high-grade glioma

Brain stem cells unintentionally talk with brain tumors, allowing their spread

/ Todd Dubnicoff / Leave a comment

A stem cell’s capacity to lay quiet and, when needed, to self-renew plays a key role in restoring and maintaining the health of our organs. Unfortunately, cancer stem cells possess that same property allowing them to evade radiation and chemotherapy treatments which leads to tumor regrowth. And a CIRM-funded study published today in Cell shows the deviousness of these cancer cells goes even further. The Stanford research team behind the study found evidence that brain stem cells, which normally guide brain development and maintenance, unintentionally communicate with brain cancer cells in deadly tumors, called gliomas, providing them a means to invade other parts of the brain. But the silver lining to this scary insight is that it may lead to new treatment options for patients.

High grade gliomas do not end well
The most aggressive forms of glioma are called high grade gliomas and they carry devastating prognoses. For instance, the most common form of these tumors in children has a median survival of just 9 months with a 5-year survival of less than 1%. Surgery or anti-cancer therapies may help for a while but the tumor inevitably grows back.

MRI image of high grade glioma brain tumor (white mass on left). Image: Wikipedia

Researchers have observed that gliomas typically originate in the brain stem and very often invade a brain stem cell-rich area, called the subventrical zone (SVZ), that provides a space for the therapy-resistant cancer stem cells to hole up. This path of tumor spread is associated with a shorter time to relapse and poorer survival but the exact mechanism wasn’t known. The Stanford team hypothesized that SVZ brain stem cells release some factor that attracts the gliomas to preferentially invade that part of the brain.

To test this chemo-attraction idea, they mimicked cancer cell invasion in a specialized, dual compartment petri dish called a Boyden chamber. In the bottom compartment, they placed the liquid food, or media, that SVZ brain stem cells had been grown in. On the upper compartment, they placed the cancerous glioma cells. A porous, gelatin membrane between the two compartments acts as a barrier but allows the cells to receive signals from the lower compartment and migrate down into the media if a chemoattractant is present. And that’s what they saw: a significant glioma cell migration through the gelatin toward the brain stem cell media.

Boyden chamber assay. Image: Integr. Biol., 2009,1, 170-181

Pleiotrophin: an unintentional communicator with brain cancer cells
Something or somethings in the SVZ brain stem cell media had to be attracting the glioma cells. So, the Stanford team analyzed the composition of the media and identified four proteins that, when physically complexed together, had the same chemo-attraction ability as the media. They were pleased to find that one of the four proteins is pleiotrophin which is known to not only play a role in normal brain development and regeneration but also to increase glioma cell migration. And in this study, they showed that higher levels of pleiotrophin are present in the SVZ brain stem cell area compared to other regions of the brain. They went on to show that blocking the production of pleiotrophin in mice reduced the invasion of glioma cells into the SVZ region. This result suggests that blocking the release of pleiotrophin by brain stem cells in the SVZ could help prevent or slow down the spread of glioma in patients’ brains without the need of irradiating this important part of the brain.

The silver lining: hsp90 inhibitors have therapeutic promise

Michelle Monje, MD, PhD

To further explore this potential therapeutic approach, the team examined hsp90, one of the other three proteins complexed with pleiotrophin. Though it doesn’t have chemoattractant properties, it still is a necessary component and may act to stabilize pleiotrophin. It also turns out that inhibitors for hsp90 have already been developed in the clinic for treating various cancers. When the researchers in this study blocked hsp90 production in the SVZ region of mice, they observed a reduced invasion of glioma cells. Though clinical grade hsp90 inhibitors exist, team lead  Michelle Monje, MD, PhD – assistant professor of neurology, Stanford University – tells me that some tweaking of these drugs will be necessary to reach gliomas:

“Our challenge is to find an hsp90 inhibitor that penetrates the brain at effective concentrations.”

Once they find that inhibitor, it could provide new options, and hope, for people diagnosed with this dreadful cancer.

Brain’s Own Activity Can Fuel Growth of Deadly Brain Tumors, CIRM-Funded Study Finds

/ cirmweb / Leave a comment

Not all brain tumors are created equal—some are far more deadly than others. Among the most deadly is a type of tumor called high-grade glioma or HGG. Most distressingly, HGG’s are the leading cause of brain tumor death in both children and adults. And despite extraordinary progress in cancer research as a whole, survival rates for those diagnosed with an HGG have yet to improve.

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But recent research from Stanford University scientists could one day help move the needle—and give renewed hope to the patients and their families affected by this devastating disease.

The study, published today in the journal Cell, found that one key driver for HGG’s deadly diagnosis is that the tumor can be stimulated to grow by the brain’s own neural activity—specifically the nerve activity in the brain’s cerebral cortex.

Michelle Monje, senior author of the study that was funded in part by two grants from CIRM, was initially surprised by these results, as they run counter to how most types of tumors grow. As she explained in today’s press release:

“We don’t think about bile production promoting liver cancer growth, or breathing promoting the growth of lung cancer. But we’ve shown that brain function is driving these brain cancers.”
 


By analyzing tumor cells extracted from HGG patients, and engrafting it onto mouse models in the lab, the researchers were able to pinpoint how the brain’s own activity was driving tumor growth.

The culprit: a protein called neuroligin-3 that appeared to be calling the shots. There are four distinct types of HGGs that affect the brain in vastly different ways—and have vastly different molecular and genetic characteristics. Interestingly, says Monje, neuroligin-3 played the same role in all of them.


What was so disturbing to the research team, says Monje, is that neuroligin-3 is an essential protein for overall brain development. Specifically, it helps maintain healthy growth and repair of brain tissue over time. In order to grow, HGG tumors hijack this critical protein.

The research team came to this conclusion after a series of experiments that delved deep into the molecular mechanisms that guide both brain activity and brain tumor development. They first employed a technique called optogenetics, whereby scientists use genetic manipulation to insert light-sensitive proteins into the brain cells, or neurons, of interest. This allowed scientists to activate these neurons—or deactivate them—at the ‘flick of a switch.’

When applying this technique to the tumor-engrafted mouse models, the team could then see that tumors grew significantly better when the neurons were switched on. The next step was to narrow it down to why. Additional biochemical analyses and testing on the mouse models confirmed that neuroligin-3 was being hijacked by the tumor to spur growth.

And when they dug deeper into the connection between neuroligin-3 and cancer, they found something even more disturbing. A detailed look at the Cancer Genome Atlas (a large public database of the genetics of human cancers), they found that HGG patients with higher levels of neuroligin-3 in their brain had shorter survival rates than those with lower levels of the same protein.

These results, while highlighting the particularly nefarious nature of this class of brain tumors, also presents enormous opportunity for researchers. Specifically, Monje hopes her team and others can find a way to block or nullify the presence of neuroligin-3 in the regions surrounding the tumor, creating a kind of barrier that can keep the size of the tumor in check.