The James Buchanan Brady Urological Institute
 
 
 
                 A PUBLICATION OF THE PATRICK C . WALSH PROSTATE CANCER RESEARCH FUND
   
   Special Lab Mice Develop Prostate Cancer That's Much Closer to The Kind Men Get

               Volume 9, Winter 2013

Oncologist Bill Nelson, M.D., Ph.D., head of the Sidney Kimmel Comprehensive Cancer Center, and The Marion I. Knott Professor of Oncology, has been studying an enzyme called GST P1 (glutathione S-transferase π) for more than a decade. In fact, it is due to his pioneering work, done with colleagues Angelo De Marzo, Bill Isaacs, and others, that we know so much about why this enzyme is so important in the development of prostate cancer. GST P1 is a genetic "fire extinguisher" that cleans up toxins in cells. It takes dangerous free radicals – produced by many of the foods we eat – and turns them into harmless, water-soluble products preventing the ravages of oxidative damage.

As much as scientists have
learned about GSTP 1, they
have not been able to study
it in the laboratory as effectively
as they wanted to – until now..

GST P1 is also one of the first lines of defense to be knocked out in prostate cancer. Without GST P1's damage-controlling effects, cancer has a far easier time taking hold and overpowering the body's ability to fight it. As much as scientists have learned about GST P1, they have not been able to study it in the laboratory as effectively as they wanted to – until now. "We have created a strain of mouse that has human GST P1 genes," says Nelson. "These are the genes that direct the production of enzymes that protect normal cells against cancer-causing chemicals, including those that appear in overcooked meats, and against oxidative damage." Nelson and colleagues Matthew Vaughn, Debika Biswal-Shinohara, Nicole Castagna, Jessica Hicks, George Netto, Angelo De Marzo, Traci Speed, Zachery Reichert, Bernard Kwabi-Addo, Colin Henderson, C. Roland Wolf, and Vasan Yegnasubramanian recently published this research in the journal, PLoS One.

Why was this specialized mouse needed? Because humans, literally, are a "different animal" when it comes to how we process food and other things. "In mice and other mammals, genes that carry the blueprints for the various enzymes that are involved in the metabolism of drugs, toxins, carcinogens, and other reactive chemicals tend to be regulated differently," Nelson explains. "For example, mice exhibit different side effects or complications to drug and chemical exposures than humans do." These differences can often be crucial. Nelson cites one classic research example in which the difference in species produced devastating consequences: "When pregnant mice were treated with thalidomide, it did not cause problems in their offspring. But when pregnant women took thalidomide (as a treatment for morning sickness), it caused severe and terrible birth defects."

In men who develop prostate cancer, the loss of GST P1 function is "the most consistent acquired gene defect," says Nelson. "What interested us, of course, was that the mouse Gstp genes were entirely different in the mouse prostate than human GSTP genes were in the human prostate." To develop a "humanized" mouse model of this important event in the formation of cancer, "we introduced, via genetic engineering, the human GSTP1 gene into a mouse that had its own Gstp genes deleted." In the research paper, Nelson and colleagues demonstrated that "in the prostate and every organ in the body where the human and mouse genes were expressed differently, these mice showed the human pattern." In the liver, the result was a different response to an overdose of acetaminophen (Tylenol). The group's current work suggests that these mice will develop a type of prostate cancer that is much more like human prostate cancer.




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