Published online before print July 3, 2008

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(American Journal of Pathology. 2008;173:545-560.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.071197

Hypoxia- and Vascular Endothelial Growth Factor-Induced Stromal Cell-Derived Factor-1/CXCR4 Expression in Glioblastomas

One Plausible Explanation of Scherer’s Structures

David Zagzag^*¶, Mine Esencay^*, Olga Mendez^*, Herman Yee^¶, Iva Smirnova^*, Yuanyuan Huang^*, Luis Chiriboga^¶, Eugene Lukyanov^*, Mengling Liu^¶|| and Elizabeth W. Newcomb^¶

From the Microvascular and Molecular Neuro-oncology Laboratory,^* the Division of Neuropathology, the Departments of Pathology, Neurosurgery, and Environmental Medicine,|| and the New York University Cancer Institute,^¶ New York University School of Medicine, New York, New York

The morphological patterns of glioma cell invasion are known as the secondary structures of Scherer. In this report, we propose a biologically based mechanism for the nonrandom formation of Scherer’s secondary structures based on the differential expression of stromal cell-derived factor (SDF)-1 and CXCR4 at the invading edge of glioblastomas. The chemokine SDF-1 was highly expressed in neurons, blood vessels, subpial regions, and white matter tracts that form the basis of Scherer’s secondary structures. In contrast, the SDF-1 receptor, CXCR4, was highly expressed in invading glioma cells organized around neurons and blood vessels, in subpial regions, and along white matter tracts. Neuronal and endothelial cells exposed to vascular endothelial growth factor up-regulated the expression of SDF-1. CXCR4-positive tumor cells migrated toward a SDF-1 gradient in vitro, whereas inhibition of CXCR4 expression decreased their migration. Similarly, inhibition of CXCR4 decreased levels of SDF-1-induced phosphorylation of FAK, AKT, and ERK1/2, suggesting CXCR4 involvement in glioma invasion signaling. These studies offer one plausible molecular basis and explanation of the formation of Scherer’s structures in glioma patients.