Scientists have discovered a novel form of cell death in which cells crawl inside other cells to die. The process, dubbed entosis, may be a method of suppressing tumors, the researchers say, but others aren't so sure.
For more than 25 years, scientists examining cultures of human cancer cells have occasionally spotted cells tucked within other cells. But the phenomenon remained largely unexplored until a team led by cell biologist Michael Overholtzer of Harvard Medical School in Boston recently saw the same thing while working with a line of normal breast cells. As in breast tissue, these cultured cells usually grow on a membrane or matrix. When they became detached, however, some cells appeared to be enveloped by other cells. Intrigued, the researchers looked closer.
Overholtzer's team found that up to 70% of the detached cells died once engulfed by another detached cell. However, up to 9% divided while enveloped and up to 18% were eventually released unharmed. Blocking the mechanisms involved in other methods of cell death including apoptosis and phagocytosis did not disrupt the process, confirming that entosis operates in a different way.
Further experiments revealed that cadherins, proteins that keep cells joined to each other, are required for entosis. The researchers are still working out the details, but they speculate in the 30 November issue of Cell that entosis occurs due to an imbalance in adhesion forces between two cells when they dislodge from the matrix. This could lead to one cell pushing into the other until it is engulfed, akin to pressing your fist into a balloon.
However entosis occurs, it appears to be widespread. The team found evidence of the process in several other cell types, including breast, ovarian, umbilical cord, and kidney cancer cells. Overholtzer says tumor suppression may be one function of entosis. When a chemical that inhibits entosis was applied to a line of breast cancer cells, colony formation--an indicator of tumor growth in vitro--increased 10-fold.
Conversely, cancer cells could be using entosis as a survival tool. It may be "a way for a tumor cell to escape recognition by chemotherapeutic drugs or the immune system" by hiding out inside another cell, says Maureen Murphy, a molecular biologist at Fox Chase Cancer Center in Philadelphia, Pennsylvania. That may explain why not all cells die during entosis.
Craig Thompson, a cancer biologist at the University of Pennsylvania, is more skeptical. The fact that some cells survive entosis, he says, suggests that it is not a very effective process for suppressing tumors and raises concern that it may be a phenomenon that primarily occurs in the lab rather than in the body.