July 29, 2002
Growth Factors Critical to Prostate Cancer Research and Treatment
HOUSTON, TX - Researchers at the Houston VA Medical Center (HVAMC) have found that disruption of fibroblastic growth factor (FGF) signaling appears to halt prostate cancer cell growth and holds promise as a future treatment.
"FGF is present in the normal prostate, but research shows that its production increases in prostate cancer," said Dr. Michael Ittmann, the chief pathologist at the HVAMC and associate professor of pathology at Baylor College of Medicine.
Growth factors are the proteins made, and usually secreted, by cells. They bind to receptors on the cell and turn on signaling that has different effects inside the cell.
"In the normal prostate, there are epithelial cells and stromal cells that support the epithelium. As prostate cancer spreads, malignant epithelial cells start to outgrow the supporting stroma," Ittmann said.
Through a Veterans Affairs (VA) Merit Review grant, Ittmann is examining the effect of increased FGF in prostate cancer and analyzing its impact on disease progression. His HVAMC lab is looking at models of prostate cancer and human prostate cancer cell lines.
The fact that there are 20 types of FGF and four different FGF receptors makes the research all the more challenging, Ittmann says.
"We are utilizing what researchers call a knock-out mouse. This mouse is missing one kind of FGF - in this case, FGF2," he said. "When these mice are given the prostate cancer gene, the cancer doesn't spread as much and the primary tumors are less aggressive."
Ittman's work at the HVAMC with these mice revealed that the presence of FGF2 promotes prostate cancer progression. Additional work by his HVAMC lab and others also linked FGF6 and FGF8 to prostate cancer.
Research focusing on the four FGF receptors also is yielding promising results.
In human prostate cancer cell lines, Ittmann's group used a technique involving a dominant-negative FGF receptor to shut down cell signaling.
"When FGF binds, it brings two receptors together. The dominant-negative receptor gets in there and ties up the other receptor in a non-productive state," Ittmann said. "We think this approach works with all four FGF receptors."
The studies found prostate cancer cells were dependent on FGF signaling. In all the cancer cell lines examined, disrupted FGF signaling led to prostate cancer cell death.
Worth noting is the fact that dominant-negative FGF receptors do not kill normal prostate cells.
"This makes targeting FGF a good way of treating prostate cancer," Ittmann said. "You need a treatment that differentiates between the cancer cells and normal cells."
Researchers at the HVAMC now plan to study this dominant-negative approach and to evaluate drugs that might inhibit FGF receptors. He sees potential for FGF-blocking therapies to be used in conjunction with other treatments.
"This idea of anti-growth factor therapy is not pie in the sky," Ittmann said. "Breast cancer is already seeing clinical use of therapies that target growth factors, and leukemia treatments are using inhibitors of specific receptors. We just need to understand the mechanism in prostate cancer better."
Prostate cancer kills 30,000 people each year and is the second leading cause of cancer death in the United States. The HVAMC recommends early detection through annual digital-rectal exams and use of the prostate-specific antigen (PSA) blood test.
"In the last few years, we've seen a drop in prostate cancer mortality. The development of screening tests and improved treatments certainly plays a factor," Ittmann said. "I think FGF- targeted therapy will one day be part of treatment plans."
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Point of Contact: VHAHOU Public Affairs04/21/04 08:25