For release: July 23, 2004
Contact: Beatrijs Lodde, (301) 594-7560
Scientists recently recognized that bone sialoprotein (BSP) is elevated in the tumors and blood of people with breast and certain other developing cancers, a rise that sometimes can be associated with the spread of cancer cells throughout the body. What has remained unclear is exactly how BSP might play a role in this process.
Now, a research group at the National Institute of Dental and Craniofacial Research (NIDCR) reports for the first time that BSP forms a complex with two other proteins, possibly enabling cancer cells to better degrade the tissue that surrounds them and break free from tumors. From there, the cells can distribute throughout the body and colonize other tissues, called metastasis. The discovery could mark this protein complex as a potential target to prevent tumor metastasis. The study was published in the June 16, 2004 issue of the Journal of the National Cancer Institute.
“Although our data are based on laboratory work, we think it provides a viable target to explore the molecular dynamics of metastasis and potentially to intervene in the cancer process,” said Dr. Larry Fisher, a scientist at the NIDCR and the senior author on the paper.
As Fisher noted, he and his colleagues have spent several years studying BSP and had become interested in the fact that this protein specifically binds and activates a second protein, called matrix metalloproteinase (MMP) 2. MMPs are enzymes that in a scissor-like manner digest the matrix surrounding cells. Normally, they are involved in tissue development and repair, but they also appear to aid in tumor cell invasion and metastasis.
They then began to wonder whether the BSP-MMP2 interaction might also involve a third party. Other groups already had shown that MMP2 can directly bind integrin αvβ3. Integrins are a family of receptor molecules positioned on the cell membrane, where they bind various proteins, including bone sialoprotein, and can initiate a variety of cellular signals, such as programmed cell death, migration, and invasion. Some integrins, like integrin αvβ3, are also overexpressed in malignant cells.
All these pro-cancer features led the scientists to hypothesize BSP may act as a bridge linking MMP2 to integrin αvβ3. This way, the scientists thought, BSP could increase the invasiveness of cancer cells by pooling their distinct functional abilities. They tested their assumptions by looking at the invasion of tumor cell lines in a specialized test plate, which mimics conditions within a tumor. Breast, prostate, thyroid and lung cancer cells all showed improved invasion in the presence of BSP and MMP2. Additionally, the three proteins were found to group together on the surface of individual cells, indicating a complex formation. Finally, all three proteins were shown to be produced at the same time in cells within a patient’s tumor. By blocking the action of each protein separately, the scientists could confirm the special relationship between the three.
In the USA about 40,000 cancer patients develop bone metastases every year. These lead to bone fractures, spine compression, severe pain and a prognosis of typically only about two to three years to live. If, in an early stage of the tumor development, patients with a high risk of bone metastases can be identified, proper treatment can be started in time. Currently, bone complications are treated with bisphosphonate therapy, which suppresses the dissolving of bone induced by tumor cells.
Identifying people at risk for cancer before cells have visibly changed can also be applied to the dental clinic. “We ourselves are interested in finding out if the proteins could be used as markers in suspicious oral lesions to distinguish aggressive tumors from harmless growths in an early phase,” said Fisher. Next, the researchers want to investigate if the protein complex formation also occurs in normal cells. “This could help us explain the original function of the proteins in nature,” according to Fisher.
Collaborating with Dr. Fisher were Drs. Abdullah Karadag, Kalu U.E. Ogbureke and Neal S. Fedarko of the NIDCR and the Division of Geriatrics at Johns Hopkins University School of Medicine in Baltimore, MD. The article is titled “Bone Sialoprotein, Matrix Metalloproteinase 2, and αvβ3 Integrin in Osteotropic Cancer Cell Invasion” and was published in the Journal of the National Cancer Institute on June 16, 2004.