On a cold, gray Saturday morning at Yale University in February 1993, instead of just reading his laboratory’s article in a cancer journal and scanning past the rest—cancer is a profoundly wide field, and there is much to read—cancer biologist John Pawelek made time to finish the entire issue. That simple decision changed the course of his research, toward a controversial explanation for the deadliest aspect of the disease—namely, why it spreads.
The issue contained a letter from three Czech doctors asking whether the fusion of tumor cells and white blood cells could cause cancers to spread, or metastasize. At the time, Pawelek was also reading a book by evolutionary biologist Lynn Margulis, who pioneered the idea that life on earth was revolutionized by ancient cells engulfing one another and fusing together, forming hybrids that had better chances at survival. “I was really excited by the connection,” he recalls. “Since there was a precedent for hybridization in evolution, why not in cancer?”
In the past 15 years Pawelek and his colleagues have shown that cancer cells can fuse with white blood cells and become highly metastatic in lab animals. Now they are searching for the same activity in humans. The leading cause of death in cancer is metastasis—tumors are generally treatable as long as they have not moved to vital organs. So if the research reveals that such hybrids help cancer spread, it could open up new avenues to fighting cancer. As Pawelek puts it: “You have to know how metastasis starts to properly fight it.”
But maddeningly little is known about what makes cancer spread. Explaining the capabilities that metastatic cells possess—to break away from their original tumors, migrate past other cells, travel around the body via lymph or blood vessels, invade tissues, and grow—would involve understanding how cells interact with one another. “And we don’t yet have good biological tools to investigate the interactions between different cell types and organs,” explains cancer geneticist Bert Vogelstein of Johns Hopkins University.
One theory behind the origin of metastasis is that mutations in one or a few genes cause tumor cells to gain the ability to migrate. Another idea suggests that no specific mutations are needed—rather cancer cells eventually accumulate abnormal numbers of chromosomes that break down the constraints that keep any normal cell from metastasizing. In Pawelek’s view, these theories do not explain how cancer cells would acquire the right genetic changes in the right order needed to spread successfully.
Instead the 66-year-old Pawelek suggests that cancer cells spread after fusing with white blood cells known as macrophages. Like metastatic cells, macrophages can roam around and infiltrate most parts of the body and are naturally resistant to toxic drugs. “Metastasis is a very different phase from ordinary cancer and to me is almost like a new disease superimposed on a preexisting cancer cell—maybe cancer cells inherit all these traits at once by hybridizing with white blood cells,” Pawelek speculates. Moreover, macrophages regularly engulf germs and unhealthy cells—they might occasionally fuse with tumor cells instead of destroying them, much as ancient cells once joined together into symbiotic relationships a billion years ago, he reasons.
In their first experiments, Pawelek and his colleagues took a strain of mouse melanoma cells known to be only weakly metastatic and fused them with mouse macrophages by exposing them to polyethylene glycol, which can dissolve cell membranes. They implanted these hybrids in roughly 5,000 mice. “These were massive experiments that took four years to accomplish, and we were just going on faith,” Pawelek recounts. The results were striking—roughly 55 percent of the hybrid cells proved “really, really deadly, very metastatic,” he declares, in contrast to melanoma cells fused with one another—none of them became metastatic. “I was convinced we were on to something.”