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Karmanos researchers identify protease that promotes prostate cancer's spread to bone

Researchers in Barbara Ann Karmanos Cancer Center’s Proteases and Cancer Program, as well as the departments of Urology and Pathology at Karmanos and Wayne State University (WSU) School of Medicine, have recently published a study in “Cancer Research” that identifies a new molecular pathway in prostate cancer and describes its role in promoting the spread of cancer cells to bones in advanced cases.
The recently identified molecular pathway – an exclusive finding of Karmanos and Wayne State researchers -- could present a new target in the treatment of the disease that afflicts approximately 225,000 men annually and kills about 30,000 men each year in the United States. Almost all men who succumb to prostate cancer have bone metastasis, according to researchers.
In the study, researchers found that MT1-MMP, a protease found in both normal and cancerous cells, is at elevated levels in advanced prostate cancer that has metastasized into the bone. Proteases are enzymes that break down extracellular proteins, which provide structural support and regulate cell behavior. Over-expression of protease MT1-MMP in prostate cancer cells increases tumor growth and bone degradation.

Michael Cher, M.D

“We want to know why prostate cancer spreads to bone; why bone is a ‘privileged’ site more than other sites; and what is the biology of the interaction between prostate cancer cells and the bone environment,” said Michael Cher, M.D., chief of Urology at Karmanos and chairman of the Department of Urology at Wayne State University School of Medicine. “That’s our long-term goal.”
Dr. Cher said that the normal role of MT1-MMP is to break down structural proteins like collagen, and the bone has a tremendous amount of collagen.
“We figured that when prostate cancer cells get in the bone, they may be directly altering the structure of the bone. That is indeed the case, but we have now found additional roles of MT1-MMP,” he said.
Not only did researchers find that MT1-MMP plays a role in breaking down the structure of bones, they also found it released a protein called RANKL, which is found on the surface of cancer cells and bone cells. When RANKL is cleaved from a cell’s surface by MT1-MMP, it goes on to bind to cellular receptors known as RANK on pre-osteoclasts, causing them to mature into osteoclasts and break down bones. It also binds to RANK on the cancer cells themselves, causing them to become more aggressive.
Researchers in Karmanos’ Proteases and Cancer Program have been studying proteases’ role in prostate cancer for approximately 15 years.
Fellow researchers on this study include Aaron Sabbota, Ph.D., a graduate of the Cancer Biology Program at Karmanos and WSU School of Medicine who worked in Dr. Cher’s lab at the time of the study; Hyeong-Reh Choi Kim, Ph.D., professor in the Department of Pathology at Karmanos and WSU School of Medicine; Xiaoning Zhe, M.D., Ph.D., of the Department of Urology at Karmanos and the WSU School of Medicine; Rafael Fridman, Ph.D., professor in the Department of Pathology and leader of the Proteases and Cancer Program at Karmanos and WSU School of Medicine; and R. Daniel Bonfil, Ph.D., associate professor of urology and pathology at Karmanos and WSU School of Medicine.
“MT1-MMP seems to have multiple ways of enhancing bone metastasis,” said Dr. Bonfil, who co-led the research. “When prostate cancer gets into bone, clinicians can recognize it because the bone structure becomes markedly changed. If we understand more about what’s causing the bone structure to change, we might develop new targets for treating bone metastasis. We’ve recently begun putting more emphasis on this particular pathway within the last three to four years.”
With the identification of the multiple roles of MT1-MMP, Dr. Bonfil added that this could have implications in the development of new therapies for other cancers that have a tendency to spread to the bone, including breast, kidney and thyroid cancers.
“We would have to study MT1-MMP in other cancers,” he said. “As it relates to prostate cancer, this work represents a new paradigm. We are now going to look for ways to target these pathways using drugs. We’re also going to be studying characteristics of circulating tumor cells in the blood stream to determine if they have the same changes in their molecular pathways as do the cells that are in the bone.”
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