The Patrick C. Walsh Prostate Cancer Research Fund   

A New “Twist” in Fighting Metastasis   

prostate cancer
Laiho: Seminal vesicles may 
hold the key for protecting 
the prostate from cancer.

When it begins, as cancers go, prostate cancer is not that bad. It’s contained within the prostate, and in its early stages, its cells are fairly orderly-looking under the microscope. But metastatic cancer is a different animal. Its cell borders become increasingly ragged and blobby, as the cancer divests itself of the things that once made it a lawabiding citizen. What happens to these cells? What makes them change so much? And here’s the million-dollar question: Could it be possible to redeem these cells – to give them a “do-over,” a second chance at good behavior? 

This thing that happens – metastasis, when cancer cells migrate from the original tumor site and set up shop at distant sites – is what turns prostate cancer into a deadly disease. “There is a process,” explains radiation oncologist Phuoc Tran, M.D., Ph.D., “called epithelial-mesenchymal transition (EMT).” EMT changes cancer cells, strips them down into efficient killing machines and makes them much more able to pick up and go to new parts of the body. “This process causes cells that are part of tightly bound and well-ordered tissue to behave like cells that are less organized and more motile.” EMT is important in normal development, Tran adds, “but it is hijacked by cancer cells in order to gain functions that are important to their ability to undergo metastasis.” Picture a staid vehicle – maybe a dependable-looking minivan – that suddenly shucks its exterior, and underneath is a menacing roadster, built for speed and looking for trouble. “Cells that have undergone EMT are much better able to go to distant body sites.” 

Could it be possible to redeem metastatic cells – 
to give them a “do-over,”
a second chance at good behavior?

Tran’s work is a testament to how far we have come in the fight against prostate cancer. Once, there was metastasis, and we watched it happen, feeling powerless. Then, we began to understand that metastasis is not one invincible enemy, but a process, with intricate but definable steps. One of these specific steps is EMT. And even this can be broken down into smaller steps – each a potential chink in the armor of metastatic cancer, a possible target for new strategies and weapons. “TWIST 1 is an important protein that drives EMT,” says Tran , The Phyllis and Brian L. Harvey Scholar. “It changes the way that genes are turned on and off. A major goal of our lab is to better predict and treat men whose tumors are more likely to metastasize by understanding the pathways and mechanisms involved in TWIST 1 protein activity.” 

Tran and colleagues have shown that TWIST 1 is present in “abnormally high amounts” in prostate cancer cells. Further, “these TWIST 1 levels increase with the Gleason score, or the aggressiveness of the prostate cancer cells,” he says. In mouse models, they have engineered prostate cancer cells that contain high levels of TWIST 1. “We have observed that TWIST 1 causes prostate cancer cells to have more metastatic ability, and found important regions of TWIST 1 that are responsible for this ability. We are now actively searching for compounds and methods to inhibit TWIST 1, with the ultimate goal of improving prostate cancer care.”

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