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IGF-1 is a polypeptide hormone that can influence growth, differentiationand survival of cells expressing the type 1 receptor (IGF-1R). Past clinical,epidemiological and experimental studies have strongly implicated IGF-1 as acontributing factor in the natural history of prostate cancer. However, verylittle has been done to prove absolutely that the expression or activation ofthe IGF-1 signaling pathway at physiologically relevant levels is sufficientto cause a healthy prostate cell to become a cancer cell.
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Norman Greenberg, Ph.D., and colleagues conducted a pair of experiments bymanipulating gene expression directly in the epithelial compartment of themouse prostate gland to better understand the role of IGF-1R. In contrast tostudies that correlated elevated levels of IGF-1 with the risk of developingprostate cancer, Greenberg's research showed that eliminating IGF-1Rexpression in an otherwise normal mouse prostate caused the cells toproliferate and become hyperplastic. Although persistent loss of IGF-1Rexpression ultimately induced cell stasis and death, both of these processesare regulated by the tumor suppressor gene p53 that is commonly mutated inhuman prostate cancers. Hence the researchers hypothesized that tumors withcompromised p53 might not respond predictably to therapies targeting IGF1signaling.
To test their reasoning they conducted a second experiment by crossingmice carrying the prostate-specific IGF-1R knockout alleles with transgenicmice that develop spontaneous prostate cancer when p53 and select other genesare compromised. The results were as predicted: Prostate epithelial-specificdeletion of IGF-1R facilitated the emergence of aggressive prostate cancer inthe genetically-engineered tumor prone mice.
Published in the May 1 edition of Cancer Research, the study supports acritical role for IGF-1R signaling in prostate tumor development andidentifies an important IGF-1R-dependent growth control mechanism, accordingto the authors. Title of the paper is "Conditional deletion of insulin-likegrowth factor-1 receptor in prostate epithelium."
"If our predictions hold true, tumor cells with intact p53 may show thebest response to therapy targeting the IGF-1R signal, however when p53 is notfunctioning normally, response to this therapy may not be as expected," saidGreenberg, the study's corresponding author and a member of the HutchinsonCenter's Clinical Research Division.
Greenberg's message to clinicians who administer IGF-R1 therapy: "We'reall hoping for good results but let's proceed with caution."
A search of the database for clinical trials registered with the NationalCancer Institute found 18 trials in process that use therapies to inhibitIGF-R1. None of them include a tumor's p53 status as a criterion forrecruiting research participants, said Greenberg.
In addition to lead author Brent Sutherland, Ph. D., of the HutchinsonCenter, contributing research also came from scientists at Baylor College ofMedicine in Houston, Texas, the Center for Cancer and Stem Cell Biology atTexas A&M University and the Institut National de la Sante et de la RechercheMedicale in Paris, France.
The study was funded by the National Cancer Institute, the Prostate CancerFoundation and Phi Beta Psi.
Note to reporters/editors: To obtain a copy of the study, please contactDean Forbes, 206-667-2896 or [email protected]
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