The scientific and popular media are both full of excitement about the use of stem cell therapies for replacing diseased or damaged tissues. In a new twist to this story, researchers are wondering if small populations of stem cells present in tumors (known as cancer stem cells) may be responsible for the ability of cancers to survive and re-establish themselves, even after the malignancies are apparently eliminated by a combination of surgery, chemotherapy and radiotherapy.

In a new report in the Journal of Clinical Oncology, Robert Wechsler-Reya, PhD, director of the Tumor Initiation and Maintenance Program at SBP, Luis Parada, PhD, from Memorial Sloan Kettering Cancer Center and Peter Dirks, MD, PhD, from Toronto’s Hospital for Sick Children, review the evidence that cancer stem cells may contribute to brain tumor re-appearance. As background, Wechsler-Reya explains that, “There are several good theories about how tumors can develop resistance to therapy and then re-appear after therapy ends. One theory proposes that the unique regenerative properties of cancer stem cells underlies the ability of tumors to rebound.”

So why wouldn’t aggressive cancer therapies destroy cancer stem cells along with the other tumor cells? Significantly, many cancer drugs are designed to be effective against rapidly-proliferating tumor cells. In contrast, both normal stem cells and cancer stem cells often exhibit low rates of proliferation. This allows them to sit quietly on the sidelines, dodging the lethal effects of the therapy and then ramping up their proliferation post-therapy to re-populate the damaged tissue. In the case of normal stem cells this leads to repair of damaged organs, while in the case of cancer stem cells it leads to re-growth of tumors.

According to Wechsler-Reya, some of the best evidence for the existence and power of cancer stem cells comes from studying brain tumors in mice. “Researchers have analyzed several types of mouse brain cancers by separating the tumor cells into pools that carry different markers (like sorting a bag of M&Ms into piles containing the different colors). These separate pools are then injected back into the brains of new mice to compare their tumor-growing abilities. Cells with markers thought to characterize brain tumor stem cells (e.g. the red M&Ms) can produce new tumors even when very few cells are injected. In contrast, the majority of tumor cells (all the other colors of M&Ms) have very poor ability to produce new tumors, highlighting the unique regenerative power of the cancer stem cell population.”

Researchers can now do similar experiments with human brain cancers by injecting tumor cells into special mice that lack an immune system and thus can’t reject the human cells. These studies show that human brain tumors also contain cancer stem cells that can regenerate tumors when transplanted in low numbers. These mouse studies may therefore serve as valuable tools for understanding human brain tumor stem cells and for devising ways to deal with them. For example, researchers hope that cancer stem cells may prove vulnerable to new types of targeted therapies that don’t depend on rapid tumor cell proliferation for their success. Such therapies would destroy cancer stem cells along with the other tumor cells, hopefully avoiding tumor re-growth.

Read a copy of the paper here.

William Stallcup, PhD, professor at Sanford Burnham Prebys Medical Discovery Institute (SBP), recently published an overview on a protein called NG2 that plays an important role in glioma. Glioma is the most common form of brain cancer, with over 20,000 new cases in the U.S. each year. More than half of all gliomas are classified as glioblastoma, for which the average survival time is only 15 months. We spoke with Stallcup about the implications of NG2 research studies.

What is NG2 and why is it important in glioma?

NG2 is a proteoglycan—a protein on the cell surface with lots of sugars attached to it. It enhances signaling that causes cells to proliferate and move around more easily—exactly what you don’t want in cancer. NG2 is a triple threat because its actions in three cell types help brain tumors grow and spread—the cancer cells themselves, and cells that form new blood vessels that supply tumors with oxygen and nutrients, and immune cells called macrophages, which gliomas convert into their support system. We’ve shown that removing NG2 from any of these cell types slows down glioma growth in mice by 60% or more.

That suggests that blocking NG2 function would be a good way to treat glioma. Is it a good therapeutic target?

To answer that, I should first explain the challenges of treating brain cancer. Not all kinds of drugs can get into the brain, but small molecules can, and those drugs usually block enzymes or receptors. Because NG2 is a different kind of protein, we’d have to think about alternative strategies, like using inhibitory RNAs to reduce production of NG2.

NG2 may also be a good prognostic indicator, since NG2 expression by glioma cells correlates with their malignancy (i.e. the more NG2, the worse the outcome for the patient). Assessing how much NG2 is made by the tumor cells might help guide decisions about how aggressive the treatment strategy should be.

Just as importantly, understanding how NG2 interacts with other proteins to promote glioma growth could point to other ways to stop these tumors from growing. And new drugs are definitely needed—most gliomas are treated with surgery and chemo, which aren’t successful in advanced cases.

What led you to study NG2 and its function in brain cancer?

I actually discovered the protein when I was a postdoc, so my lab has been studying it for the last 30-plus years. A lot of our early work showed how NG2 supports proliferation and migration of immature brain cells during development. When NG2 was found to be present at high levels in glioma, we realized that our expertise put us in a great position to advance knowledge of this often devastating cancer.