A PUBLICATION OF THE PATRICK C. WALSH PROSTATE CANCER RESEARCH FUND

A Protein Found Only in the Very Worst Prostate Cancers
May Lead to New Ways to Treat Them

What happens in cancer is, in many ways, very similar to what happens to our bodies before we’re ever born, when our cells are dividing rapidly and we’re growing like crazy. Thus, pathologist David Berman, M.D., Ph.D., has spent the last several years trying to understand how cancer spreads by looking back in time, to those embryonic days.

Just as plants and animals were different in prehistoric time — think dinosaurs and lots of giant ferns — in our own far less distant past, our cells were different, too. Before birth is the prime time for stem cells — tiny chameleons, known for their ability to change and assume the properties of other kinds of cells.

Nestin is a structural protein — part of the scaffolding that cells use to keep their shape — that’s widespread in embryos, but not often found in adult cells. Scientists have long used it as a marker of neural stem cells, hibernating cells that wake up in time of need and zoom to the rescue, to replace lost or injured cells. “We still don’t exactly understand Nestin’s function in stem cells,” says Berman, the R. Christian B. Evensen Scholar. But he and fellow pathologist Wolfram Kleeberger, M.D., knew that Nestin was produced by cancer cells, and decided to learn more about it.

Just as plants and animals were
different in prehistoric time —
think dinosaurs and lots of giant
ferns — in our own far less distant
past, our cells were different, too.

They looked at cells cultured from several different types of cancer, and found Nestin most often in prostate cancer cell lines. This is significant, because the cultured prostate cells that researchers use are hardened characters — absolute degenerates compared to the far easier- to-cure cancer cells found in most men who are diagnosed today with regular screening for prostate cancer. So advanced are most of these cells that they have passed the crucial point of being able to grow even without the male hormone, testosterone.

And there, in the midst of these worst-case prostate cancer cells, was Nestin. Kleeberger then broadened the search, looking for the protein in tissue samples from a variety of men — ranging from those who were cured by surgery to those who died of widespread metastatic disease. These samples were collected and organized by pathologists G. Steven Bova, Mehsati Herawi, Ai-Ying Chuang, and Jonathan Epstein, and urologist Matthew Nielsen. The team paid particular attention to whether men had been treated with hormone blockade, the most commonly used drug treatment for prostate cancer.

“What we found was surprising and intriguing,” says Berman. “Nestin was present exclusively in the most deadly cancers — the ones that had metastasized and failed hormone blockade.” Next, he and Kleeberger designed laboratory experiments using a new technology called “short hairpin RNA,” which allowed them to shut down the Nestin gene in prostate cancer. Kleeberger found that silencing Nestin “dramatically reduced the ability of cancer cells to migrate and invade in laboratory cultures, and to metastasize in mice,” Berman continues.

Then they asked a new question: What was it that stimulated cancer cells to start making Nestin in the first place? Kleeberger, looking at cells from a man with testosterone- dependent, metastatic prostate cancer, found that the simple act of depriving the cells of testosterone — which is what happens during hormonal therapy for prostate cancer — activated the Nestin gene.

Berman sees these results as both bad news and good news for men with advanced prostate cancer. “The bad news is the startling suggestion that testosterone blockade might actually speed up metastasis by inducing Nestin production,” he says. However, he is quick to caution that more studies are needed to explore this. “The good news is that Nestin now gives us a foothold for tackling metastasis in a new way.” Berman expects that further studies will reveal a whole group of proteins that work alongside Nestin to help cancers spread, and that these would be “prime targets for new or existing drugs that would block metastasis. The fact that Nestin production is limited to cancers and to a few rare cell types in the body suggests great possibilities for this approach.”

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