Metastasis: The Killing Fields
Some cancers are very limited in where they can establish a home. Prostate cancer cells can live only in bone, for example. Others, like breast cancer, are more promiscuous, spreading to bone, lung and brain, and melanoma can make a home anywhere.
How fast each spreads is also cancer-specific. Some cancers may take decades to metastasize—if they ever do—whereas others will spread in months, even when the primary tumor is caught early. “Lung cancer cells go out with all guns blazing because they’ve acquired mutations that make them immediately capable of setting up shop in different organs,” says Joan Massagué, chair of the Cancer Biology and Genetics Program at Memorial Sloan-Kettering Cancer Center in New York City. “In contrast, it takes years for some breast cancer and prostate cancer cells to evolve the special abilities they need to establish metastatic colonies.”
Such wide variations have made it difficult to find the right targets—such as certain genes or processes—for cancer therapy. “Metastatic cells look different in every organ,” says Christoph Klein, head of the division of oncogenomics at the University of Regensburg in Germany. “And because chemotoxic agents target the cancer cell’s DNA, there is always the danger that cells that aren’t killed will evolve mutations that give them greater metastatic potential.”
Yet, as understanding of metastases has increased, researchers have begun studying the primary tumor’s microenvironment—the nonmalignant cells in and around the tumor—for ways to prevent metastasis. “We now think the tumor co-opts these cells to promote its own survival, growth and invasion,” says Jeffrey W. Pollard, deputy director of the Cancer Center at the Albert Einstein College of Medicine in New York City.
Pollard is focusing on the white blood cells known as macrophages, which normally clean up debris in the wake of disease or injury and help identify invading viruses and bacteria. Macrophages should also identify cancer cells and mount an immune response against them. But cancer cells emit proteins called growth factors, which send out chemical distress signals to attract the macrophages to the tumor site. After they’ve been subverted by the cancer cells’ distress signals, which send the macrophages scurrying to the tumor as if it were a wound or an infection, the macrophages release enzymes that break down the matrix that binds the cancer cells to one another—just as they remodel the cell matrix during wound healing or inflammation. Once free of their cellular bonds, the cancer cells can disperse.
The macrophages are also tricked by the cancer cells into producing vascular endothelial growth factor (VEGF), which stimulates the production of small, abnormal blood vessels around the tumor that enable the cancer cells to enter the bloodstream through leaks in the vessel walls. And in response to the cancer cells’ production of colony-stimulating factor-1 (Csf-1), which promotes the formation of macrophage colonies and controls their function, the macrophages synthesize another growth factor—epidermal growth factor (EGF)—which attaches to a receptor on the cancer cells and lures them out of the tumor mass and toward the blood vessels. In all these ways, the cancer cells hijack the normal function of macrophages to further their own agenda.