Bone protein may lead to better treatments for virulent cancers
by C.W. Wolff

Research under way in a bustling laboratory on the sixth floor of the School of Dental Medicine may lead to therapies for regenerating periodontal bone. It also may produce a therapy for stopping or controlling the metastasis of breast or prostate cancer to bone.

In the world of molecular biology, where scientists sometimes follow a protein wherever it may lead them, these two destinations are not as far apart as they may seem.

Dr. Jinkun Chen © Kathleen Dooher

Bone sialoprotein (BSP), a major protein in bone and other mineralized tissue, has been the research focus for years of Dr. Jinkun (Jake) Chen, director of the Division of Oral Biology at the dental school.

Chen came to Tufts in the summer of 2002 with a track record of more than 100 published studies, a history of interdisciplinary research and expertise in creating transgenic mouse models. He also brought funding from the National Institutes of Health (NIH) for his ongoing research and two members of his current seven-member research team.

Chen’s lab was the first to demonstrate the presence of BSP in the earliest stages of bone formation. In fact, BSP, which is instrumental in mineralization of bone and tissue, is at its highest post-birth levels in the first two weeks of life when bones are continuing to develop. Those levels drop sharply after the first two weeks and thereafter are typically noticeable only in the regeneration of bone, for instance after a bone fracture.

One of the issues Chen’s lab is investigating is whether a lack of BSP causes deterioration of periodontal bone.

“People over age 40 often suffer periodontal bone resorption, especially if they have periodontal disease,” says Chen. “The gums recede; bone that holds the teeth in place is reabsorbed, and teeth may fall out. The bone does not regenerate. We don’t know why.”

Along with research on gene expression and regulation of tooth and bone formation, Chen is experimenting with tissue engineering, attempting to regenerate periodontal bone in mouse models. The research, supported by a $1.4 million grant from NIH, may be the first to use bone marrow stem cells to regenerate periodontal tissue. If the experiments are successful, the door may be opened to regenerating periodontal bone in patients by using their own bone marrow cells to grow new bone.

The cancer connection
Chen’s interest in bone metastasis was sparked by a 1994 study by a group of Belgian scientists that found BSP in human breast cancer cells—an unexpected discovery because BSP was thought to be limited to bone and other mineralized tissue.

BSP also was found in prostate cancer cells. Both breast and prostate cancers are more likely than other cancers to spread to bone. Bone lesions caused by metastasis are found in 90 percent of people who die of breast cancer, and higher BSP levels in breast cancer cells correlate to higher metastasis and death rates.

Chen and his colleagues used a novel approach, involving chicken embryos, to study in vivo the effect of BSP on human breast cancer cells’ ability to break into a blood vessel. They found BSP appeared to enhance that early step in metastasis, while the introduction of BSP antibodies hindered it.

Their most recent study focused on the role BSP might play in the “homing” of breast cancer cells to bone. The study, published earlier this winter in the International Journal of Oncology, supported a strong role for BSP and perhaps, even more exciting, a strong anti-metastasis role for a BSP antibody.

The experiment involved injecting 15 mice with human breast cancer cells. One group of five mice received cells with an over-expression of human BSP. The second group received cells that repressed BSP, and the third group had no extra BSP injected. Four weeks later, X-rays showed metastatic lesions on the leg bones of all of the mice in the first group, three of the mice in the control group and only one of the mice in the repressed-BSP group.