Roles of the EGF Receptor and Microglia in Glioma Invasion

Jeffrey E. Segall, Ph.D

Albert Einstein College of Medicine

Funded in December, 2005: $100000 for 1 years
LAY SUMMARY . ABSTRACT .

LAY SUMMARY

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Molecular Imaging May Help Determine How Brain Tumor Cells Invade Normal Brain Tissue

Investigators will use molecular imaging to determine whether immune “microglial” cells that reside in the brain interact with deadly brain tumor cells, enhancing the tumor cells’ entry into healthy brain tissues.

Deadly brain tumors called “gliomas” invade and destroy healthy brain tissue. The researchers hypothesize that there is a mutually reinforcing interaction between the tumor cells and microglial cells that enhances this deadly process.  According to the researchers, glioma cells secrete factors that attract and activate microglia, while microglia in tern secrete substances that stimulate the glioma cells to move out more effectively into surrounding brain tissue.

The researchers will use mutliphoton microscopy to examine the interactive behavior of the immune cells and brain tumor cells for long periods of time, deep within the brain.  They predict that the imaging will reveal that the immune microglial cells and the brain tumor cells that are located near one another show greater activity compared to the activity of the two types of cells that are distant from one another.  Additionally, the researchers will determine whether inhibiting microglial cells’ actions also curtails the tumor cells’ actions and, conversely, whether inhibiting glioma cell actions curtails the immune cells’ actions.    

Significance:  If this study demonstrates that immune-brain tumor cell interactions expedite tumor invasion of brain tissue, the findings are expected to stimulate the search for drugs that could inhibit either type of cell’s actions to limit brain tumor spread.  This, ultimately, would be expected to improve the effectiveness of surgery to remove the tumor.

ABSTRACT

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Roles of the EGF Receptor and Microglia in Glioma Invasion

We are investigating the mechanisms by which glioma brain tumor cells invade into normal tissue. A defining characteristic of these tumor cells is their ability to rapidly infiltrate into the surrounding brain. Currently, there are no anti-invasive therapies available, making treatment of these brain tumors poorly effective. We are focusing on the role of microglia and macrophages in the invasive process. Microglia and macrophages are immune cells that perform similar tasks. Both cell types phagocytose foreign particles and respond to injury. Whereas macrophages function throughout the body, including the brain, microglia are present in the brain only. We will use the term microglia to cover both microglia and macrophages that are present in the brain.

We hypothesize that glioma cells interact with microglia and macrophages during the invasive process via a paracrine loop. We use the term paracrine loop to indicate that there are mutual and stimulating interactions between the glioma cells and the microglia. We hypothesize that glioma cells secrete specific factors that attract and activate microglia and macrophages. We further hypothesize that, in turn, the microglia secrete mediators that stimulate the glioma cells to move out into the surrounding brain tissue and invade more effectively. We have specific candidates that we will test as being the mediators, based on studies that we have previously performed with breast cancer.

Our goal is to combine imaging methods that we have developed to study breast cancer with glioma invasion models in order to enhance our understanding of how glioma cells spread and invade surrounding brain tissue. We predict that microglia near glioma cells will show increased activity in terms of extension and retraction of their protrusions compared to microglia far from the glioma cells. Similarly, we predict that glioma cells near microglia will show increased activity and movement compared to glioma cells that are further away from microglia.

The potential significance of this study for human health is in the development of better treatment strategies for helping patients with brain cancer. Validation of our hypothesis may lead to the identification of novel targets for novel anti-invasive therapeutic strategies in brain cancer. Inhibition of glioma invasion is expected to render surgical removal or local radiation therapy more efficient and is therefore likely to be beneficial to the patient.