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Glioblastoma multiforme is the most common type of brain tumor and the most malignant and fatal. Some of the features that make this disease extremely difficult to treat are its aggressive invasiveness, high proliferation rate and resistance to standard treatments. In fact, this particular tumor consists of many different types of cells and while some may respond well to certain therapies, others may not be affected at all.
Being able to discriminate between cell populations is therefore essential in order to target different tumor cells with specific therapeutic approaches. Scientists from the Department of Neurosurgery, Charité, Germany, recently developed a novel protocol that allowed for the distinction between microglia, the resident immune cells of the brain, and circulating macrophages, other bone marrow-derived cells that participate in tumor growth. Glioblastoma multiforme progression causes an abnormal accumulation of microglia and the recruitment of additional macrophages of peripheral origin, which together represent up to 30% of the tumor mass.
Their protocol for differentiating between these two cell populations provided for the use of innovative bone marrow chimeras, model mice obtained using head radiation protective shields. During this procedure, recipient mice were subjected to a dose of radiation which killed bone marrow-derived cells and bone marrow stem cells that could potentially become microglia and macrophages. At a later stage, the animals were injected with new labeled bone marrow cells from donor mice and underwent tumor cell implantation through an incision on the scalp. When analyzing the cell populations building up the tumoral mass, the researchers were able to distinguish between the circulating macrophages, which derived from the new labeled bone marrow cells, and the original microglia of the recipient mice.
Contrary to traditional total body irradiated chimeras, head protected ones preserved the blood brain barrier integrity from alterations that may cause unspecific, extensive migration of macrophages from the periphery into the brain. The study demonstrated that head protected mice and controls exhibited significant smaller populations of macrophages compared to traditional chimeras, which were subsceptible to unspecific, not tumor-related infiltrates.
This finding indicated that resident microglia, and not macrophages as previously thought, are the predominant cell population in glioblastoma multiforme. The infiltration of macrophages occurs only at a later stage of progression, during the exponential growth phase. Using Analyze software, the researchers were able to measure tumor volumes from MRI images and establish that bigger tumor sizes strongly correlated to a higher number of macrophages.
The head protected irradiated model allowed for a precise assessment of tumor composition which may lead to new directions in glioblastoma treatment research and finally to the development of new therapies in the battle against this deadly brain tumor.
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