Machines that can image mice are ushering in a new era for research that depends on animal models of cancer
Small-animal models of human diseases particularly genetically engineered mice are increasingly recognized as powerful discovery tools in cancer research. But their potential has yet to be fully realized.
One major limitation: Because imaging equipment designed for humans isn't sensitive enough for creatures as small as mice, researchers have been unable to observe the growth of a cancer, or the activity of an anti-cancer drug, in the living body of a laboratory mouse.
Enter Simon Cherry. Cherry, a professor of biomedical engineering and director of the UC Davis Center for Molecular and Genomic Imaging, has scaled state-of-the-art medical imaging machines down to mouse size. He invented the first mouse PET machine while at UCLA more than a decade ago. Two years ago, he introduced the MicroPET II, now the smallest commercially available PET scanner on the market, with eight times the resolution of his first machine. Cherry has also helped to create a micro CT and micro PET-CT, and is working to develop a lowercost micro PET that would be affordable to more research laboratories around the country.
Last year, the National Cancer Institute selected Cherry out of a pool of 35 leading imaging scientists nationwide to receive a $3.4 million Small Animal Imaging Resource Program grant. Only 11 other SAIRP grants have been awarded since the program's inception; the other recipients are from Memorial Sloan-Kettering Cancer Center, Johns Hopkins University, Massachusetts General Hospital/Harvard University, Duke University, Stanford University, University of Michigan, University of Arizona, University of Pennsylvania, Washington University, Case Western Reserve University and UCLA.
The grant recognizes that UC Davis, home to what is widely regarded as the best mouse cancer pathology group in the world, is also emerging as a top center for imaging mouse models of cancer.
With Cherry's tools, scientists who work with transgenic mouse models of cancer including mice that bear human tumors are able to obtain unprecedented amounts of data. Researchers can follow the development of a cancer, or assess whether an experimental treatment is beneficial, in the same mouse over time. Before micro imaging became available, such information could be obtained only by sacrificing the animal.
The Center for Molecular and Genomic Imaging is a 4,000-square-foot, dedicated core facility for small-animal imaging. Located in the new Genome and Biomedical Sciences Facility on the Davis campus, the center has three micro PET scanners as well as bioluminescence imaging, ultrasound, and 2-D digital fluorescence and autoradiography imaging. With SAIRP grant support, Hongjie Liang, a biomedical engineering doctoral student in Cherry's lab, recently developed a micro PET-CT scanner as well.
Positron emission tomography or PET imaging, widely used in human cancer patients, works by detecting short-lived radioactive isotopes that emit positrons. Those isotopes are typically attached to glucose, which is taken up to the greatest extent by the most metabolically active cells in the body, notably malignant tumors. On a PET scan, a cancer literally lights up. The tumor's anatomic location, however, can't be determined with precision.
That's where computerized tomography (CT) comes in. CT excels at imaging body structures and can reveal the precise location of even a small tumor. When CT and PET are married, the resulting image shows not just the precise anatomic location of an abnormal growth, but also how fast that lesion is consuming glucose. If the lesion is no hungrier than nearby cells, it is probably malignant. If it's ravenous, malignancy is likely (see Molecular Imaging).
For research that depends on mouse models of cancer and other human diseases, the micro PETCT scanner is a major advance.
"For the first time we can now measure molecular processes and their underlying anatomic location in a mouse with a single imaging instrument, thus combining the strengths of structural and functional imaging," Cherry said.
Micro imaging applications
Collaborators on the SAIRP grant include pathology professor Robert Cardiff, who directs the renowned UC Davis Mutant Mouse Pathology Laboratory, and Alexander Borowsky and Jeffrey Gregg, also members of the pathology faculty. Cardiff, Borowsky and Gregg have developed several novel mouse models of cancer, including a mouse engineered to develop ductal carcinoma in situ, or DCIS, a precursor to breast cancer in humans.
Using Cherry's microscanners, the team is able at to non-invasively follow the natural growth of the DCIS-like lesions in mice and pinpoint their earliest transition to invasive disease. Such investigation is impossible in human patients, because the standard of care is to remove DCIS tissue.
Other SAIRP collaborators include Kit Lam, professor and chief of hematology and oncology at UC Davis Cancer Center, and Joe Tuscano, associate professor of hematology and oncology.
Lam has been screening various molecules and compounds against human cancer cells in an effort to find potential new anti-cancer compounds. He tests those that appear promising in a mouse model of that particular cancer, using Cherry's micro PET to track the compound's anti-tumor activity.
Tuscano is developing antibodies against certain cancers, including lymphoma, and also tests the drugs in mouse models, with imaging studies in the offing.
Outside investigators take advantage of Cherry's scanners, too. Genentech, for example, is testing various candidate compounds against mouse models of human cancer and uses Cherry's micro PET and micro PET-CT machines to assess their efficacy.
Cherry's long-term goal is to translate findings in animal models of cancer into new advances that will benefit human cancer patients. He's found that the most important advances often start with the smallest steps.