Researchers at Children’s Hospital Boston have identified a potent suppressor of tumor metastasis. The compound, a protein called prosaposin, is itself produced by tumors and triggers the body to cut off nourishment to other, newly formed tumors.
The findings, published in the July 21 Proceedings of the National Academy of Sciences, could lead to drugs that render a tumor harmless by preventing its spread, thereby blocking a key step in the progression toward malignancy.
Senior author Randolph Watnick, an HMS assistant professor of surgery in the Vascular Biology Program at Children’s, was initially motivated by the age-old puzzle of metastasis. Why do certain patients survive after a tumor is surgically removed, while other, similar patients die after surgery because tumors invade all parts of their body?
An answer began to emerge when Watnick, collaborating with first author Soo-Young Kang, a research fellow in the Vascular Biology Program, discovered in mice elevated levels of the protein thrombospondin-1 (Tsp-1) in the tissue around tumors known to be non-metastatic. Conversely, mice containing metastatic tumors displayed low levels of Tsp-1. Realizing that this pattern could be explained by the presence of an unknown molecule secreted by the tumors, the researchers applied a combination of chromatography and short hairpin RNA to isolate the mystery compound from the tumors. They found prosaposin.
What is remarkable about prosaposin, according to the researchers, is the novel mechanism behind its cancer-fighting powers. Instead of targeting tumors directly, the protein coaxes cells in the stroma, a type of connective tissue that is abundant throughout the body, to produce Tsp-1. In turn, Tsp-1 blocks angiogenesis, or blood vessel formation, in budding tumors. Without nutrients carried by the blood, the growth of new tumors is stunted or forestalled completely. The effect on metastasis is dramatic. In lab tests, mice injected with prosaposin exhibited 20 times fewer tumors than untreated control mice.
“Other proteins have been found to inhibit metastasis, but they directly prevent migration of tumor cells or act on nearby tissue to prevent blood vessel growth,” said Watnick. “Prosaposin is the first protein that fights metastasis by indirectly blocking angiogenesis.”
Children’s Hospital has filed a patent on prosaposin with the intent of licensing the compound for commercial development. Watnick and his collaborators are currently working to identify the specific regions responsible for the anti-metastatic effects. They have also isolated a compound that performs the opposite function of prosaposin in a set of experiments pending publication.
Students may contact Randolph Watnick at randy.watnick@childrens.harvard.edu for more information.
Conflict Disclosure: The authors declare no conflicts of interest.
Funding Sources: Gackstatter Foundation, National Aeronautics and Space Administration, Department of Defense; the content of the work is the responsibility solely of the authors.
