ANN ARBOR, Mich. -- Prostate cancer is a cruel disease. Left untreated,prostate cancer cells often metastasize, or spread, to bone where theyform fracture-prone tumors that are extremely painful.
More than 80 percent of men who die from prostate cancer die withmetastatic disease in their bones. But scientists know very littleabout how migrating prostate cancer cells set up housekeeping in bonetissue and produce the dense bony lesions characteristic of prostatecancer.
Now, new research by scientists at the University of Michigan'sComprehensive Cancer Center suggests that prostate cancer manipulatesan important group of signaling proteins called Wnts (pronounced"wints") to establish itself in bone. By changing the amount andactivity of Wnt proteins, prostate cancer cells upset the normalbalance between formation and destruction of bony tissue.
"There is strong evidence that Wnt proteins play a centralrole in regulating normal skeletal development in an embryo," saysChristopher L. Hall, Ph.D., a senior research fellow in urology at U-M."But this is the first time Wnts have been shown to be involved inabnormal bone production in adult animals with prostate cancer."
Hall is first author of a paper to be published in the Sept. 1issue of Cancer Research, which presents results from U-M studies ofWnt proteins in human prostate cancer cell lines and in laboratory miceinjected with prostate cancer cells.
"Normal bone growth and remodeling depends on a controlledbalance between production of new bone and resorption of existingbone," says Evan T. Keller, D.V.M., Ph.D., a professor of urology andpathology in the U-M Medical School, who directed the U-M study. "Whena tumor forms in bone, it upsets this balance."
Several types of cancer metastasize to bone, according toKeller, but most of them tip the balance toward destruction --producing what scientists call osteolytic lesions, or holes in thebone. Prostate cancer is unique in its ability to trigger increasedbone production, which creates what's called an osteoblastic lesion.
"In metastatic prostate cancer, we think that both processesare going on," Keller says. "Our hypothesis is that prostate cancercells first induce more bone resorption to help the invading cellsbecome established in bone. But then there's a switch to increased boneproduction. Although we don't know the exact mechanism responsible forthe switch, we know that it's related to the activity of Wnt proteinsin prostate cancer cells."
In the first phase of their research, U-M scientists measuredthe amount of Wnt protein in cells from normal human prostate tissue,localized prostate cancer and metastatic prostate cancer cells. Usingthe same cell lines, they also looked for the presence of a proteincalled DKK-1, which is known to inhibit Wnt activity. They discoveredthat the amounts of Wnt and DKK-1 protein present in human prostatecells 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 andlow levels of DKK-1, while cells with osteolytic activity showeddecreased Wnt activity and high levels of DKK-1."
"Our results suggest that DKK-1 may act like a switch onprostate cancer cell activity," Keller says. "When we altered the cellsto increase the amount of active DKK-1, it blocked Wnt's signal,changing prostate cancer cells from an osteoblastic to a highlyosteolytic cell line."
To test their hypothesis, U-M scientists injected humanprostate cancer cells into the tibias, or long leg bones, of one groupof immune-deficient mice. Twelve weeks later, U-M researchers removedand examined bone tumors from the mice. They found that these miceproduced tumors with a dense overgrowth of bone. A second group ofmice, injected with prostate cancer cells made to express the Wntinhibitor, DKK-1, developed highly osteolytic tumor lesions, whichdestroyed most of the bone.
"This demonstrated that Wnts promote the overproduction of bone by prostate cancer cells," Keller says.
In previous research, the U-M team found that preventing theosteolytic changes associated with bone resorption also preventedprostate cancer from establishing itself in bone. By learning how DKK-1blocks Wnt's signal to prostate cancer cells, they hope to learn how tocontrol physical changes in bone that encourage the development ofmetastatic tumors.
"Our goal is to find ways to manipulate this Wnt pathway toslow the growth of tumors in bone or decrease the tumor-associatedpain," Keller says. "We won't be able to stop the primary tumor fromreleasing cells, but by preventing early bone resorption, we may beable to prevent metastatic cells from getting a foothold in bone."
In future research, U-M scientists will try to identify whichof the nearly 20 known Wnt proteins is involved in bone changesassociated with metastatic prostate cancer.
The research was supportedby the National Cancer Institute. U-M research investigator Jinlu Dai,M.D., Ph.D., was a collaborator on the research study, along with AnnaBafico, Ph.D., and Stuart A. Aaronson, M.D., from the Mount SinaiComprehensive Cancer Center.
Cancer Research: 65 (17), September 1, 2005.
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