Glioblastoma Tumor Removal can Actually Increase Growth

Glioblastoma Tumor Removal can Actually Increase Growth
August 26, 2016

Treating cancer is often described as a fight. That metaphor makes a lot of sense, as many cancers are difficult to beat into submission: they can push back and regrow during and after treatment and the treatments themselves can be as bruising to patients as they are to the cancer.

Cancer research can lead to the discovery of ways doctors and patients can punch harder and counter the hits coming from the cancer and therapy, but sometimes studying the opponent and the fight itself can be just as valuable.

A new study from UNC School of Pharmacy and the Lineberger Cancer Center at UNC is characterizing the fight against glioblastoma multiforme, an aggressive and deadly form of brain cancer that affects more than 20,000 Americans every year. The main finding: don’t hit him, you’ll just make him mad.

GlioblastomaShawn Hingtgen, a professor at the UNC School of Pharmacy, and Dr. Ryan Miller, a pathologist with UNC's Lineberger Cancer Center, found that surgically removing the main tumor from glioblastoma, which branches throughout the brain, makes the rest of the tumor more aggressive, causing it to grow more quickly. He published the study in the journal Neuro-Oncology.

"Surgery lights the resection cavity on fire," Miller said about the healing process after tumor removal surgery. "An unfortunate byproduct of this normal wound healing response is an increased proliferation of the tumor cells that remain after surgery."

Glioblastoma is a tumor of the brain’s glial cells, support cells that provide structure and other help to the neurons; the cells responsible for sending and receiving messages. Glioblastoma typically starts with the astrocytes, a common glial cell that makes up the blood-brain barrier among other things.

Roughly 90 percent of the cells in the brain are glial cells, so glioblastomas have plenty of places to spread to. They tend to start in the frontal or temporal lobes of the brain—near the forehead or temple—but this well-nourished and rapidly growing cancer can snake its arms away from the primary tumor.

Currently, there is no cure for glioblastoma but treatment often begins by surgically removing as much of the tumor as possible, followed by radiation and chemotherapy to try to hold the rest of the cancer at bay. Hingtgen wanted to see what the cancer was doing after surgery in order to work on a new post-operative treatment he and his group were developing.

To do this, Onyi Okolie, a graduate student in Hingtgen’s lab, implanted tumors in mice and let them grow to the point where they would begin experiencing symptoms. He then cut out about 90 percent of each tumor, which is about as much as doctors typically remove during surgery.

Okolie, Miller and Hingtgen then tracked what happened to the remaining tumor cells in the mice. Those remaining cells grew and multiplied up to 75 percent faster than they did before the surgery.

"This model shows the tumor after surgery is very different than the tumor before surgery," Hingtgen said. "And it is this 'post-surgery' tumor that is present in human glioblastoma patients."

After the surgery, non-cancerous astrocytes detected that the surgeon had been rooting around and pulling out what they perceive as healthy tissue. The astrocytes release chemicals that signal surrounding glial cells to grow and multiply faster than they normally would. That signal reaches the tumor cells as well, causing the cancer to go into overdrive.

GlioblastomaIt is not an uncommon response in nature to overcompensate growth after an injury. Native Americans in the Northeast found that if they burned a blueberry bush, it would produce more blueberries when it grew back. The blueberry bushes detected the serious injury and grew back more quickly. Farmers still use this technique today, pruning the bushes down to the root every few years because more blueberries will grow as a result.

According to the American Brain Tumor Association, the median survival time—the amount of time after which 50 percent of patients with a disease die—for glioblastoma treated with radiation and chemotherapy is 14.6 months. For a cancer with this type of prognosis, the fact that surgery just makes this aggressive cancer more aggressive seems like an overflow of bad news. Still, there is some optimism in the fight against glioblastoma.

First, according to the Mayo Clinic, removing even a piece of a tumor can help reduce the symptoms of glioma, the family of brain cancers to which glioblastoma belongs. Even if the cancer cells become more aggressive, there is still benefit to surgery.

Second, when Hingtgen started this experiment, he was working on a new type of stem cell treatment for glioblastoma. He and his colleagues are reprogramming skin cells into neural stem cells that can kill the cancer, and building a scaffold to hold them in place. So far, he has only worked in mice but survival times were increased by 160 to 220 percent depending on the type of tumor. In a few years, with more studies, this stem cell treatment could make its way to humans.

Third, by discovering exactly what goes on around the cancer cells after surgery, researchers can design therapies based on the post-surgical environment. Miller says that could be a new research paradigm for cancer drugs.

The fight against Glioblastoma is still difficult, but with more knowledge of how it punches, we're another step closer to winning that fight.

—Daniel Lane

Daniel covers science, medicine, engineering and the environment in North Carolina.