HOUSTON - Researchers have located a gene dubbed dead end that when mutated or lost, causes testicular tumors in mice. They say their study, published in the online journal Nature, on May 18, 2005 will likely offer future insights into the genetic causes of the disease in humans because the cancer originates from the same cell type, the primordial germ cell, in both mice and men.
If that notion is validated through further research, the finding could lead to a way to either screen for the human disease or treat it, say the researchers, who represent The University of Texas M. D. Anderson Cancer Center, Case Western Reserve University, Duke University Medical Center, the National Cancer Institute and the Lawrence Berkeley National Laboratory.
"One can envision that this gene or others in its pathway could possibly be used for screening or therapeutic purposes in young males predisposed to develop testicular cancer or those who have a family history of this disease," says the lead investigator, Angabin Matin, Ph.D., an assistant professor in the Department of Molecular Genetics at M. D. Anderson. "This will of course require further research regarding the function of this gene in human cancers."
Although the connection is more tenuous, the researchers add that their finding also could offer a clue as to the link between male infertility and testicular cancer, since loss of the dead end gene in a laboratory fish model of reproductive diseases leads to the inability to procreate. "And in humans, testicular cancer and infertility have been frequently associated with one another," Matin notes.
Still, the researchers say this study is most relevant to human testicular cancer. According to the National Cancer Institute, testicular cancer usually strikes men between the ages of 15 and 39 and is the most common form of cancer in men between the ages of 20 and 34. Although it accounts for only about 1 percent of all male cancers, the rate of testicular cancer among white men has more than doubled in the past 40 years. It is also one of the most curable forms of cancer.
The study is the culmination of 30 years of research that has focused on a strain of male mice known as the "129 family" that spontaneously develops tumors in their testicles. Although researchers had suspected that a faulty or missing gene was to blame, researchers had a difficult time in pinpointing a single genetic change because germ cells were so altered that tumors developed just a week after the mice were born.
Matin, working as a post-doctoral researcher at Case Western Reserve University with Joseph Nadeau, Ph.D., a co-author of this paper, decided to study tumor development in mouse embryos. In 2001, she mapped the location of ter, a mutation which was directly associated with development of the testicular tumors. At the same time, another group of researchers in Germany found a gene they called dead end. When missing, this gene was linked to sterility in zebrafish, a commonly used invertebrate model for human development and disease.
Knowing that genes involved in reproduction in many vertebrates have been found to be similar, Matin suspected that dead end might be the source of the ter mutation because they seemed to be located in corresponding regions of the genomes of mice and zebrafish. So she and a team of researchers set about to confirm that ter was indeed the mouse version of dead end.
In zebrafish, loss of dead end resulted in the loss of primordial germ cells, those stem cells that give rise to sperm in males. In the 129 family of mice, loss of dead end results not only in sterility, but also in the development of tumors, for reasons that the researchers do not yet understand. The tumors in mice usually do not metastasize, but that is probably because the mice do not live long enough for the cancer to mutate enough to spread, the researchers believe.
"We haven't filled in the picture yet, but when dead end is lost or not expressed in germ cells, they don't die as they do in zebrafish, but they frequently survive and become transformed in a way that produces germ cell tumors," Matin says.
Evidence exists in humans that these tumors also arise during fetal development, and this is most likely due to a similar genetic susceptibility, she says. "The tumors that we study in mice represent a model for testicular tumors observed in human infants," she says. "In this case, it may be that such early development of the cancer results when the infant has lost both copies of his dead end gene."
The researchers theorize that testicular cancer that develops in young adults may also originate from a genetic mutation during fetal development - perhaps by inheritance of a single dead end mutation - and tumor development occurs later due to environmental exposures or other genetic susceptibilities and losses.
"Extrapolating from the findings in Ter mice, although germ cell tumors present clinically in infants and young adults, it is apparent that genetic and environmental influences during embryogenesis increase the susceptibility of primordial germ cells to tumorigenesis," she says.
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