Science Editor

Though it is metastases that ultimately kill most cancer patients, the majority of cancer drugs continue to be directed against primary tumors. Part of the reason is that metastases often have more in common with their tumor of origin than with each other.

But a paper in the June 23, 2009, online edition of the Proceedings of the National Academy of Sciences reported on a protein that affects the metastatic potential of tumors across a range of tumor types: prosaposin, a secreted protein that makes tissues less hospitable to invading tumor cells by activating the angiogenesis inhibitor thrombospondin-1.

The authors set out to find more general regulators of metastasis by comparing the protein expression profiles of several breast and prostate cancer cell lines, and found one candidate that held up over all cell lines studied. "As tumor cells became more metastatic, there was a precipitous drop in thrombospondin-1 in both the tumor and the tumor-associated stroma," senior author Randolph Watnick told BioWorld Today. Watnick is assistant professor of vascular biology at Children's Hospital Boston; the study's authors hail from Children's Hospital, Harvard University and the University of Bergen in Norway.

The same relationship held when tumor cells were injected into mice; the higher the expression of thrombospondin-1 in stromal tissue, the fewer lung metastases both breast and prostate cancer cells were able to form.

Thrombospondin-1 is sort of the opposite of VEGF, an antiangiogenic protein that inhibits blood vessel formation through its effects on cell adhesion proteins. It also is regulated by p53, myc and RAS, putting it, the authors wrote in their paper, "at a critical nexus of tumor suppressors and oncogenes."

The authors next searched for factors that could induce thrombospondin-1 expression in the stroma, and found that tumors apparently switch on thrombospondin-1 by secreting the protein prosaposin. Prosaposin activates p53, a transcription factor that is a potent tumor suppressor. P53, in turn, activates transcription of thrombospondin-1.

While the idea that cancer cells secrete a factor that keeps them from spreading may at first seem counterintuitive, Watnick said that the reason is probably to be found in the tumor's changing needs as it grows.

Prosaposin is a precursor protein that usually is cleaved into four smaller proteins. Those that are important for lipid hydrolysis - and tumors in the early growth stages are "critically dependent" on lipid hydrolysis for growth and energy, Watnick said. As tumors grow, their requirements change. Aggressive tumors are most likely the ones that find a way to turn off prosaposin once they become less dependent on lipid hydrolysis, he explained.

Watnick and his colleagues are testing how general prosaposin's relationship to metastasis is; he said that levels of the protein are inversely correlated with metastatic potential in at least two other types of carcinomas, suggesting that a therapeutic approach based on prosaposin could be broadly useful - though not universally so. A report last year found that the protein does not affect the metastatic potential of skin cancers.

Watnick cautioned that much work remains to be done on the basic biology of prosaposin before it will be clear whether prosaposin, or the pathway it is a part of, would make a good antimetastatic agent. That said, he added, Harvard's technology transfer office is "always interested" in talking to industry about potential collaborations.

In a press release announcing the findings, Children's Hospital said that a patent had been filed on the discovery, and that "the hospital's Technology and Innovation Development Office is in active discussions to license prosaposin for commercial development."