How Brain Stem Cells Become Cancerous and Form Aggressive Brain Tumors

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• The Stem Cell-Brain Tumor Connection
• Historical Evidence of Stem Cell Involvement
• Modern Research Models for Brain Tumor Stem Cells
• Key Genetic Factors in Brain Tumor Development
• How Stem Cells Form Brain Tumors
• Implications for Brain Tumor Diagnosis and Treatment
• Full Transcript

The Stem Cell-Brain Tumor Connection

Brain stem cells play a crucial role in the development of aggressive brain tumors, particularly glioblastoma multiforme (GBM). Dr. Sebastian Brandner, MD, explains that when brain stem cells malfunction, they can grow uncontrollably and form malignant tumors. This connection between stem cells and brain cancer has become a major focus of neuro-oncology research over the past decade.

The most aggressive primary brain tumors originate from neural stem cell populations, which normally help maintain and repair brain tissue. When these cells' growth signals become dysregulated, they transform into cancer stem cells that drive tumor formation and progression.

Historical Evidence of Stem Cell Involvement

Dr. Brandner's research uncovered compelling historical evidence linking brain stem cells to tumor formation. As early as the 1930s and 1940s, primitive research methods showed brain tumors frequently developed near stem cell-rich regions. Chemical carcinogenesis studies from the 1960s and 70s further supported this connection.

"When I reviewed these old papers," Dr. Sebastian Brandner, MD, notes, "I realized many brain tumors were located precisely in areas known to contain high concentrations of neural stem cells." This geographical correlation provided early clues about stem cells' role in brain cancer pathogenesis.

Modern Research Models for Brain Tumor Stem Cells

Contemporary research uses advanced mouse models to study how brain stem cells become cancerous. Dr. Sebastian Brandner, MD, explains the "conditional knockout mouse models" technique, where specific tumor suppressor genes like p53 and RB are selectively inactivated in stem cell populations.

These models have successfully recreated various brain tumor types, including astrocytomas, oligodendrogliomas, and primitive neural tumors. By introducing genetic mutations into adult brain stem cells, researchers can observe the entire tumor formation process from its cellular origins.

Key Genetic Factors in Brain Tumor Development

Several critical genes regulate stem cell behavior and prevent cancerous transformation. Dr. Sebastian Brandner, MD, highlights three major tumor suppressor genes: p53 (the "guardian of the genome"), the retinoblastoma (RB) gene, and p10. When these protective mechanisms fail, stem cells lose growth control.

The research shows that specific genetic alterations in neural stem cells can trigger uncontrolled proliferation. These mutations accumulate over time, eventually leading to full-blown brain tumors that infiltrate surrounding healthy tissue.

How Stem Cells Form Brain Tumors

The transformation from normal stem cell to brain tumor follows a distinct progression. First, genetic mutations disrupt normal growth regulation. Then, the affected stem cells begin dividing autonomously, ignoring inhibitory signals. Initially forming small growths, these cancerous stem cells eventually infiltrate brain tissue and develop into recognizable tumors.

Dr. Sebastian Brandner, MD, emphasizes that this process explains why glioblastomas (GBMs) are so aggressive - they originate from stem cells that naturally migrate throughout the brain, carrying their cancerous potential with them.

Implications for Brain Tumor Diagnosis and Treatment

Understanding the stem cell origin of brain tumors opens new avenues for diagnosis and therapy. Dr. Brandner suggests that targeting cancer stem cells specifically could lead to more effective treatments for glioblastoma and other aggressive brain cancers.

Current research focuses on developing therapies that disrupt the unique biological pathways of tumor stem cells while sparing healthy neural tissue. This approach could potentially prevent tumor recurrence by eliminating the root cellular source of brain cancers.

Full Transcript

Dr. Anton Titov, MD: Stem cells is a very hotly discussed topic. That includes brain stem cells. It is less known that stem cells can give rise to brain tumors. The most aggressive brain tumors (glioblastoma multiforme) arise from brain stem cells.

You have done very interesting research on stem cell biology of brain tumors. Could you please discuss the brain stem cells? How they give rise to the brain tumors? How that can be used in diagnosis and treatment of brain tumors?

Dr. Sebastian Brandner, MD: You are correct. Stem cells over the last 10 years have been really in the focus of the brain tumor pathogenesis. Brain stem cells are a key to the pathology and biology of brain tumors.

But let’s look back through history. 50 or 80 years back, first in 1930s and 1940s, first ideas about brain stem cells appeared. The first mouse models have predicted that there might be a type of cell in the brain. Stem cells were known for nearly 100 years.

Since 1930s and 40s, there were very primitive-appearing research methods. It was chemical carcinogenesis. These brain tumors always arose from areas that are close to brain stem cell regions. In the 1960s and 70s additional clinical trials were done and they showed brain stem cells.

I went to review these old papers just a couple of years ago. I put all information about brain stem cells together in a review article. I realized that many brain tumors were located in regions which are stem cell-rich. I understood this fact by looking at old photographs from the 1960s.

Brain tumor stem cell concept evolved further in the 1990s. A certain type of mouse models were generated. You can specifically inactivate and silence genes that are known to be involved in a brain tumors pathogenesis. This was p53 tumor suppressor gene.

Also there were other genes. Retinoblastoma gene, RB gene. It was also the retinoblastoma gene and p10 gene. All these genes have been tagged with little tags. Sometimes you then put a little enzyme into the brain. These tags are pulled together and the gene between them is deleted. That is called "conditional knockout mouse models".

We have been using those to demonstrate that stem and progenitor cells in the adult mouse brain can give rise to proper brain tumors. We have modeled astrocytomas. We have modeled primitive neural tumors. We have modeled oligodendrogliomas.

We can show that sometimes we introduce into the stem cell layer in the mature brain. We put stem cells into adult brain. These mutations give rise to gliomas. Brain tumors appear selectively in this cell population.

We are not the only ones doing research on brain tumor stem cells. There are many other groups who have done that with different methodologies. This is a very strong parallel evidence. It points all to the same role of brain stem cells in brain tumors.

If something goes wrong with the growth signals of a stem cell, then they can start growing autonomously. Brain tumor stem cells grow without being controlled. They grow without being inhibited by the inhibiting factors.

Dr. Anton Titov, MD: So brain tumor stem cells are just out of control. They keep growing.

Dr. Sebastian Brandner, MD: First, it is a small little growth. Then brain tumor stem cells start infiltrating the brain. They form a proper brain tumor.

Stem cells promise many treatments. But it is stem cells that give rise to brain tumors. This includes gliomas and glioblastoma multiforme. Glioblastoma is the most aggressive intrinsic brain tumor.