Abstract
BackgroundCNS injury including stroke, infection, and tumor growth lead to astrogliosis, a process that involves upregulation of glial fibrillary acidic protein (GFAP) in astrocytes. However, the kinetics of astrogliosis that is related to these insults (i.e. tumor) is largely unknown.ResultsUsing transgenic mice expressing firefly luciferase under the regulation of the GFAP promoter (GFAP-luc), we developed a model system to monitor astrogliosis upon tumor growth in a rapid, non-invasive manner. A biphasic induction of astrogliosis was observed in our xenograft model in which an early phase of activation of GFAP was associated with inflammatory response followed by a secondary, long-term upregulation of GFAP. These animals reveal GFAP activation with kinetics that is in parallel with tumor growth. Furthermore, a strong correlation between astrogliosis and tumor size was observed.ConclusionsOur results suggest that non-invasive, quantitative bioluminescent imaging using GFAP-luc reporter animal is a useful tool to monitor temporal-spatial kinetics of host-mediated astrogliosis that is associated with glioma and metastatic brain tumor growth.
Highlights
CNS injury including stroke, infection, and tumor growth lead to astrogliosis, a process that involves upregulation of glial fibrillary acidic protein (GFAP) in astrocytes
We show that these GFAP-luc; Rag2-/- mice injected with malignant glioma cells can be used to monitor and quantify tumor-induced astrogliosis response of the host
Immunohistochemical analysis of GFAP activity in tumorbearing brain To determine the effect of orthotopic tumor xenografts on GFAP activity we subjected immunodeficient Rag2-/mice (i.e. T and B cells defective) [9] to stereotactic injection with DBTRG glioma cells as described in the Methods
Summary
CNS injury including stroke, infection, and tumor growth lead to astrogliosis, a process that involves upregulation of glial fibrillary acidic protein (GFAP) in astrocytes. GFAP expression has been widely used as a marker for astrogliosis and the host response to injury [2,3,4] and its analysis has generally relied on immunohistochemistry rather than quantification. We show that these GFAP-luc; Rag2-/- mice injected with malignant glioma cells can be used to monitor and quantify tumor-induced astrogliosis response of the host. Analysis of the serial imaging supports a model in which intracranial tumor injection induces an early GFAP response, which is likely a consequence of the local wounding of the stereotactic injection. This early response resolves and is followed by a secondary astrogliosis response correlating with tumor progression both in terms of kinetics and localization
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