Harnessing the Power of Stem Cells in the Clinic

Evan Y. Snyder, MD, PhD; Robert Wechsler-Reya, PhD

Disclosures

October 06, 2011

Editorial Collaboration

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Evan Y. Snyder, MD, PhD: Hi, I'm Dr. Evan Snyder, Professor at Sanford-Burnham Medical Research Institute. Welcome to "Developments to Watch" from Sanford-Burnham and Medscape.

Joining me today is my colleague Dr. Rob Wechsler-Reya, Professor and Director of the Tumor Development Program at the Cancer Institute and a stem cell biologist. Today's program will focus on key research addressing the role of stem cells in the development of brain tumors and other cancers and how this research will affect clinical practice. Hi, Rob.

Robert Wechsler-Reya, PhD: Hi.

Introduction

Dr. Snyder: Obviously stem cells have garnered the interest of the community, and you in particular have drawn this interesting connection between stem cells and cancer, particularly brain tumors. But that's not really how you started out. You actually started out as a developmental biologist trying to figure out how the brain develops. How did you make that transition?

Dr. Wechsler-Reya: I think that early on in my scientific career, I realized that the processes of basic development and of cancer biology are quite similar. During development, we all start out as a small number of cells and the cells have to undergo division to generate more cells. They have to be able to differentiate into all the different cell types in the body. It's those very processes that go wrong in cancer -- cells that divide too much but are unable to differentiate or die are what we call a tumor. And so by studying the normal controls of those processes during development, I think we can learn a lot about cancer and how it develops.

Dr. Snyder: Do you think brain tumors that develop in kids -- and I know you'll talk a little bit more about the particular kind of cancer you work on, medulloblastomas -- do you think brain tumors that develop in kids are different from the brain tumors we see in adults?

Dr. Wechsler-Reya: I think they are in a number of fundamental ways. The tumors that develop in kids most commonly are medulloblastoma and low-grade astrocytoma, and I'll talk about those in a minute. In adults, the most common tumor is glioblastoma. So just from a clinical perspective, those are extremely different tumors. Glioblastoma is the most common adult brain tumor. It's also the most lethal, and almost all patients who develop glioblastoma die from it.[1]

The clinical picture in kids is very different. Medulloblastoma and low-grade astrocytoma respond quite well to treatment. Seventy percent to 80% of kids with medulloblastoma, for example, can be cured with a combination of surgery, radiation, and chemotherapy. The problem in kids is that when kids are treated too aggressively, there are extraordinary side effects, cognitive deficits, endocrine disorders, and increased susceptibility to other tumors later in life.[2,3]

What we need from the perspective of the treatment of kids with brain tumors is a better understanding of this disease so that we can develop more targeted, less toxic therapies, and that's the goal of the work that we're doing.

The "Dark Side" of Stem Cells

Dr. Snyder: Right, that's really interesting. So, in a way, this gets us to the field of stem cells. Most people, when they think of stem cells, think of stem cells for their curative power, rebuilding things, regenerative medicine, and things of that sort. But there is also potentially a dark side to stem cells. Do you want to talk a little bit about that?

Dr. Wechsler-Reya: Sure. I think that the capacity of stem cells to create tissues during development and potentially to repair tissues and disease is extraordinary. I also think that those processes, the capacity of cells, to undergo extensive self-renewal and to differentiate into different cell types can be hijacked in the context of cancer.

The very same cells and the very same signals that can be beneficial in the context of development or regeneration can lead to uncontrolled self-renewal, to uncontrolled proliferation, and thereby lead to cancer. There are many examples now of genes and signaling pathways that are critical for the normal function of stem cells. They're the very things that endow cells with this ability to be used for repair.

But mutations in those pathways are found in the context of human cancers. And so, again, understanding how these processes work normally gives you insight into how they go wrong in tumors.

I think stem cells are one of those; stem cell biology is one of those fields where the intersection between normal development and cancer is incredibly acute. If we understand how to control stem cells, we can apply that to try to develop better therapies for cancer.

Dr. Snyder: So if I understand correctly, what you're saying is that in some cases, the source of a cancer, or a brain tumor, is a stem cell. The same stem cell that's used to put the brain together can, for some reason, go awry, go to the dark side, and then give rise to a malignancy. Is that correct?

Dr. Wechsler-Reya: That's right, and I think there are a number of cases where stem cells, or progenitors, the cells that are immediately derived from them, have been shown to give rise to cancers. If we look at, for example, medulloblastoma, there is evidence -- this is a highly malignant tumor of the cerebellum -- there is evidence that mutations in the signaling pathways that control growth of stem cells and progenitors in the cerebellum can give rise to this tumor.[4]

Interestingly, medulloblastoma is actually probably 4 or 5 different diseases.[5] In some cases, these diseases may arise from multipotent stem cells that can give rise to neurons and glial cells; in some cases, they might arise from progenitors that can only give rise to neurons. But in each case, by studying the signals that control the normal cell and looking at the mutations that occur in the cancer, we can learn a lot about how the cancer arises.

Mutations in pathways that make stem cells self-renew and make more of themselves have been found in human medulloblastomas and have been found to be at the root of this transition of a normal stem cell into a tumor cell.[4,5]

Evolution of the Role of Stem Cells

Dr. Snyder: Even though you used to study the brain, there is a growing belief that even in other organ systems, stem cells are the genesis of cancers. Is that correct?

Dr. Wechsler-Reya: I think that's very frequently the case. You might ask why is that true, why are stem cells so susceptible to transformation into a cancer? I think it's because stem cells are really wired for this purpose. The function of stem cells is to make more of themselves and then to make more of the differentiated cells in the tissue.

They're really good at self-renewal, and therefore it's just a small step away from normal self-renewal to convert one of these cells into a cancer. This is thought to be the case in leukemia, in breast cancer, in prostate cancer -- in a whole range of malignancies -- that the stem cells of a particular tissue are highly susceptible to transformation into a cancer.[6]

I might add that by understanding how those cells behave in the normal tissue, we can take leaps toward understanding what went wrong in a cancer and what we might use to be able to target that cancer. In many cases, by studying the actual mutations, we can come up with targeted therapies. But in other cases, simply by knowing the pathways that control the growth or the survival of this stem cell, we might be able to find an approach to take down the cancer simply based on stem cell biology.[7]

Dr. Snyder: Do you think that a particular stem cell of a particular individual may be predisposed to have a problem, where, in a way, you're born with this propensity or predisposition, or is this something that happens through some external force, and it just so happens that the stem cell is kind of the Achilles heel, so to speak, of the whole developmental process?

Dr. Wechsler-Reya: I think we can distinguish between 2 different kinds of cancers, although there may be a spectrum between them. There are the inherited cancer syndromes in which a patient is born with a mutation in a particular gene. Typically that mutation in and of itself is not sufficient to cause the cell to give rise to a cancer, but secondary and tertiary mutations will allow that cell to become a tumor.[8]

There are overall a small number of cases of cancer in which we know of a hereditary predisposition. We know of inheritance of a particular mutated gene. But in many cases, the same genes that are found to be mutated and inherited as mutated genes are also the targets of mutation in what we call sporadic cancers, where the patient's complement of genes is normal when they're born, but as a result of some insult, some exposure to chemical or environmental toxins, they might acquire a mutation in that gene.

And if that mutation happens in a stem cell or in an early progenitor, then that cell is predisposed to go on to form a tumor because it already has the machinery for creating more of itself normally.

The Promise of Targeting Cancer Stem Cells

Dr. Snyder: There is another sense that people and investigators have talked about in regard to stem cells in cancer, and this is the cancer stem cell hypothesis. Obviously it's very controversial, and this is the notion that once you actually have a cancer develop, those cells are not all the same; some are more virulent than others and those get to be called cancer stem cells.

What do you think about that concept, and are the 2 concepts linked in any way?

Dr. Wechsler-Reya: I think it's a very interesting and powerful theory. That doesn't mean it's 100% right. I think that the notion that tumors are heterogeneous is as old as the study of tumors. But the structure and the heterogeneity and the significance of that heterogeneity is something that's begun to be appreciated only recently.

The idea is that within a tumor, be it a leukemia or a brain tumor or a breast cancer, there is a subpopulation of cells that is the source of the tumor. The cells that renew themselves extensively and that give rise to all the other cells in the tumor, just like a normal stem cell, would renew itself and give rise to all the cells in a tissue.[9] That notion is new and I think it's very powerful.

The significance of this is that if we use conventional cancer therapies, which frequently target rapidly dividing cells, and we eradicate most of the rapidly dividing cells in a tumor, we may be left with a small subpopulation of cells that is not so rapidly dividing, or that is resistant to the therapies. And if this cell type is capable of giving rise to the entire tumor again, then we haven't really gained much traction in terms of treating the tumor.

So the idea that there are these cancer stem cells or tumor-propagating or tumor-initiating cells within certain types of cancer -- this may not be true for all cancers. But if there is a subpopulation of cells within the tumor that have this ability to self-renew and give rise to the rest of the tumor, we had better find a way to kill those cells, otherwise we'll never be able to eradicate the disease. So identifying and studying these cells and learning about their vulnerabilities, I think, is a key effort in cancer biology right now.

Just to address the question you asked afterward, which is: Is there a relationship between the cancer stem cell and the normal stem cell that gave rise to it? I think in some cases there may be. This has not really been well studied or well proven, but the idea that a normal stem cell acquires a mutation that allows it to perpetuate itself and then eventually it becomes that cancer stem cell in the tumor is very attractive.

If that's the case, then it gives us even more incentive to study the biology of the normal stem cell that gave rise to the tumor in the first place because targeting that cell and targeting the cancer stem cell may involve the same approaches.

Dr. Snyder: So stem cell biology, then, is not simply an arcane area of investigation. It really can give rise to perhaps better targeted therapies, perhaps targeting whatever we're going to call it, this tumor-initiating stem cell?

Dr. Wechsler-Reya: I think that that's the hope -- that by studying these cells, we will be able to develop more effective and less toxic therapies for cancer and for other diseases. The evidence that we've gotten from the studies in my lab already suggests that. Several years ago we identified a population of stem cells in the normal cerebellum. These are cells that we think are -- during development -- giving rise to the neurons and glial cells but make up the normal cerebellum.[4]

We've recently found that if you introduce into those cells mutations that are found in human medulloblastomas, we can create models of the tumor, models of the disease. We know that if we take a normal stem cell and put in 1 or 2 mutant genes, then these cells are capable of giving rise to tumors in mice. Those tumors look for all the world, both histologically and at a molecular level, very much like the human tumors.

This is very powerful for a couple of reasons. This allows us, for one thing, to have a model of the disease that we can use to study the biology and to test therapies. For another, it now gives us a handle on the biology of the cell that gave rise to the tumor. So if we know that normal stem cells are dependent on a particular signal, then the tumor cells may be dependent on that signal as well. Disrupting it may be a novel approach to therapy.

Bridging the Clinic and the Lab

Dr. Snyder: That's very exciting. How can clinicians help you with your research?

Dr. Wechsler-Reya: Getting to the issue of models, to me this is one of the major rate-limiting steps in our progress toward cures for cancer. Typically -- and this is true in children and in adults -- a lot of clinical trials are designed with fairly minimal preclinical data to suggest that an approach to therapy is actually going to be effective. And we know, in fact, that the vast majority, 90% or so, of clinical trials do not end up being successful.[10] If we could increase the success rate by going into the clinic with things that had a highly likelihood of succeeding, I think we'd be in much better shape.

So the question is, how do you do that? I think you do that by developing better preclinical models of the disease. In the case of medulloblastoma, if we have transgenic animals that develop tumors that look like the human disease, that's a huge advantage in being able to take candidate therapies and test whether they work.

That's one type of model. Another type of model of human disease, of human cancer, is to take patient samples from the operating room -- in the case of surgery for medulloblastoma -- take patient samples and put them into mice so that you can grow them in a context that's very similar to how they're growing in patients. These xenograft models are incredibly powerful as tools for testing therapies.

What we've been doing over the last few years is getting samples from the neurosurgeons, from the operating room. I have a student or a post-doc go with a test tube, collect a tissue sample, bring it back to the lab, and then inject it into mice so that we have a xenograft model growing only in mice, not in cell culture, but passage from mouse to mouse.

If you take these models and you have a series of them that represent the different subtypes of medulloblastoma or any other type of cancer, then you can begin to test candidate therapies. Our collaboration with clinicians is to get patient samples and to really work in partnership with them with an eye toward developing targeted therapies. To me, that's the wave of the future, understanding what type of disease, what subtype of a disease we're treating, looking at the lab, looking at the studies in the lab, and saying, "Here's a therapy that works on a model of this tumor; let's try a clinical trial of that therapy in patients."

Dr. Snyder: That's very exciting. So just to wrap up, it looks as if what clinicians can see on the horizon, both near-term and even far-term, are therapies that target the development of the cancer, the stem cell, whether it's a starting cell or the cell that keeps the tumor going. That really will change the entire way that clinicians look at cancers, not just killing them, but actually changing their fate.

That was a really interesting topic. Thanks for the lively discussion. I really appreciate you stopping by and participating in the program.

Dr. Wechsler-Reya: My pleasure.

Dr. Snyder: We would both like to thank you for joining us today. I hope you will join us for additional programs in the "Developments to Watch" series on Medscape.

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