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Turning tumors’ tools on them in the fight against metastasis
BOSTON—Tumor cells may turn out to be their own worst enemies, as they may have given away one of the secrets to defeating cancer recurrence and reducing the incidence of metastasis. As reported in the online early edition of the Proceedings of the National Academy of Sciences during the week of June 22, researchers at Children's Hospital Boston have isolated a potent inhibitor of tumor metastasis that is made by tumor cells themselves and could possibly be harnessed as a cancer treatment.
In studying the migration of cancer cells to other parts of the body and trying to get a handle on reducing metastasis, which is one of the leading causes of death from cancer, Dr. Randoph S. Watnick, an assistant professor in the Vascular Biology Program at Children's Hospital, has found that metastatic tumors prepare "landing places" in distant organs by secreting certain proteins that encourage tumor growth and attract feeder blood vessels. With the help of his colleagues, he has now shown evidence that non-metastatic tumors secrete a protein called prosaposin that inhibits metastasis by causing production of factors that block the growth of blood vessels.
The team tested the hypothesis in breast, prostate and lung cancer in mice, and found that the localized tumors secreted high levels of prosaposin. Metastatic tumors, on the other hand, secreted very little.
When they injected the mice with tumor cells that were known to be highly metastatic, but to which prosaposin had been added, lung metastases were reduced by 80 percent and lymph node metastases were completely eliminated. In addition, survival time was significantly increased. When they suppressed prosaposin expression in tumor cells, they saw more metastases.
Watnick and colleagues also demonstrated that prosaposin stimulates activity of the well-known tumor suppressor p53 in the stroma, or connective tissue, surrounding tumors—which in turn stimulated production of thrombospondin-1, a natural inhibitor of blood vessel growth both in tumor stroma and in cells at distant locations.
"While we may not be able to keep patients from getting cancer, we can potentially keep them metastasis-free," Watnick notes, who is impressed by the mechanism of action that he and his colleagues have discovered. "This doesn't target cancer cells directly and it isn't antigen-specific. Finding this protein at all was a very welcome surprise, and being in the stroma is a completely novel finding; this isn't an area people have really thought of exploring or exploiting before."
Because of its mechanism of action, prosaposin should have a broad base of potential oncology indications, if it works in humans as hoped.
A patent has been filed by Children's Hospital Boston on the discovery, and the hospital's Technology and Innovation Development Office is in active discussions to license prosaposin for commercial development.
Watnick doesn't have any direct involvement with the licensing talks, but he has been told that several companies have been approached—and shown interest—ranging from Big Pharma to biotechs to small start-ups.
"We've done some correlation with a few other types of cancer to gauge prosaposin's potential, but one thing we hope is that with a company taking up a licensing deal, they can really pursue studies of various indications as broadly as possible," Watnick says.
Initially, according to Children's Hospital, Watnick's scientific interest was focused on metastatic cancer cells, and he had hoped to use proteomics techniques to isolate different proteins that steered metastases to different parts of the body. Such work could explain, for example, why lung cancer often metastasizes to bone and prostate cancer often metastasizes to the liver. But the late Dr. Judah Folkman, founder of the Vascular Biology program at Children's Hospital, reportedly encouraged him to focus on the metastasis inhibitor, prosaposin, telling Watnick: "You might have a drug right here."