Why are cancers more likely to spread to spine?

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Unraveling the Mystery of Cancer Cells’ Affinity for Vertebrae! Scientists Discover a Novel Type of Vertebrae Stem Cells that Secrete Proteins to Attract Cancer Cells.

Tumor metastasis to other tissues and organs is a leading cause of cancer-related deaths. Bones, including the spine, are common sites for the metastasis of solid tumors like breast and prostate cancer. Interestingly, despite being part of the skeletal system, tumors preferentially metastasize to the vertebrae, rather than long bones such as the arms and legs.

In the 1940s, it was hypothesized that this preference was due to differences in blood flow. Forces similar to coughing were thought to affect blood circulation, causing cancer cells to migrate to the spine and establish new tumors.

This long-held belief, spanning 80 years, has now been overturned.

On September 14th, a new study by researchers from Weill Cornell Medicine and New York Special Surgery Hospital was published in the journal “Nature.”

Scientists discovered a novel type of vertebrae stem cell known as vertebral skeletal stem cells (vSSC). These cells express a secreted protein called MFGE8, which has the ability to attract cancer cells and promote their growth.

This finding partially explains why tumors exhibit a preference for the vertebrae during bone metastasis.

Why are cancers more likely to spread to spine?

In fact, despite both being part of the skeletal system, vertebrae and long bones have different developmental origins and physiological characteristics. Therefore, researchers speculate that vertebrae and long bones may have distinct mechanisms of formation, which could contribute to the development of certain vertebrae-related diseases.

Researchers isolated typical bone stem cells from long bones and vertebrae and conducted transcriptome analysis. They found significant differences in the transcriptome between long bone stem cells (lbSSC) and vertebrae stem cells.

In their analysis, researchers identified embigin (EMB) as a notable cell marker that can distinguish non-stem cells from bone-forming and cartilage-forming cells within the defined bone stem cell population. This discovery is invaluable for defining the immune phenotype of bone stem cells.

By comparing the differential genes between long bone stem cells and vertebrae stem cells, researchers ultimately identified two transcription factor genes, Zic1 and Pax1, which drive the expression of specific markers in vertebrae stem cells and can be used as markers for these cells.

Vertebrae stem cells play a crucial role in the development of the spine. Researchers specifically deleted the osteogenic transcription factor osterix from these cells, resulting in severe vertebral defects in mice. These defects included severe spinal curvature, the loss of most dorsal neural arches, a 50% reduction in bone mass, and complete paralysis in 100% of the mice.

However, some residual vertebrae remained in the mice, suggesting the existence of other vertebrae stem cells.

Why are cancers more likely to spread to spine?

Vertebral stem cell dysfunction causes vertebral agenesis in mice

Given that vertebrae stem cells are responsible for vertebral formation, they are likely to be involved in diseases that primarily affect the vertebrae, such as tumor metastasis to the spine.

Researchers injected breast cancer cells such as EO771, 4T1.2, and Py8119 into mice to create a spontaneous metastasis model. As expected, they observed more initial seeding cancer cells in the vertebrae, and this was independent of changes in blood flow.

Furthermore, when researchers transplanted long bone stem cells and vertebrae stem cells to create bone-like organs in the mice’s legs, they found that the organs derived from vertebrae stem cells had a higher rate of tumor cell infiltration. In other words, their ability to recruit metastatic cancer cells was greater.

Why are cancers more likely to spread to spine?

Vertebral stem cells more likely to attract cancer cells to metastasize

Further analysis revealed that the key factor at play was the secretion of milk fat globule epidermal growth factor 8 (MFGE8) by vertebrae stem cells. MFGE8 expression was higher in vertebrae stem cells compared to long bone stem cells, but there was no significant difference in its expression among other bone cell types, such as osteoclasts, endothelial cells, and various white blood cells.

MFGE8 effectively induced the migration of breast cancer, prostate cancer, and lung cancer cells. When Mfge8 was knocked out in mice, the differential migration-inducing abilities of long bone stem cells and vertebrae stem cells on cancer cells were no longer significant.

There is no difference in the ability of backbone stem cells to induce migration after knocking out Mfge8

Moreover, MFGE8 not only influenced cancer cell migration but also promoted cancer cell growth after metastasis. When Py8119 cells were injected into the L6 vertebrae of Mfge8 knockout mice, cancer cell growth was less pronounced compared to the control group.

Researchers believe that this study’s significance goes beyond understanding the mechanism behind the preference for spinal metastasis in cancer. It may also provide new insights into other spinal disorders. Many clinical spinal issues may find answers in vertebrae stem cells.

Currently, researchers are exploring methods to block MFGE8, which may potentially reduce the risk of spinal metastasis in cancer patients.

References:

[1] Sun, J., Hu, L., Bok, S. et al. A vertebral skeletal stem cell lineage driving metastasis. Nature (2023). https://doi.org/10.1038/s41586-023-06519-1

[2] https://www.nature.com/articles/d41586-023-02851-8

[3] https://www.nature.com/articles/d41586-023-02768-2

[4] https://news.weill.cornell.edu/news/2023/09/study-reveals-why-cancer-may-spread-to-the-spine