A protein known to be involved in a rare hereditary cancer syndrome, scientists claim, may have a role to play in the regulation of liver stem cells and the development of liver cancer.
A research team from the Massachusetts General Hospital said that the protein called merlin, encoded by the NF2 gene, controls the activity of adult stem cells that give rise to the two major types of liver cells.
Advertisement"We found that mutation of the NF2 tumor suppressor gene in the mouse liver led to a dramatic overproliferation of liver stem cells - the cells that contribute to the liver's remarkable ability to regenerate," Andrea McClatchey, of the MGH Center for Cancer Research, who led the study said.
"These mice go on to develop the two forms of liver cancer that are most common in humans, suggesting that liver stem cells may be the cells of origin of these tumors," she added.
The liver has a rare ability to regenerate and replace damaged or missing tissue. If one lobe is removed for transplantation, the rest of the donor's organ will return to its previous size and the transplanted lobe will grow to match the needs of the recipient.
This regeneration usually involves proliferation of the most characteristic liver cells, called hepatocytes, and of bile duct cells; but if that growth is blocked or those cells are damaged, a population of less-differentiated progenitor cells will start to expand. These liver stem cells have been identified in rodents, and potential equivalents found but not confirmed in humans.
The researchers found that infant mice lacking functioning NF2 in their livers developed dramatic overgrowth of liver stem cells, to the point of crowding out hepatocytes.
Mice that did not die from a lack of functioning liver cells soon developed the two major types of liver cancer, and the fact that stem cell overgrowth preceded tumor development strongly suggested that the undifferentiated progenitors were the source of the tumors.
McClatchey said that the study's findings provide new information about liver stem cells and how their proliferation is controlled; identifies a new animal model for liver cancer, the lack of which has seriously impeded understanding the disease; and suggests that liver tumors may originate from liver stem cells and that excess EGFR signaling leads to liver tumor development.
"These results are consistent with our previous studies showing that merlin helps to regulate EGFR activity at the cell membrance," she said.
"We also showed that merlin's role in cell-to-cell communication is essential for cells to stop growing when they fill the appropriate space. Since liver progenitors need to be poised to regenerate in case of injury, they may be particularly sensitive to the loss of merlin's regulatory function," she added.
The research was published in the August issue of Genes and Development.