The knockout mouse may some day be knocked right off its pedestal. Revered as the best animal model for cancer, the mouse may have to share its glory with such unassuming vertebrates as the woodchuck, the ferret, and zebrafish.
In truth, the mouse has nothing to worry about from its land-based kin. Research with mammals like the woodchuck and ferret is focused on single types of cancer. But the zebrafish may one day swim circles around the overworked mouse. This striped tropical fish appears capable of revealing some of the most fundamental processes involved in cancer.
Plenty of Room at the Top
"I dont think anyone is worried about other animals supplanting the mouse. The more models the better," said Tom Doetschman, Ph.D., professor of molecular genetics at University of Cincinnati College of Medicine. Doetschman designs knockout mice for a living. "It might be very helpful to have models from other species."
The zebrafish is the animal model that Doetschman and others say is most promising for cancer research. Keith C. Cheng, M.D., Ph.D., associate professor of pathology at the Jake Gittlen Cancer Research Institute at Penn State University in Hershey, has developed genetic screens to study genomic instability and cell differentiation. At the third Zebrafish Workshop, held in Australia in February, he revealed that some of his mutants seem to show susceptibility to cancer.
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The zebrafish generates mutants readily. It can make embryos derived only from the mothers genetic information, which means the phenotype of the mutation being studied will appear in the very next generation. "Theres no dads DNA to get in the way," Cheng explained.
Plus zebrafish embryos are transparent and develop outside the mothers body. Organs and tissues can be viewed without sacrificing the fish, making it easier to screen for mutant phenotypes. And there is no shortage of embryos. Between its third and sixth month, the female zebrafish can pump out hundreds of eggs every other week.
"The zebrafish will be the next mouse," said Jim Casey, M.D., associate professor of virology at Cornell Universitys College of Veterinary Medicine in Ithaca, N.Y. His work on a unique cancer in walleye, a member of the perch family common to northern lakes, may bolster the zebrafishs claim to fame. Casey and Paul Bowser, Ph.D., professor of aquatic medicine at Cornells College of Veterinary Medicine, have shown that the seasonal tumors observed on walleye are caused by a newly identified retrovirus dubbed walleye dermal sarcoma virus.
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On New Yorks Oneida Lake, about 30% of adult walleye become covered with benign, wart-like tumors during April spawning season. In summer, the tumors disappear. "When the walleye fishing season opens in May and June, the fish are totally clean," said Bowser. After a single season of tumors, the fish become refractory to the cancer. "One year the fish look ugly as hell, then they look OK," Bowser said.
He and Casey have been able to infect young walleye in the lab by putting them in virus-filled water or by painting the virus on their surfaces. Unlike their adult counterparts, the young fish get invasive, life-threatening tumors. The researchers are looking at the seasonal changes in tumor occurrence and the invasive nature of the cancer in young fish to study the interplay of defense mechanisms with invading pathogens.
To take the research a step further, they hope to use the recently identified viral oncogenes coded for by the walleye retrovirus and by five other fish retroviruses, move them into retroviral vectors, and induce tumors in zebrafish.
Casey added, "Information we get from studying these genes will be important in understanding tumorigenesis broadly." The walleye dermal sarcoma virus is a complex retrovirus that contains the cyclin D gene, also found in the Kaposis sarcoma herpesvirus, that is known to be important to governing the cell cycle of the host cell. It may be important in keeping cell division going in tumorigenesis.
On Dry Land
The molecular mechanisms by which the hepatitis B virus causes cancer may become clearer with the help of the woodchuck (see article, p. 472). Woodchucks that are chronically infected with hepatitis B in the laboratory have 100% risk of developing liver cancer, according to Bud C. Tennant, D.V.M., James Law Professor of Comparative Medicine at Cornells College of Veterinary Medicine.
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"If I could use a mouse model for my work, I would," Tennant confessed. The stout-bodied marmots are big and hard to deal with compared to mice. Plus they only breed once a year.
But you cant beat them for studying hepatitis B and liver cancer. Plus the woodchuck has a toxicity profile for certain nucleoside analogues that appears to be identical to that seen in humans, making them ideal for preclinical assessment of antiviral drugs for treatment of chronic HBV infection, he said.
"There are many naturally occurring types of cancer seen in both domestic and wild animals, and theyre underutilized," Tennant noted. A population of California ground squirrels, cousins to the woodchuck, have also been studied for their virus-induced liver disease. And then theres the tree shrew, a squirrel-like mammal from the forests of Southeast Asia, also being used as a model to study HBV-induced liver cancer, and for studying chemopreventive agents for liver cancer.
Other veterinarians are pushing the study of naturally occurring cancers in domesticated dogs and cats (see News, Jan. 20, 1999, p. 112). Like humans, they experience lymphoma/leukemia, osteosarcoma, melanoma, and mammary tumors.
Xiang-Dong Wang, M.D., Ph.D., is putting his faith in the ferret. He and colleagues at the Human Research Center on Aging at Tufts University in Boston are using this domesticated version of the European polecat to try to understand why human intervention studies have shown -carotene supplements enhance lung carcinogenesis in smokers.
Unlike most laboratory animals, ferrets absorb and metabolize -carotene like humans. They can also inhale levels of tobacco smoke to produce precancerous lesions in the lungs, just like human smokers.
His study of high doses of -carotene, published 2 years ago in the Journal of the National Cancer Institute, revealed a possible mechanism for the harmful effect seen in the human trials. A second study, published in Carcinogenesis in December, tested low doses, like those obtained from five to nine daily servings of fruits and vegetables. It showed a minor protective effect, Wang said.
"Based on our animal study with the ferret, we ferreted out that 6 mg per day of -carotene is safe, and 30 mg per day is harmful," Wang deadpanned.
Wang said he could have used a different animal for his study. Monkeys absorb -carotene like humans, but they cost $1000 per animal. The calf was a possibility, but too large to study in his lab. The Mongolian gerbil was an option, but it could not be used for the smoking part of the study. So hes happy to use ferrets, which cost $75 each. "Ferrets are fearless subjects and gentle. They like to engage in social interactions while we play with them."
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