"In metastatic prostate cancer, we think that both processes are going on," Keller says. "Our hypothesis is that prostate cancer cells first induce more bone resorption to help the invading cells become established in bone. But then there's a switch to increased bone production. Although we don't know the exact mechanism responsible for the switch, we know that it's related to the activity of Wnt proteins in prostate cancer cells."

In the first phase of their research, U-M scientists measured the amount of Wnt protein in cells from normal human prostate tissue, localized prostate cancer and metastatic prostate cancer cells. Using the same cell lines, they also looked for the presence of a protein called DKK-1, which is known to inhibit Wnt activity. They discovered that the amounts of Wnt and DKK-1 protein present in human prostate cells varied inversely with the developmental stage of prostate cancer.

"As the cancer progressed, DKK-1 levels went down," Hall says. "Cells with osteoblastic activity had high levels of Wnt activity and low levels of DKK-1, while cells with osteolytic activity showed decreased Wnt activity and high levels of DKK-1."

"Our results suggest that DKK-1 may act like a switch on prostate cancer cell activity," Keller says. "When we altered the cells to increase the amount of active DKK-1, it blocked Wnt's signal, changing prostate cancer cells from an osteoblastic to a highly osteolytic cell line."

To test their hypothesis, U-M scientists injected human prostate cancer cells into the tibias, or long leg bones, of one group of immune-deficient mice. Twelve weeks later, U-M researchers removed and examined bone tumors from the mice. They found that these mice produced tumors with a dense overgrowth of bone. A second group of mice, injected with prostate cancer cells made to express the Wnt
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Contact: Sally Pobojewski
pobo@umich.edu
734-615-6912
University of Michigan Health System
1-Sep-2005