ATHENS, Ohio -- Studies of a protein implicated in the development of skin tumors in fish could lead to a better understanding of a similar protein's role in breast and other human cancers, according to researchers at Ohio University.
Scientists have been exploring the role cyclin D, a protein that regulates cell replication, plays in the development and death of tumors found on walleye, a North American freshwater fish. The skin tumors, walleye dermal sarcoma, appear and disappear seasonally, says Don Holzschu, assistant professor of molecular biology at Ohio University and a lead researcher on the project.
First reported in a National Cancer Institute monograph in 1969, these tumors -- which appear in the fall and die during the spring spawning season -- seem to pose no health risk to humans, according to officials with Ohio Sea Grant. Walleye infected with the tumors have been reported in rivers and lakes throughout North America, including in Ohio, New York and Canada.
Researchers suspect infected walleye spread the virus that causes the tumors during the spawning season, when all the fish are grouped together. "It's just like sending your child to daycare," Holzschu says. "It's a perfect time to spread the virus." It's thought that the virus grows over the summer and tumors begin to appear in the fall. By spring, the tumors are dying and the infection is passed to other fish.
While the seasonal nature of the tumors is enough to keep the scientists' interest, new studies have added to their fascination with this project. In their analysis of the viruses that cause walleye dermal sarcoma and another skin disease, walleye dermal hyperplasia, researchers have discovered the culprits for these infections are three retroviruses that are unlike any ever studied.
A retrovirus is a virus that has RNA as its nucleic acid and uses the enzyme reverse transcriptase to copy its genome into the DNA, which then integrates into the host cell's chromosomes. Retroviruses usually have three core genes, responsible for encoding viral enzymes and all viral structural proteins. But when researchers dissected the genomic structure of these three walleye retroviruses, they discovered three additional genes, one of which produces cyclin.
"This is a very unique retrovirus," Holzschu says. "This is the first time the cyclin gene has been found in any retrovirus in humans or animals."
Human cyclin D1, a protein similar to the cyclin D observed in Holzschu's walleye studies, has been implicated in several human cancers, including cancer of the breast and esophagus.
Because cyclin serves as a reproductive control agent in cells, conventional wisdom suggests that if large amounts of cyclin are produced, cells will replicate at a higher rate. So, when researchers examined the growing tumors on the walleye in the fall, they expected to find cyclin. But instead, they found only small amounts of the mRNA that codes for cyclin. In contrast, in the spring, when the tumors were dying, the researchers found a high level of cyclin mRNA. Researchers presume that the presence of this mRNA precedes the production of cyclin.
"It's possible that the overproduction of this protein causes the cells to die," Holzschu says. "If we could figure out why these tumors in walleye are dying and determine the role cyclin is playing, we might be able to use that as a principle for killing some tumors in people."
Their studies of the role cyclin plays in tumor onset and regression is a relatively new focus for Holzschu and his collaborators at Cornell University. Lorie LaPierre, a former doctoral student at Cornell who now is a postdoctoral researcher in biomedical sciences at Ohio University, was studying walleye retroviruses when she discovered that these viruses contained the cyclin gene.
Holzschu and LaPierre began working on the project while at Cornell University in the lab of James Casey, professor of microbiology and immunology, and co-author of this new research. Holzschu has continued the work since coming to Ohio University two years ago. He, Casey and another collaborator, Paul Bowser, professor of microbiology and immunology at Cornell, are among a handful of scientists studying the incidence of tumors in walleye.
"Of the walleye populations studied in Canada and New York, close to 30 percent of the walleye can have these tumors in some years," Holzschu says.
Tumors that spontaneously appear and disappear have been documented in other cold-blooded animals, but Holzschu says this is the first time these tumors have been linked to a retrovirus. The scientists have deciphered the retrovirus' gene sequence and have identified most of the proteins these genes produce. Now they are looking at what biochemical and physiological factors may be influencing tumor development and death in walleye.
One theory Holzschu is investigating is a link between hormonal changes that occur during spawning and tumor regression. It's possible these hormones may have a direct effect on the tumors, or on the cyclin, which in turn could prompt tumor cells to undergo apoptosis, or programmed cell death.
The research was published in a recent issue of the Journal of Virology and was supported in part by the American Cancer Society and the U.S. Department of Agriculture. Holzschu holds an appointment in the College of Arts and Sciences and LaPierre is in the College of Osteopathic Medicine.
Attention reporters and editors: A photo of a walleye with skin tumors may be downloaded from the Web at http://www.ohio.edu/news/pix/FISH.JPG. To receive the image as a JPG attachment by e-mail or to obtain a copy of the journal article on which this story is based, contact Melissa Rake at 740-593-1891 or Kim Walker at 740-593-1043. A cutline and photo credit follows below.
Photo credit: Paul Bowser, Cornell University. Cutline: These skin tumors, walleye dermal sarcoma, appear in the fall and die in the spring.
Journal
Journal of Virology