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New cell death program solves mystery of bird’s eye cells

After invading its neighbor, a cancerous MCF7 cell (left) is attacked by a large lysosome (marked by a green ring) inside its host. Non-cancerous MCF10A cells (right) display the same behavior.

Although pathologists have observed for over a century a peculiar cytological feature of human cancers − cells internalized in other cells − they remained puzzled as to how such so-called “bird’s-eye cells” formed in the first place. That is, until HMS researchers in the laboratory of Joan Brugge, PhD, metaphorically stumbled over the cell death process that explains the cell-in-cell phenomenon. The discovery of this novel, nonapoptotic type of programmed cell death illustrates the serendipity of scientific research.

A major focus of the Brugge laboratory is exploring mechanisms of cell survival relevant to breast cancer. In one research approach, investigators detach normal breast epithelial cells from their niches in the extracellular matrix (ECM), and then observe how the displaced cells die. As postdoctoral researcher Michael Overholtzer, PhD, was watching these cells drift in suspension, he began to notice that some became completely encased in their neighbors. When he happened to mention this curious finding to pathologist Andrea Richardson, MD, PhD (BWH), she told him that pathologists have witnessed this phenomenon in cancer cells for decades.

Intrigued by the cancer link, Overholtzer conducted additional experiments using  normal breast epithelial cells, MCF10As, and cancerous MCF7 cells. Through time-lapse microscopy, he found that about 25 percent of MCF10A cells and 30 percent of MCF7 cells were forming into bird’s-eye structures. Moreover, unlike apoptotic cells that become engulfed by adjacent cells, matrix-deprived cells appeared to be aggressively pushing their way into neighboring cells − like refugees seeking temporary shelter.

Not all of these internalized cells are fated to die, however. Overholtzer observed that host cells formed capsules, or vacuoles, around the invaders, eventually killing most of them through acidification and degradation by lysosomes; but a few escaped the host cell and slipped back into the culture. Remarkably, while internalized, these cells appeared to be very much alive − moving about and even dividing into daughter cells − clearly demonstrating their viability and distinguishing this type of cell death from apoptosis or necrosis. “Pathologists have speculated for years that some internalized cells are alive,” says Overholtzer, “and our data suggest they were right.”

Through this work, says Brugge, “we have elucidated the death program that underlies the formation of cell-in-cell structures and is provoked by the cell’s loss of attachment to the extracellular matrix, which occurs independent of apoptosis.” Researchers named the novel process entosis, from a Greek word meaning within or inside, and published their findings in the Nov. 30 issue of Cell. “What is incredibly exciting is that we have also found live cell-in-cell invasion in fluid exudates from metastatic tumors and in primary tumor tissue from breast cancer patients,” adds Brugge.

But why entosis occurs, what it reveals about cancer, and whether it happens in vivo remain unclear. “Our first instinct is that entosis inhibits tumor progression by killing ‘homeless’ cancer cells before they can colonize distant sites,” says Overholtzer. “One could also imagine that entosis promotes tumor progression by providing nutrients for some cells from their neighbors.” Clearly, more research is needed to define the role of entosis in tumor growth.

– Lonnie Christiansen