Protein Suppresses Prostate Cancer Metastasis

A protein whose function is lost in a broad array of cancers normally suppresses prostate cancer metastasis, researchers have shown in studies with mice. Testing for loss of the protein, called Protein 4.1B, could help clinicians predict which cancers are likely to spread.

Led by Howard Hughes Medical Institute investigator Richard O. Hynes, the researchers published their findings the week of July 16, 2007, in the online Early Edition of the Proceedings of the National Academy of Sciences. Besides Hynes and his colleagues at the Massachusetts Institute of Technology, other co-authors were from The Wistar Institute and Tufts School of Veterinary Medicine. “If you determine that a tumour shows reduced levels of Protein 4.1B, one would know to worry more about it metastasizing and plan treatment accordingly.”Richard O. Hynes Protein 4.1B is a member of a family of similar proteins, many of which link proteins in the cell membrane to the cell’s internal cytoskeleton. Other researchers had shown that Protein 4.1B function is frequently lost in an array of cancers, including brain, lung, and breast cancers. Hynes and his colleagues had shown that the protein was also lost in highly metastatic prostate cancer cells. To test how loss of Protein 4.1 affected tumours in living animals, the researchers implanted clumps of human prostate cancer tumours into the prostates of mice-a process called orthotopic implantation. “This technique of transplanting tumours is more representative of a real tumour than just implanting them under the skin,” explained Hynes. “Since the tumour is implanted in the prostate, where it normally would be, it metastasizes as it normally would, with cells detaching and invading other tissues.” From these mice, the researchers isolated variants of prostate cancer cells that showed different metastatic potential. A genetic comparison of the cells revealed that the highly metastatic cells had lost Protein 4.1B gene activity. What’s more, when the researchers suppressed the Protein 4.1B gene in poorly metastatic cells, they became highly metastatic. The researchers also eliminated the gene for Protein 4.1B in mice engineered to spontaneously develop prostate cancer – a particularly good model of prostate cancer, Hynes said, because tumours in the mice mimic human cancers as they progress from early tumour formation to metastasis. When he and his colleagues knocked out the gene for Protein 4.1B, these mice produced more invasive cancers. Studies of the metastatic cancer cells in the mice revealed that they did not divide more rapidly than cells with Protein 4.1B. Rather, their study suggests that Protein 4.1B normally triggers death in metatstatic cells, thereby preventing cancer from spreading. The findings in mice are likely relevant to human prostate cancers, said Hynes, because other researchers had found Protein 4.1B to be reduced in metastatic prostate cancers, compared to normal prostate tissue. “Our findings show that Protein 4.1B loss is causally related to the progression of prostate cancer,” said Hynes. “Although such a causal link has not yet been shown in other cancers, we also believe that Protein 4.1B is a more widely significant factor in metastasis in other cancers than has been realized.” Hynes said that a clinical test for Protein 4.1B activity could be useful as part of a panel of genetic tests to assess the metastatic potential of prostate cancers. “If you determine that a tumour shows reduced levels of Protein 4.1B, one would know to worry more about it metastasizing and plan treatment accordingly,” he said. (Source: Proceedings of the National Academy of Sciences Howard Hughes Medical Institute : September 2007)