A study led by Weill Cornell Medicine researchers shows that spinal vertebrae originate from a unique stem cell type that secretes a protein that favors tumor metastasis. This breakthrough paves the way for new research directions in spinal diseases, provides insights into why solid tumors often metastasize to the spine, and may lead to new orthopedic and cancer treatments.
In the study, published in Nature on September 13, researchers found that vertebrae are derived from a type of stem cell that is different from other bone-building stem cells. Using bone-like "organisms" made from spinal stem cells, they found that the known tendency of tumors to spread to the spine - rather than to long bones such as the leg bones - is largely due to a protein called MFGE8 secreted by these stem cells.
"We suspect that many orthopedic diseases that preferentially involve the spine are due to the unique properties of vertebral stem cells," said study senior author Matthew Greenblatt, MD, associate professor of pathology and laboratory medicine at Weill Cornell Medical Center, a member of the Sandra and Edward Meyer Cancer Center, and a pathologist at NewYork-Presbyterian/Weill Cornell Medical Center.
In recent years, Dr. Greenblatt and other scientists have discovered that different types of bone originate from different types of bone stem cells. Because vertebrae develop along a different path early in life than other bones, such as arm and leg bones, and appear to have a unique evolutionary trajectory, Dr. Greenblatt and his team hypothesized that there may be a unique type of spinal stem cell.
The researchers first isolated the well-known skeletal stem cells, which generate all bone and cartilage, from different bones in laboratory mice based on known surface protein markers of skeletal stem cells. They then analyzed the gene activity of these cells to see if they could find unique patterns of cells associated with the spine.
New stem cells that form the spine are transplanted into a model organism and allowed to form miniature vertebrae (red). Breast cancer tumor cells (green) invade bone, suggesting that this new spinal stem cell is responsible for recruiting breast cancer cells. Source: Sun Jun
This work resulted in two important findings. The first is that the overall new definition of skeletal stem cells based on surface markers is more accurate. This new definition excludes a group of non-stem cells included in the old stem cell definition, obscuring some previous research in the field.
The second finding is that skeletal stem cells from different bones do have systematic differences in gene activity. Through this analysis, the team identified a unique set of markers for spinal stem cells and confirmed the functional role of these cells in forming spinal bones in further experiments in mice and in experimental dish cell culture systems.
The researchers next examined the relative attractiveness of the spine compared with other types of bone for tumor metastasis, including breast, prostate, and lung cancer. Conventional theory in the 1940s suggested that this "spinal tropism" was related to blood flow patterns and that the spine was more susceptible to metastatic tumors than the long bones. But when the researchers reproduced the spinal tropism phenomenon in animal models, they found evidence that blood flow was not the cause—in fact, they found a clue pointing to spinal stem cells as the possible culprit.
"We observed that the initial seeding site of metastatic tumor cells was mainly in the bone marrow region, where spinal stem cells and their progeny cells are located," said Jun Sun, Ph.D., first author of the study and a postdoctoral researcher in Greenblatt's laboratory.
The team then found that removing spinal stem cells eliminated the difference in metastasis rates between spinal bones and long bones. Ultimately, they determined that spinal stem cells secrete more of the protein MFGE8 than long-bone stem cells and was a major factor in spine tropism. To confirm the relevance of these findings to humans, the team collaborated with researchers at the Hospital for Special Surgery to identify the human counterparts of mouse spinal stem cells and characterize their properties.
Researchers are currently exploring ways to block MFGE8 to reduce the risk of spinal metastasis in cancer patients. More broadly, Dr. Greenblatt said, they are studying how the unique properties of spinal stem cells contribute to spinal disease.
"There is a subspecialty within orthopedics called spinal orthopedics, and we believe that most conditions in that clinical category are related to this stem cell that we just identified," Dr. Greenblatt said.