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Stopping cell movement in glioblastoma


Jessica Arden is a student earning both her Doctor of Medicine and Doctor of Philosophy in the University of Toledo College of Medicine and Life Sciences Biomedical Science Program.

Daniel Miller/University of Toledo Enlarge

This is one in a series of articles written by research students in the University of Toledo College of Medicine’s Biomedical graduate program exploring basic issues of human health.

Glioblastoma is an aggressive type of brain cancer that‘s difficult to treat, partly because the cancer cells are spread widely throughout the brain and tumors grow very quickly.

Because the cancer cells can move great distances, surgical removal of the tumor cannot be accomplished. Additionally, the cancer cells at the more distant sites are more difficult to kill with other treatments such as chemotherapy and radiation.

In an effort to treat glioblastoma, University of Toledo scientists and clinicians are trying to block these cells from moving. While no therapy has yet been found that successfully prevents this movement, there has been progress in better understanding the molecular processes that allow cancer cells to invade farther into the brain.

Movement of brain cancer cells (and all other cells that move within the body) is dependent on the cytoskeleton, a meshwork of fibers that give the cells shape and structure — much like the bones that make up our body’s skeletons. Unlike our skeletons of bone, these fibers are not permanent structures but instead are constantly formed and broken down. The focus of this research is to study one of the tools that builds these fibers, a protein called mDia.

Over the past several years, the research team at UT-College of Medicine and Life Sciences has studied how mDia proteins make some of the cytoskeletal fibers that are required for the “re-building” phase of cytoskeletal turnover, which helps cells to move through brain tissue. Research on this project has revealed that mDia building activity is necessary for glioblastoma cells to keep moving in a specific direction over time. This ability to move in one direction likely allows these cells to move along normal structures like blood vessels or bundles of nerves, which has been seen in patients.

Glioblastoma cells move along these structures much like cars driving along a highway. Just as cars must keep moving in one direction in order to move from one highway exit to another, glioblastoma cells also need to be able to move in a constant direction. This is an important tool that tumor cells need to spread throughout the brain.

Since mDia is needed for glioblastoma cancer cells to move forward, the research team tested whether specific drugs that target mDia could keep glioblastoma cells from moving. First, a drug was tested that turns mDia "off," which means that this drug keeps mDia from making fibers. When a large mass of tumor cells was treated with this drug, it caused cells to move more slowly but did not completely prevent the tumor cells from spreading. This suggests that while mDia is important for the way that brain cancer cells normally move, these cells have the ability to move in other ways that are not dependent on mDia.

The team tested a second drug that switches mDia "on," so that it is making fibers all of the time. Normally, mDia activity is carefully regulated, meaning it is only "on" and making fibers at controlled times. However, treating cells with the drug that turns mDia "on" forces cells to make too many fibers. Theoretically, if cells are full of fibers they should be so stiff that they will be unable to move. In fact, the team found that this drug blocks the ability of glioblastoma cells to spread away from a central mass.

The new drug has only been tested in cell cultures and rat tissue. Human trials would need to be conducted to verify its effectiveness.

Discovering that the drug that switches mDia "on" might be able to prevent glioblastoma from spreading throughout the brain could ultimately help treat patients who have this type of cancer.

Jessica Arden is a student earning both her Doctor of Medicine and Doctor of Philosophy in the University of Toledo College of Medicine and Life Sciences Biomedical Science Program. For more information, email eduArden@rockets.utoledo.Jessica. or go to​med/​grad/​biomedical.

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