Cancer clues from a worm

Scientists have long wondered how germ cells — the cells that mature into eggs and sperm — retain the flexibility to give rise to all of the body's different tissue types, while other kinds of cells are committed to specialized fates like muscle or skin.

Dr. Jim Priess and colleagues have now discovered a key regulator of this process in Caenorhabditis elegans, a microscopic soil worm that has proven to be an ideal model for studying the complex steps of development common among all organisms.

They found that when C. elegans germ cells have defects in two genes, the germ cells differentiate inappropriately into tissues in a fashion reminiscent of a type of tumor known as a teratoma. In teratomas, germ cells lose their flexibility and prematurely differentiate into a freakish mixture of tissues such as bone, muscle and teeth — hence their name derivation from teraton, the Greek word for monster. The worm genes involved in this process have counterparts in humans, raising the possibility that the human genes might have related roles.

The study was led by Dr. Rafal Ciosk, now an investigator at the Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland, when he was a postdoctoral fellow in the Priess Lab in the Basic Sciences Division. The findings are published in the Feb. 10 issue of Science.

"Very little is known how these tumors develop," said Ciosk, whose work in the Priess Lab was supported by the Leukemia & Lymphoma Society. "Although we need more understanding at the molecular level to say in detail how what we have found in worms relates to human tumors, we have established the first genetically tractable model to study the phenomenon." About 10 percent to 20 percent of all ovarian tumors and less than 5 percent of testicular tumors are teratomas.

The study grew from Priess' long-standing interest in understanding totipotency — the potential of certain types of cells to become any type of cell in the body as opposed to being dedicated to a particular type of tissue. Totipotency is also a hallmark of embryonic-stem cells, whose fate scientists hope to manipulate to grow healthy tissues that can cure diseases like juvenile diabetes or Parkinson's disease.

Earlier studies have revealed how germ-cell totipotency is established during the earliest stages of worm development, while the organism is still an embryo. That work revealed that embryonic-germ cells maintain totipotency by blocking the activation of genes required for cells to become specialized tissue types. Specifically, the embryonic cells block the first step in gene activation, a process called transcription, during which a gene's DNA blueprint is decoded into RNA.

Priess and colleagues knew that adult germ cells must use a different mechanism to maintain totipotency, as these cells are active in transcription. They discovered that totipotency in the adult germ cells required two genes, called mex-3 and gld-1, that regulate the process by which RNA is decoded into proteins. When Ciosk inactivated mex-3 and gld-1 in the worm, something very unusual occurred, said Priess, an investigator of the Howard Hughes Medical Institute.

"Rafal called me over to look at the worms under the microscope," Priess said. "Cells inside the gonad (the organ that produces germ cells) were actually contracting, just like muscle cells, while normal gonads do not contain any muscles." Further studies showed that the muscle cells originated from germ cells that differentiated inappropriately.

Priess said that the next step will be to figure out which specific proteins mex-3 and gld-1 prevent from being made in the worm germ cells, which may also provide insight into what happens when human germ-cell development goes awry. "If we can identify the targets they regulate, it might be possible to induce totipotency in cells that have already begun to specialize," Priess said. "This is a powerful genetic system to identify players in the process."