Scientists have discovered a new type of stem cell in the spine that appears crucial to resolving a long-standing mystery: why far more cancer cells spread to the spine than to other bones in the body.
When breast, lung and prostate cancers metastasise to multiple bones in the body, three to five times more cancer winds up in the spine than in the lower and upper limbs. Scientists have known of this disparity for decades, but the reason for it has remained unclear, The Washington Post reports.
One theory held that differences in blood flow might be the cause. But the latest findings suggest an alternative that could have implications for cancer care, spine fusion surgery and osteoporosis.
Stem cells are like the body’s raw materials. They can divide and form more stem cells, or develop to reach a more specific destiny as skin, red blood cells, neurons or any of the estimated 200 different cell types in the human body.
In the journal Nature, researchers from Weill Cornell Medicine and the Hospital for Special Surgery in New York report the discovery of what they have called vertebral skeletal stem cells in the spine.
These cells make a protein that acts as a “come here” signal to tumour cells, a finding that raises new treatment possibilities.
“We predict this discovery will lead to the targeting of these cells to disrupt the function and ultimately reduce the spread of cancer to the spine,” said Matthew Greenblatt, one of the study’s authors and a pathologist at Weill Cornell Medicine.
In work spanning five years, scientists found the cells first in mice, then in humans. The cells, which are responsible for bone formation in the vertebrae, appear as the bone hardens.
To demonstrate the crucial role of vertebral skeletal stem cells, researchers developed a mouse from which they could snip out some of its DNA. Using an enzyme, they removed a specific bone-forming gene from the newly discovered vertebral stem cells.
Mice that had the gene removed displayed clear spinal defects, proving the importance of the new stem cells in forming the spine.
Scientists then transplanted the stem cells into the leg muscle of a mouse. The transplanted cells made new miniature bones from scratch, and produced all of the types of skeletal cells that are found in the spine. Researchers concluded that the vertebral skeletal stem cells help to form the spine before birth, then help maintain it after birth.
To find the same stem cells in humans, researchers studied very small pieces of vertebrae removed during laminectomies, surgeries that relieve pressure on the nerves and spinal cord.
“It’s very rare you find a new stem cell, which is one of the things that makes us excited about this,” Greenblatt said. “We think there are more to discover.”
By comparing the stem cells that form spinal bone with those that form limb bones, they discovered one protein that is made at much higher levels in the vertebrae. Mice that lacked this protein experienced far less cancer spreading to their spines.
Feini Qu, a core faculty member at the University of Washington’s Institute for Stem Cell and Regenerative Medicine, called the study “a breakthrough that helps us understand the developmental origin of the vertebrae”.
Qu, who was not involved in the project, added that the research “might help us understand ways to be more creative” in slowing or stopping spinal metastasis.
Sean Morrison, founding director of the Children’s Research Institute at UT Southwestern Medical Centre in Dallas, said he considered the cells described by the researchers to be skeletal stem cells, a type whose existence has been known about for years.
But Morrison, who is also an investigator for Howard Hughes Medical Institute, added that the paper still shows skeletal stem cells found in different parts of the body have somewhat different properties.
“The skeletal stem cells in the vertebrae have a surprising capacity to attract cancer cells that you don’t see in other skeletal stem cells,” he said.
C Rory Goodwin, a neurosurgeon and spine surgeon at Duke Health, commended the paper’s authors and said the discovery of the stem cells may help researchers improve the poor outlook for cancer patients whose disease has spread to the spine.
“When patients have spine metastasis, that’s usually toward the end of the line,” Goodwin said. Average survival, he said, was between 10 and 14 months once cancer reaches the spine, “with some patients surviving much less than that.”
In addition, the discovery provides an explanation for why osteoporosis varies significantly in the spine vs other parts of the skeleton. This knowledge could help doctors tailor treatment of the disease when it appears in the spine.
In separate work, Greenblatt and his co-author on the Nature paper, a spine surgeon at the Hospital for Special Surgery, are investigating the role the new stem cell plays in responding to spine fusion surgery. They want to determine whether an implant of the new stem cell at the time of surgery can improve fusion.
The two scientists also suspect there may be a second type of vertebral skeletal stem cell. When they blocked the ability of the new stem cell to form bone, they still found small amounts of bone in some regions of the spine, raising the question of whether a second stem cell type might be responsible.
Study details
A vertebral skeletal stem cell lineage driving metastasis
Jun Sun, Lingling Hu, Sravisht Iyer, Matthew Greenblat, et al.
Abstract
Vertebral bone is subject to a distinct set of disease processes from long bones, including a much higher rate of solid tumour metastases1,2,3,4. The basis for this distinct biology of vertebral bone has so far remained unknown. Here we identify a vertebral skeletal stem cell (vSSC) that co-expresses ZIC1 and PAX1 together with additional cell surface markers. vSSCs display formal evidence of stemness, including self-renewal, label retention and sitting at the apex of their differentiation hierarchy. vSSCs are physiologic mediators of vertebral bone formation, as genetic blockade of the ability of vSSCs to generate osteoblasts results in defects in the vertebral neural arch and body. Human counterparts of vSSCs can be identified in vertebral endplate specimens and display a conserved differentiation hierarchy and stemness features. Multiple lines of evidence indicate that vSSCs contribute to the high rates of vertebral metastatic tropism observed in breast cancer, owing in part to increased secretion of the novel metastatic trophic factor MFGE8. Together, our results indicate that vSSCs are distinct from other skeletal stem cells and mediate the unique physiology and pathology of vertebrae, including contributing to the high rate of vertebral metastasis.
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