OTTAWA—Among the many potential uses of neural stem cells, the most promising and attainable may be for enhancing the treatment of brain tumors, according to Evan Snyder, MD, PhD. Neural stem cells’ ability to migrate to areas of pathology and home in on a tumor, coupled with delivery of a gene product, may make them the ideal vehicle in brain tumor therapy.

“Neural stem cells are not meant to replace any of the other therapies [for brain tumors],” said Dr. Snyder, who is Program Director of the Burnham Institute in La Jolla, California. “This would simply be one way to augment some of those that exist. The bonuses of the neural stem cell are that if you use the right gene, it has a built-in suicide mechanism that can access the tumors even if injected far away. You can readminister them as necessary, and even if they provoke an immune response, so what? That’s all the better.” Dr. Snyder made his presentation at the 33rd National Meeting of the Child Neurology Society.

Before effectively realizing the therapeutic potential of neural stem cell therapy, one must understand the biology behind it, noted Dr. Snyder. One hypothesis concerning that biology is that “at least in the nervous system, stem cells and brain tumors may actually be two sides of the same coin,” he offered. “I almost like to think of brain tumors as Jedi knights that have gone to the dark side. They have so much of the same fundamental biology. Also, cross-talk between stem cells and the brain actually may [help lead to] therapeutic opportunities.”

It was during pediatric stem cell research that investigators first demonstrated the brain’s plasticity. Some of that plasticity was nestled in a cell that came to be called a neural stem cell, which then spawned a rich diversity of cell types. “It’s kind of interesting that we are starting to contemplate that [perhaps] the same cells may be the ones that ultimately, if the Jedi knight goes to the dark side, become tumors,” said Dr. Snyder. “However, they harbor a very similar biology. The fact that the cells can give rise to a wide range of mature cell types means that if you take them—and I’m going to use mouse and human stem cells interchangeably—and put them in the developing mouse brain, they will integrate throughout the brain in a seamless fashion, giving rise to a rich diversity, kind of a heterogeneity, of cell types, which talk to each other. It’s suggested that reconstructing the brain means not only giving rise to neurons but also the various supports that surround them. This is at the heart of stem cell biology, at least for brain repair. It’s also shown that stem cells, especially when one did a transplant, seemed to home in to where pathology was. When they found pathology, there seemed to be kind of an interaction in stem cell change and recipient change, based to a large degree on cross-talk. It was based on harnessing some of that biology that we started thinking about what would the therapeutic opportunities for stem cells be.”

STEM CELLS AND PATHOLOGY

Dr. Snyder collaborated with Karen Aboody, MD, and others to establish an experimental brain tumor in the cerebrum of an adult mouse, where they placed neural stem cells. “If you took the stem cells right at the heart of the brain tumor, within 48 hours they would fill out the brain tumor and appeared to come to a screeching halt right at the edge of where the brain tumor interfaced with normal tissue, except under one circumstance,” said Dr. Snyder. “The invading brain tumor cell has a neural stem cell, which jumped on top of it, almost like a sheriff riding a bad guy out of town, expressing its foreign gene in direct juxtaposition to the brain tumor cell. Even very virulent tumors promoted the same kind of response.”

The researchers then tested how robust this phenomenon was by establishing the tumor on one side but placing the neural stem cells on the opposite side. When looking at the corpus colostrum, they noticed a classic migratory profile, one that was moving in the direction of the brain tumor. “After a while [Dr. Aboody] looked at the brain tumor and saw the blue-stained cells infiltrating the brain tumor,” said Dr. Snyder. “The only source of these blue cells had to have been the neural stem cells on the opposite side. Human neural stem cells did exactly the same thing.”

Neural stem cells also present other opportunities for enhancing preexisting antitumor therapies, noted Dr. Snyder, one being viral vector–mediated gene therapy. “The one problem with that has been mostly delivery—getting the vector to find the tumor, particularly when the tumor is so infiltrative and so migratory,” said Dr. Snyder. “We just wondered what would happen if instead of your normal packaging line, which is usually a fibroblast and tissue culture incubator, what if the packaging cells themselves were these engrafted migratory neural stem cells? So rather than a fibroblast, we would have these cells be a launching pad for these viral vectors. And that, in fact, turned out to be a very effective and feasible way of doing that.”

MECHANISMS OF MIGRATION

The molecular basis of this migratory pattern of neural stem cells is beginning to be understood, and it extends beyond biology, noted Dr. Snyder. “There could be things made by the tumor itself, factors directly coming from the tumor, perhaps factors emanating from the blood vessels, particularly, neovascularization of the blood vessels,” he offered. “Maybe, simply, these [cells] are cotravelers. Stem cells harbor so much of the same biology as brain tumor cells, and maybe they are just following the same cues in this fortuitous kind of cotravel, which has given rise to this concept that maybe tumors and stem cells are really two sides of the same coin. Or maybe they could be factors emanating from the damaged brain. It became striking that we could see the same kind of homing in of neural stem cells for pathology, whether it was a tumor or even a stroke.... What was intriguing was that the etiology of pathology didn’t seem to matter. Either we were looking at one of the greatest artifacts possible, or we needed to figure out what was common to all these pathologies that could draw a stem cell to it. What do they have in common? What we realized was that all of them, regardless of their etiology, had an inflammatory signature, which then led us to the hypothesis that maybe it was the inflammatory response itself that was directing neural stem cells to where the pathology was.”

Dr. Snyder theorized that where pathology exists, whether it be tumor or infarct, there may first be an invasion of inflammatory cells that “lay down bread crumbs for the neural stem cells then to follow in there. So it’s as if there is a fire, a flare goes up, and the neural stem cells go in there to where the fire is.... They then start expressing anti- inflammatory, antiscarring molecules and then ... may start giving rise to neurons. The challenge is trying to balance the bad about inflammation with the good.”

LOW-HANGING FRUIT

The ultimate goals of neural stem cell therapy would be not only to kill the tumor but also to help repair the brain, said Dr. Snyder. “This is the kind of repair we see in stroke-like lesions,” he stated. “I have no evidence whatsoever that this could even possibly begin to happen in a brain tumor case. It’s something somewhere down the line to shoot for. So, what’s the low-hanging fruit in the stem cell field? Well, I actually think one of the low-hanging fruit is brain tumors, for all of the reasons I mentioned, because you are not asking a whole lot of them. The other low-hanging fruit also fit into some of the pediatric age-groups, some of the neurogenetic diseases ... and then various aspects of other more complex diseases where you are looking for anti-inflammation, antiscarring, neuroprotection, things of that sort. But in approaching, for example, brain tumors, we will learn a lot about improved safety and efficacy and then start being able to climb up the tree to higher- and higher-hanging fruit.”

NR

—Colby Stong

Suggested Reading
Aboody KS, Brown A, Rainov NG, et al. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci U S A. 2000;97:12846-12851.
Yan J, Welsh AM, Bora SH, et al. Differentiation and tropic/trophic effects of exogenous neural precursors in the adult spinal cord. J Comp Neurol. 2004;480:101-114 [epub ahead of print].
Yip S, Aboody KS, Burns M, et al. Neural stem cell biology may be well suited for improving brain tumor therapies. Cancer J. 2003;9:189-204.

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