Metastasis: The Killing Fields
In his experiments, Pollard used mice in which a breast-cancer-causing gene had been turned on. He then introduced a gene mutation that halts production of Csf-1. Though the mice developed tumors, the tumors were deficient in macrophages, and few of the cancers metastasized. “We found that if you stop the activity of the macrophages by inhibiting their signaling pathways, you can stop the migration of tumor cells and metastasis,” says Pollard, who thinks that drugs targeting macrophages or other noncancerous cells known to aid metastasis could slow or stop their proliferation.
Another theory about how metastasizing cells escape their bonds in the original tumor could explain many other steps of the metastatic process. In most normal, noncancerous tissue, cells are packed tightly together and can’t move. But when an embryo is developing, cells have to migrate from one location to another to take on new functions and build the many types of tissue that will form a complete organism. To aid in that process, something known as the epithelial-mesenchymal transition, or EMT, occurs. It enables epithelial cells, which will form the skin and line many body cavities, to lose their characteristically tight junctions and become mesenchymal cells that act like stem cells, traveling through the embryo and differentiating into the cells that form connective tissue, blood vessels and lymphatic tissue. In adults the EMT program is dormant in healthy cells, though it is sometimes briefly reactivated during wound healing as the body builds new tissue.
MIT’s Weinberg and other researchers now think the same process may explain how a cancer cell is able to move from the primary tumor and become a micrometastasis—the small clump of cells in a distant tissue that will eventually grow into a detectable macroscopic mass. “The EMT program, which lies latent in all cells’ genes, is exploited by the cancer cell, enabling it in one fell swoop to invade the tissue around the primary tumor, survive in the circulation, escape the bloodstream and seed a micrometastasis,” Weinberg says. “So cancer cells don’t have to cobble together all these distinct capabilities.” And if there’s just one master program orchestrating this complex series of steps, there could be a single target for disabling it.
EMT was discovered 20 years ago by scientists studying how the embryos of frogs and flies develop. It wasn’t until recently, though, that accumulating evidence began to suggest that EMT could also explain part of the metastasis process. “At first it seemed implausible that a normal embryonic process could be appropriated and exploited by cancer cells,” says Weinberg. But biologist Jean-Paul Thiery of France’s National Center for Scientific Research found that rat cancer cells in culture could transform themselves into mesenchymal cells, and in 2004, in human tumors, Weinberg found a transcription factor that’s crucial to EMT. “Now, with the benefit of that additional research, it makes perfect sense and has proved to be absolutely critical to advancing our knowledge of malignant progression,” he says.
Unfortunately, the so-called cancer stem cells that EMT produces have proved particularly difficult to study. When found in solid tumors, the cells were too few in number to analyze, and if they were propagated in the laboratory, they lost their stem-cell-like properties. Recently, however, Weinberg’s research team was able to generate large numbers using a reagent that coaxed cancer cells to undergo EMT, and a group of Harvard and MIT researchers has performed a large-scale analysis to gauge the effects of thousands of chemical compounds on these cells.