Method for Halting Prostate Cancer Cell Growth Studied

Researchers at the Houston VA Medical Center have made a discovery that appears to halt prostate cancer cell growth and holds promise as a future treatment.

Michael Ittmann, M.D., Ph.D., the Houston VA Medical Center’s chief pathologist and associate professor of pathology at Baylor College of Medicine, found that disruption of fibroblastic growth factor signaling appears to halt the proliferation of prostate cancer cells. FGF is present in the normal prostate, but its production increases in prostate cancer.

Growth factors are the proteins made, and usually secreted, by cells. They bind to receptors on the cell and “turn on” signaling that leads to different effects inside the cell.

“In the normal prostate, there are epithelial cells that line the outer wall of the prostate and stromal cells that act as scaffolding and support the epithelium. As prostate cancer spreads, malignant epithelial cells start to outgrow the supporting stroma,” Ittmann said.

Through a Veterans Affairs Merit Review grant, Ittmann is examining the effect of increased fibroblastic growth factor in prostate cancer and analyzing its impact on disease progression. His Houston VA Medical Center 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 said.

“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, which suggests that without FGF2 present, cancer cells don’t spread as quickly.”

Additional work by Ittman’s 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 nonproductive 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.”

Houston VA Medical Center researchers now plan to study this dominant-negative approach and to evaluate drugs that might inhibit FGF receptors.

Ittmann sees potential for FGF-blocking therapies to be used in conjunction with other treatments.

“This idea of antigrowth 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.”

The hospital recommends early detection through annual digital-rectal exams and use of the prostate-specific antigen 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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©2006 Texas Medical Center

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