Feature
Of Mice and Men: Tracking the Origins of
Metastatic Prostate Cancer
Peter Choyke, M.D.(Photo: R. Baer)
Kelly and her team have found that some of these clonal cell lines are sensitive to androgen deprivation, but there is a component of cells that does survive androgen deprivation. Kelly noted that in a very recent paper from Memorial Sloan Kettering Cancer Center, researchers also found cells from human prostate cancer-derived cell lines that have tumor-initiating capacity and are insensitive to androgen.
“From our mouse work, and now this human cell line, it does appear that a relatively undifferentiated tumor-initiating cell will lead to luminal adenocarcinoma of the prostate,” concluded Kelly.
Understanding more about the cells responsible for driving tumor formation will provide new insights into how to more effectively diagnose potentially progressive disease and target these specific populations therapeutically.
Tracking the Spread
Another challenge for prostate cancer research lies in the differences in androgen sensitivity that result when cells are removed from the environment of the organism. “It’s complicated to take apart the response,” said Kelly, noting that cells are just not as sensitive to androgen deprivation in culture.
Among the clonal cell lines that Kelly’s team has generated from their mouse model, a few behave like human prostate cancer cells in that they are androgen-sensitive and give rise to adenocarcinoma. “So we are looking at metabolically labeling and tracking these cells in the mouse,” said Kelly.
Peter Choyke, M.D., Program Director of the Molecular Imaging Program at CCR, runs both preclinical and clinical imaging facilities. “Our goal is to develop molecular imaging tools that are translatable into people with the hope that we can diagnose, stage, or monitor cancer patients in a noninvasive way over time,” said Choyke. Among the tools in his research armamentarium is a micro- positron emission tomography (PET) scanner for use on small animals.
Choyke and Kelly are planning to use PET to look at metabolic changes in prostate cancer cells relative to normal tissue, both as a tool to better understand prostate cancer progression in the whole organism and as a means to improve the ability to image these cancer cells in men.
“There’s a lot of interest in the metabolomics of cancer and, from an imaging perspective, one of the interesting aspects of prostate cancer is that, early on, it is not particularly well visualized by the standard PET scan,” explained Choyke. Whereas most tumors differentially depend on glucose uptake, prostate cancers early in development do not, and PET scanning relies on cells taking up radiolabeled glucose (18F-fluorodeoxyglucose or FDG).
“As the prostate cancer advances and becomes more malignant, it starts to take up more FDG. So, there is some kind of glucose utilization switch that occurs later in its development,” said Choyke.
There’s a lot of interest in the metabolomics of cancer.
From studies that Kelly has conducted on prostate cancer cells, she has additional reasons to believe that prostate cancer cell metabolism is altered during the progression of the disease. In addition to changes in glucose metabolism, she believes that changes in fatty acid metabolism might also be important, and that early prostate cancers differentially utilize fatty acids. Choyke and Kelly plan to study this by using PET to monitor uptake of the fatty acid precursor, 11C-acetate, which corresponds to the activity of an enzyme that synthesizes fatty acids.
Specifically, Kelly will use a model in which their clonal cell line is introduced into the prostates of mice that have been castrated and implanted with testosterone pellets. Subsequent removal of the pellets will mimic androgen-deprivation therapy and result in the development of androgen-independent malignancies.
“We want to know whether a marker of fatty acid metabolism—11C-acetate—would be a sensitive way of finding prostate cancer cells either in a primary state or following androgen deprivation,” explained Kelly.
One of the biggest challenges to studying and treating any metastatic disease is being able to find and track the cancer as it spreads. Ultimately, Kelly hopes that studying this progression in a carefully characterized and controlled mouse model will provide insights to address that challenge in man.
To learn more about Dr. Kelly’s research and to view a video, please visit her CCR Web site at:
http://ccr.cancer.gov/staff/staff.asp?Name=kellyk.
To learn more about the Molecular Imaging Program at CCR, please visit Dr. Choyke’s CCR Web site at:
http://ccr.cancer.gov/staff/staff.asp?Name=choyke.
The Veterinary Perspective
Former CCR Fellow Scott Martin, Ph.D., now leads the RNAi screening initiative at NCGC. (Photo: R. Baer)
In 2003, Mark Simpson, D.V.M., Ph.D., Head of the Comparative Molecular Pathology Unit of CCR’s Laboratory of Cancer Biology and Genetics, launched a new training initiative under the NIH Graduate Partnership Program titled the Comparative Molecular Pathology Research Training Program. His aim was to provide opportunities for veterinarians to gain postdoctoral training in pathology and human biomedical research. The program operates with multiple NIH institute intramural programs and university partners, with training leading to a Ph.D. and eligibility to certify as a specialist in veterinary pathology.
“We recognized that an incredible set of advancements were forthcoming from the genomic revolution and the sequencing of the human genome,” said Simpson. “But understanding the function of most genes requires their study in the context of the biology of a model organism, that is, an animal.”
A veterinary pathologist, Simpson knew that this training would support a bridge between molecular discovery and whole animal pathophysiology. “What was needed was to bring more veterinarians to the NIH and provide them with the opportunity to get research training in human biomedical research,” said Simpson. “Training alongside medical and basic scientists fosters a shared vocabulary and approaches to translational research.”
Philip Martin, D.V.M., arrived at the NIH in 2005, part way through a residency in veterinary pathology. “The program was perfect for me because it allowed me to fulfill my residency requirements, including the national board certification exam, as well as pursue a Ph.D., which is important for pathologists who are interested in animal models of human disease.”
Martin is currently finishing up his dissertation in the laboratory of Kathleen Kelly, Ph.D., but, in the meantime has accepted a full-time position as a pathologist at CCR’s Center for Advanced Preclinical Research (CAPR) in Frederick, Md. CAPR is dedicated to improving preclinical evaluation for effective cancer diagnosis and treatment.
“If we’re going to study mice as models of human disease, we need to be sure that it is a relevant form of disease,” explained Martin. “The need to analyze the pathology is extremely important. Many models, upon rigorous pathological examination, are not the type of cancer that the investigators were hoping to study.”
“Having Philip’s perspective in the lab has really helped me understand the strong and weak points of mouse models,” said Kelly.
Simpson hopes that this initiative will contribute not only to prevention and treatment of disease in humans, but also in animals. “There’s a special perspective we bring because of our orientation to disease in multiple species.” By integrating the comparative perspective with human biomedical research, Simpson aims to train D.V.M./ Ph.D. scientists who are capable of leading research collaborations at the forefront of scientific discovery.
