TheScientist | Though the mechanisms of engulfment may differ among cell and cancer types, the end result is nearly indistinguishable—a whole, living cell is housed within a large vacuole inside a tumor cell. Internalized cells usually follow one of three paths. They can continue living, at least temporarily, within the host cell, even dividing within their vacuole homes. Occasionally, they escape from the host cell to once again become a single, individual cell in the extracellular space. By and large, however, death is the most common fate for cells engulfed by tumor cells. Wang and colleagues demonstrated evidence of the apoptotic death of NK cells following their uptake by tumor cells. Nearly 90 percent of the internalized lymphocytes underwent traditional, programmed cell death, as evidenced by the activation of caspase 3. Work by Overholtzer’s group, on the other hand, suggests that cell engulfment between tumor cells represents a different type of cell death altogether—one mediated by lysosomes. The vacuoles housing the internalized tumor cells, his group observed, became acidic and surrounded by lysosomal membranes, indicative of fusion with lysosomes. Furthermore, when the researchers overexpressed B-cell lymphoma 2 (Bcl-2) to inhibit apoptosis, it had little effect on the death of internalized cells. On the other hand, inhibiting lysosomal acidification of the vacuoles could rescue the captured cells, when it was combined with apoptotic inhibitors. Interestingly, when only the lysosomal inhibitors were introduced, more cells appeared to undergo an apoptotic death, suggesting that apoptosis serves as a backup mechanism to the more common lysosomal death of the internalized cells.Fais suggests it is simply the acidic environment of the tumor-cell vacuoles in metastatic melanoma cells that kills the internalized lymphocytes, though lytic enzymes may help to further digest the cell, he says. He argues that the engulfment and subsequent killing of cells such as lymphocytes is cell cannibalism in the most literal sense—one cell eating another. Once the victim is digested, the tumor cell can theoretically derive nutrients from it, promoting cancer survival and growth.
“We know that nutritional stress is a common feature of tumors,” says Eileen White, a cancer biologist at The Cancer Institute of New Jersey and Rutgers University. “We know they’ll undergo this process of autophagy where they’ll eat themselves. If they have the capability of eating each other or other cells—that would open a whole new door for tumors to sustain themselves.”
As evidence for this hypothesis, Fais showed in vitro that cell cannibalism increased under starvation conditions, and that the ingestion of T cells promoted the survival of melanoma cells. “The T cell is great because it has all these wonderful complex carbohydrates on the surface,” says cancer biologist Thomas Seyfried of Boston College. “They can all be degraded to glucose and other fuels [that tumor cells] could be using.”
But even if cells are deriving nourishment from their cannibalistic activities, it’s likely not the only benefit of the behavior, says immunologist Yufang Shi, who studies apoptosis at the Chinese Academy of Sciences and the Child Health Institute of New Jersey. “For one cell to digest another cell and to get energy . . . this is very uneconomical,” Shi explains. “You have to really make the cell into amino acids and polysaccharides. It’s very hard to use that as energy.” The fact that cell cannibalism increased when the cells were starving may simply be due to the fact that nutrient deprivation can cause cells to become detached from the extracellular matrix, Shi added—an event that Overholtzer’s group suggests could promote cell engulfment as a result of imbalanced cell-cell adhesion forces.
Another possibility is that the engulfed cells are driving the process. Internalized immune cells, for example, may have the potential to suppress tumor growth. During his initial graduate studies in the 1980s and again when he resumed this work more recently, Wang observed that some NK cells internalized by tumor cells can actually kill their host cells from the inside out. “After they enter into the tumor cells, they make the tumor cells erupt,” Wang says. “When [these NK cells] die, they also release a lot of enzymes,” Shi explains. “They are cytotoxic cells, so they can kill by releasing directly into the target cell, like the suicide bombers.”
But whether the internalized NK cells are initiating the engulfment is still unclear. If, on the other hand, the tumor cells are actively consuming the lymphocytes, it could provide a way for cancer to evade attack by the immune system. “I have a suspicion that maybe tumor [cells] in some conditions can kill the NK cells as a way to escape the surveillance of the immune system,” Wang says. This may become particularly important as the cancer metastasizes, Yao adds. “One of the physical challenges for those tumor cells will be how to survive in the new sites. One way is by taking [up] those NK cells and other immune cells to damage the immune response of cancer [patients].”
The bizarre phenomenon may also contribute to the genetic instability of cells, perhaps contributing to the formation of cancer early on. This March, Overholtzer and colleagues published the finding that cell-in-cell structures can act as cleavage barriers that disrupt cell division, leading to changes in ploidy—the number of sets of chromosomes in the cell—which are known to drive tumor progression.5 Conversely, cell engulfment may act to suppress tumor growth, such as when tumor cells eat other tumor cells. “Entosis has a dual nature,” says Overholtzer. “It clearly can kill [tumor] cells, but also, it can disrupt ploidy—one is predicted to be tumor suppressive, one is tumor promoting.”
For now, the question of function remains “a puzzle,” Fais says, and “I don’t have all the pieces.” But with evidence growing for significance of cell engulfment in tumor pathogenesis, researchers are now considering whether the phenomenon could serve to aid in diagnosis or in the development of new cancer treatments. “I think in the next few years this will be a very active field,” Shi says.
