Brain tumors and mouse models: New insight into the development of gliomas

July 31, 2001

In the latest issue of Genes & Development, a team led by Dr. Eric Holland at the Memorial Sloan-Kettering Cancer Centre in New York reports on the development of new mouse models of brain tumors.

Gliomas are the most common form of primary brain tumors, with approximately 30,000 people in the USA newly diagnosed each year. Murine models offer a route to understand how different types and severities of gliomas arise, and an experimental system in which to test potential therapies.

Gliomas are brain tumors that have the characteristics of glial cells. Glial cells are specialised cells whose normal job is to maintain the function and interactions of neurons. Gliomas can show characteristics of either or both types of glial cells, astrocytes and oligodendrocytes. Gliomas are graded according to their severity: Grade 1 are the least serious, while Grade 4 malignant gliomas are the most serious - these patients have an average survival time of 1 year from the date of diagnosis.

Previous research has shown that genetic mutations in two different cell signaling pathways can contribute to the formation of gliomas. The first group of mutations disrupt the differentiation process by which an undifferentiated 'progenitor' cell develops into a specific type of glial cell. Such cell signaling pathways are affected by molecules called growth factors, such as platelet derived growth factor (PDGF). The second set of mutations disrupts the cell cycle arrest pathway, which regulates glial cell proliferation.

Based on these findings, Dr. Holland and colleagues used genetic tools to express PDGF in different brain cells to investigate what underlies the different characteristics of gliomas. Two mouse models were generated. One strain of mice expressed excess growth factor in undifferentiated cells, while the second second strain of mice expressed PDGF in differentiated astrocytes. Both strains of mice developed mostly low grade gliomas.

Dr. Holland and colleagues discovered that the timing of PDGF expression can determine which characteristics a particular glioma displays. Dr. Holland found that excess PDGF expression in mature astrocytes may generate gliomas by 'dedifferentiating' the astrocytes into glial progenitor-like cells. Further experiments showed that the severity of the gliomas in both strains of mice could be increased by the loss of an important cell cycle arrest gene. Dr. Holland and colleagues conclude that some low grade gliomas are made up of proliferating glial progenitor cells that are somehow blocked in their ability to differentiate. Meanwhile, high grade malignant gliomas are likely to have acquired additional mutations in genes important in regulating the cell cycle.

Identifying pathways that lead to gliomas is a key step towards the design of new therapeutic strategies for the treatment of these tumors. The fact that the low grade gliomas in these mice consisted of undifferentiated glial progenitor-like cells suggests that these types of tumor may respond well to drugs that promote glial cell differentiation. These mice provide an excellent model for testing such drugs and offer hope for a new generation of glioma therapies.
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Cold Spring Harbor Laboratory

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