologist and cancer researcher Lynda Chin, at Harvard Medical School in Boston, says that a cancer cell may become more genetically “scrambled” the closer it gets to metastasis. In other words, the cell’s DNA accumulates changes that drive it to escape and survive in alien, hostile environments. It’s also possible, she says, that genetic mutations enabling metastasis are present in the cells earlier on.
When a malignant tumor metastasizes, its cells travel to other parts of the body. Unlike most of the body's normal cells, these cells can penetrate the membrane that separates different tissues in the body (first arrow at upper left of illustration). After invading adjacent tissue, the cancer cells enter blood and lymphatic vessels or body cavities. When the cells escape from the vessels into surrounding tissue, they can form secondary tumors far from the cancer's original site. [Art: Nicolle Rager Fuller]
Cancer biologist Robert Weinberg at the Massachusetts Institute of Technology in Cambridge suggests the ability of certain cells to metastasize comes from genetic changes occurring at the earliest stages of a tumor’s growth. Taking an even longer view, cancer geneticist Kent Hunter, an investigator at the Laboratory of Population Genetics at the National Cancer Institute, proposes that some individuals may be born with an inherited susceptibility to metastasis. The support for that theory comes primarily from his studies in mice, which have yet to be confirmed in human cells.
But if he’s right, then a key opportunity awaits: Assuming that inherited genes push cancer cells to metastasize, regardless of the specific type of cancer or its cause, then doctors might screen for those genes with a blood test, says Chin. Armed with that information, they might launch more aggressive treatment sooner, and possibly save lives in the process. “If we knew at diagnosis that there was a high risk of metastasis, then we might be more aggressive in follow-up after surgery,” Chin explains. “We might do monthly evaluations instead of checking on the patient twice a year, or we could try different therapies.”