Prostate cancer uses Wnt signaling proteins to promote growth of bone tumors
September 2, 2005. Advanced prostate cancer often metastasizes, or spreads, to bone. There the cancer cells form fracture-prone, extremely painful tumors.
More than 80 percent of men who die from prostate cancer die with metastatic disease in their bones. But scientists know very little about how migrating prostate cancer cells invade bone tissue and produce the dense bony lesions characteristic of prostate cancer.
Now, new research by scientists at the University of Michigans Comprehensive Cancer Center suggests that prostate cancer manipulates an important group of signaling proteins called Wnts (pronounced "wints") to establish itself in bone. By changing the amount and activity of Wnt proteins, prostate cancer cells upset the normal balance between formation and destruction of bony tissue.
"There is strong evidence that Wnt proteins play a central role in regulating normal skeletal development in an embryo," says Christopher 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 in abnormal bone production in adult animals with prostate cancer."
Hall is first author of a paper to be published in the Sept. 1 issue of Cancer Research, which presents results from U-M studies of Wnt proteins in human prostate cancer cell lines and in laboratory mice injected with prostate cancer cells.
"Normal bone growth and remodeling depends on a controlled balance between production of new bone and resorption of existing bone," says Evan T. Keller, D.V.M., Ph.D., a professor of urology and pathology in the U-M Medical School, who directed the U-M study. "When a tumor forms in bone, it upsets this balance."
Several types of cancer metastasize to bone, according to Keller, but most of them tip the balance toward destruction - producing what scientists call osteolytic lesions, or holes in the bone. Prostate cancer is unique in its ability to trigger increased bone production, which creates whats called an osteoblastic lesion.
"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 theres a switch to increased bone production. Although we dont know the exact mechanism responsible for the switch, we know that its 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 Wnts 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 inhibitor, DKK-1, developed highly osteolytic tumor lesions, which destroyed 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 the osteolytic changes associated with bone resorption also prevented prostate cancer from establishing itself in bone. By learning how DKK-1 blocks Wnts signal to prostate cancer cells, they hope to learn how to control physical changes in bone that encourage the development of metastatic tumors.
"Our goal is to find ways to manipulate this Wnt pathway to slow the growth of tumors in bone or decrease the tumor-associated pain," Keller says. "We wont be able to stop the primary tumor from releasing cells, but by preventing early bone resorption, we may be able to prevent metastatic cells from getting a foothold in bone."
In future research, U-M scientists will try to identify which of the nearly 20 known Wnt proteins is involved in bone changes associated with metastatic prostate cancer.
Links, sources and related
Transdermal Estradiol Therapy for Prostate Cancer
Reverses osteoporosis of androgen suppression, reduces blood clot risk compared with oral estrogen
Prostate Problems Mailing List
http://ppml.acor.org/
Hormone Refractory Prostate Cancer http://www.hrpca.org/index.html
Intermittent Androgen Deprivation Therapy for Prostate Cancer The Oncologist June 2004
by J. Strax Aug 11, 2005.
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