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05Jul 2017

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Brain tumor activates asphalt machine

Glioblastoma invasion casein kinase 2 inhibitor Cell Reports July 5th 2017

Brain tumor cells can develop the ability to manufacture their own molecular road for spreading across the brain. Researchers of René Bernards' group at the Netherlands Cancer Institute discovered this mechanism and published their findings in Cell Reports on July 5th.

Tumor cells in the brain face a difficult challenge when they want to invade other parts of the brain. Most cells need a substrate to be able to move, like the extracellular components collagen and fibronectin. Unlike other organs, the brain lacks these molecular structures.

Researchers of the Netherlands Cancer Institute investigated how cells of the most common and aggressive type of primary brain tumor glioblastoma manage to spread throughout the brain. Patients with glioblastoma face a very poor prognosis: less than 1 in 10 of them is still alive after 2 years.

The researchers tested glioblastoma cells and their ability to migrate through tissue slices of mouse brain. They developed this 3D-model specifically to study the invasive behavior of glioblastoma cells in a physiological relevant context. Not only did they discover that the cancer cells that were able to move to other parts were expressing their own collagens, it also became clear that cells could develop this ability over time. Further experiments showed that being able to express collagens was indeed responsible for the capacity to move.

"This means that glioblastoma cells can have their own asphalt machine that allows them to move to other parts of the brain", says group leader Rene Bernards. "They express and excrete collagens, and use them as their personal road through the brain. It surprised me that collagens, proteins that are considered to be a bit boring, are a critical ingredient for invasiveness."

This mechanism of invasion through collagen production may seem an interesting therapeutic target for glioblastoma treatment, since an inhibitor of the signal route involved is already available. This casein kinase 2 (CK2) inhibitor CX4945 indirectly allows interferon regulatory factor 3 (IRF3) to block collagen production and thereby reduce the spreading capacity of cancer cells. Bernards: "The development of this drug was stopped after unsuccessful early clinical trials in patients with other cancer types. Testing this compound for applications in glioblastoma might be useful. However, the problem is that invasion has already occurred at the time of diagnosis. That's why I doubt that this approach will become clinically relevant. The main value of our findings lies in the discovery of how cells can reprogram to become invasive."

 

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