Scientists from Memorial Sloan Kettering have found that tumor cells that reach the brain—and successfully metastasize into new tumors—do so by attaching to capillaries and expressing specific proteins that overcome the brain's natural defense against metastatic invasion. They reported their study (“Serpins Promote Cancer Cell Survival and Vascular Co-Option in Brain Metastasis”) in Cell.
Research has shown that most tumor cells die before they can take root in the brain, which is better protected than most organs against colonization by circulating tumor cells. To seed in the brain, a cancer cell must dislodge from its tumor of origin, enter the bloodstream, and cross the blood-brain barrier.
Until now, little research has been done into how metastatic brain tumors develop, but previous mouse experiments that imaged metastatic breast cancer cells over time have shown that, of those cancer cells that do make it to the brain, fewer than one in 1,000 survive.
“We didn’t know why so many of these cells die,” says Joan Massagué, Ph.D., director of the Sloan Kettering Institute and senior author of the study. “What kills them? And how do occasional cells survive in this vulnerable state—sometimes hiding out in the brain for years—to eventually spawn new tumors? What keeps these rare cells alive and where do they hide?”
In their study, Dr. Massagué, with Fellow Manuel Valiente, Ph.D., and other team members, found that in mouse models of breast and lung cancer (two tumor types that often spread to the brain) many cancer cells that enter the brain are killed by astrocytes. These killer cells, the most common type of brain cell, secrete a protein called Fas ligand (FasL). When cancer cells encounter this protein, they are triggered to self-destruct. The exceptional cancer cells that escape the astrocytes do so by producing a protein called serpin, which acts as a sort of antidote to the death signals fired at them by nearby astrocytes.
“We identify plasmin from the reactive brain stroma as a defense against metastatic invasion, and plasminogen activator (PA) inhibitory serpins in cancer cells as a shield against this defense. Plasmin suppresses brain metastasis in two ways: by converting membrane-bound astrocytic FasL into a paracrine death signal for cancer cells, and by inactivating the axon pathfinding molecule L1CAM, which metastatic cells express for spreading along brain capillaries and for metastatic outgrowth,” wrote the investigators. “Brain metastatic cells from lung cancer and breast cancer express high levels of anti-PA serpins, including neuroserpin and serpin B2, to prevent plasmin generation and its metastasis-suppressive effects.”
After imaging defiant metastatic cells in the brains of mice, researchers noticed that the cells that were able to survive grew on top of blood capillaries, each cell sticking closely to its vessel “like a panda bear hugging a tree trunk,” noted Dr. Massagué. They found that the tumor cells produce a protein that acts like Velcro to attach the cells to the outer wall of a blood vessel.
“This hugging is clearly essential,” continued Dr. Massagué. “If a tumor cell detaches from its vessel, it gets killed by nearby astrocytes. By staying on, it gets nourished and protected, and may eventually start dividing to form a sheath around the vessel.”
Under the microscope, the researchers watched these sheaths of cancer cells around the blood capillaries grow into tiny balls, which eventually became tumors.
The tumor-cell survival factors uncovered by this study might one day be targeted with drugs to further diminish people’s risk of metastasis, according to Dr. Massagué, who is particularly interested in the ability of tumor cells to hug blood vessels as this behavior may be essential for the survival of metastatic cancer cells not only in the brain but also in other parts of the body where metastatic tumor growth can occur.