Neuroscience research group; Dr. Rainer Glass, PhD and Dr. Michael Synowitz, MD

Dr. Rainer Glass (left) and Dr. Michael Synowitz (right) (Photo: Thomas Oberländer/Helios Clinics Berlin-Buch).

Dr. Rainer Glass, PhD and Dr. Michael Synowitz, MD are members of the Cellular Neuroscience research group of Professor Dr. Helmut Kettenmann at the Max Delbrück Center (MDC) for Molecular Medicine in Berlin, Germany. Rainer Glass works as a Biologist at the MDC and Michael Synowitz as a Neurosurgeon at the Charité-University Medicine, Berlin. They both work on the molecular and cellular mechanisms of primary brain tumor/host interaction, focusing on gliomas, which are the most frequent primary tumors of the brain. In 2005, Dr. Glass and Dr. Synowitz were awarded the renowned U.S. ‘Young Investigator Award’ by the American Brain Tumor Association, for their discovery that normal stem cell/precursor cells of the brain are able to destroy glioblastomas.

Rainer Glass and Michael Synowitz currently focus their research activities on the interaction of gliomas with microglia and stem cells. This cutting-edge research is being used to develop therapy concepts to destroy tumor stem cells, and Volocity software is providing key insights.

Investigating how microglial cells influence glioma cells

It has become well established that gliomas contain cells of varying tumorigenicity and that gliomas interact strongly with the immune system, especially with microglial cells which are the sessile immune cells of the central nervous system (CNS). In the healthy brain, resting microglial cells continuously monitor the well-being of the CNS. Upon disease, or after pathological events such as trauma, stroke or brain tumor growth, resting microglial cells transform into an activated form which proliferate and migrate to the site of injury. Here, they phagocytose pathogens or damaged cells and release a variety of factors to coordinate immune responses. However, in gliomas microglia have an adverse role. Microglial cells are attracted towards glioma in large numbers and it has been shown that microglia density in gliomas positively correlates with malignancy, invasiveness and grading of the gliomas.

Over the last couple of years, Dr. Glass and Dr. Synowitz, along with colleagues in the research group of Professor Dr. Kettenmann, have used Volocity to explore the tumor-promoting role of microglia. They have recently shown that glioma depend on membrane type 1 metalloprotease (MT1-MMP) expression in glioma-associated microglia to facilitate tumor invasion into the brain parenchyma, and that microglia significantly contribute to glioma progression in mouse and rat-glioma models (Markovic et al., 2005; Synowitz et al., 2006; Markovic et al., 2009).

Investigating how stem cells influence glioma cells

Current treatments for glioblastomas are designed to target the bulk tumor mass and therefore potentially fail to account for the different molecular and clinical properties of cancer stem cells. Even if therapy succeeds in killing the vast majority of the “normal” tumor cells, the remaining therapy-resistant cancer stem cells can cause local recurrence or metastasis at a later time.

Dr. Glass and Dr. Synowitz began using Volocity software in 2005, in their efforts to characterize the biology of cancer stem cells and develop new therapies that target this type of cancer cell. Volocity is used in this research for both quantitative analysis and 3D visualization. Tumor stem cells can be visualized in glioma e.g. by expression of the marker molecule CD133 or CD15.
Neural stem and precursor cells of the adult brain contribute to plasticity in the hippocampus and may provide a cellular source for brain repair. However, the stem cell niches may also be the point of origin for glioma. The research group has previously established that endogenous neural precursor cells (NPCs) from the subventricular zone (SVZ) migrate towards experimental glioma. Recently they have shown that neural stem cells and NPCs release bone morphogenetic protein (BMP; a factor known to control neurogenesis in the SVZ) in the vicinity of glioblastoma cells, which serves as a paracrine tumor suppressor in the CNS by inducing differentiation of glioma stem cells (Glass et al., 2005; Waelzlein et al., 2008; Chirasani et al., 2010).  

These findings could point to a new approach, which involves the reprogramming of tumor stem cells into less harmful cells, which could then be destroyed with an existing therapy.

Dr. Synowitz writes "Volocity has helped us enormously to visualize and analyze cellular composition of the subventricular zone and the tumor margin during glioma development in three dimensions."

Image: 3D visualization of the subventricular zone, the volume is shown rendered in the ‘3D Opacity’ image mode of Volocity.

Selected references:

1. Chirasani et al. Bone morphogenetic protein-7 release from endogenous neural precursor cells suppresses the tumorigenicity of stem-like glioblastoma cells. Brain (2010) 133 (7): 1961-1972.
2. Markovic et al. Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion. PNAS USA (2009) 106 (30): 12530-12535.
3. Walzlein et al. The antitumorigenic response of neural precursors depends on subventricular proliferation and age. Stem Cells (2008) 26 (11): 2945-2954.
4. Synowitz et al. A1 adenosine receptors in microglia control glioblastoma-host interaction. Cancer Research (2006) 66 (17): 8550-8557.
5. Markovic et al. Microglia stimulate the invasiveness of glioma cells by increasing the activity of metalloprotease-2. Journal of Neuropathology & Experimental Neurology (2005) 64 (9): 754-762.
6. Glass et al. Glioblastoma-induced attraction of endogenous neural precursor cells is associated with improved survival. J. Neuroscience (2005) 25 (10): 2637-2646.

To find out more about the fascinating research of the Cellular Neuroscience research group, please visit http://www.mdc-berlin.de/en/research/research_teams/cellular_neurosciences/index.html