“Until recently, we had no idea what caused cancer cells to metastasize,” Weinberg says. But it’s becoming clear that a complex cascade of events has to happen for any cancer cell to leave a tumor and become the basis of another. First, cells in the initial tumor produce enzymes that break down the surrounding tissue, clearing the way for the cells to invade it. Some, but not all, of these cells are then able to enter the bloodstream. Only some of those, in turn, can emerge from the bloodstream to lodge in a new place in the body. And only a portion of those cells remain malignant enough to persist at the new site and grow from a tiny colony into a large, life-threatening tumor.
In one sense, we’re lucky metastasis is so elaborate; this means that most cancer cells never make it all the way through the process to start their own tumors. But it presents a challenge to researchers. “The biology of metastatic cells seems to be so complex as to be bewildering beyond anyone’s ability to understand it, simply because there are so many genes and proteins involved,” Weinberg says.
His recent research suggests, however, that cancer cells orchestrate this complex achievement in a simple way: through master-regulator proteins called transcription factors, each of which activates or deactivates a large number of genes.
Transcription factors regulate genetic activity in all cells. A handful of them are particularly important during embryonic development, when cells travel to new areas and take on new functions to help turn a single-celled zygote into a complex animal made up of many kinds of carefully organized, highly differentiated tissues. “This movement in the embryo is at least superficially similar to metastasis,” says Weinberg. The embryonic transcription factors are generally inactive in adults; as a result, most normal adult cells (blood cells are an exception) are stationary and tightly bound to their neighbors. But Sendurai Mani and Jing Yang, former postdocs in Weinberg’s lab who studied the roles of two embryonic transcription factors important in breast cancer metastasis, found that certain tumor cells somehow reactivate these proteins, thus regaining the mobility and flexibility of embryonic cells.
Until three or four years ago, Weinberg says, biologists thought cancer cells within a tumor were pretty much equivalent: any given cell was just as likely to initiate metastasis as its neighbors. His lab’s work suggests that this is not the case. Mani and Yang studied four breast cancer cell lines derived from a single mouse tumor. Despite their common ancestry, these cells have divergent properties. All four types can form tumors, but only three can make it into the circulatory system; only two can reach the lung, a common site of secondary breast cancer tumors; and only one can form successful new tumors there. This last cell line overproduces two transcription factors, which are at least partly responsible for its metastatic success.
The discovery that cancer cells rely on a few transcription factors is heartening, says Weinberg. It gives researchers a small number of very important targets to go after, instead of a large number of less important ones. The highly malignant activities of some cancer cells can be traced to a few central regulators, “each of which acts by modulating the expression of a whole cohort of responder genes,” Weinberg says. “Rather than having to cobble together complex behavioral programs, cancer cells simply resort opportunistically to resurrecting behaviors that are normally suppressed in adult tissue.”
The Complicated Role of Healthy Cells
And that’s not the only secret to metastasis. “Highly malignant cancer-cell traits [are] not dictated exclusively by the genes residing inside the cancer cells,” says Weinberg. Another key to the cells’ success is their generous neighbors.
Tumors cannot survive without enlisting the support of many normal cells. Most famously, they recruit cells to build new blood vessels that carry oxygen and nutrients in and carry carbon dioxide and other waste out. But these blood-vessel-forming cells are only one of a multitude of cell types lured into tumors. Research by Weinberg and his postdoc Antoine Karnoub shows that normal cells called mesenchymal stem cells also play an important role in metastasis.