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(American Journal of Pathology. 2005;167:1379-1387.)
© 2005 American Society for Investigative Pathology

In Situ Analysis of Integrin and Growth Factor Receptor Signaling Pathways in Human Glioblastomas Suggests Overlapping Relationships with Focal Adhesion Kinase Activation

Markus J. Riemenschneider^*, Wolf Mueller^*, Rebecca A. Betensky, Gayatry Mohapatra^* and David N. Louis^*

From the Department of Pathology,^* Molecular Neuro-Oncology Laboratory and Molecular Pathology Unit, Massachusetts General Hospital and Harvard Medical School, Boston; and the Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts

Deregulated integrin signaling is common in cancers, including glioblastoma. Integrin binding and growth factor receptor signaling activate focal adhesion kinase (FAK) and subsequently up-regulate extracellular regulated kinases (ERK-1/2), leading to cell-cycle progression and cell migration. Most studies of this pathway have used in vitro systems or tumor lysate-based approaches. We examined these pathways primarily in situ using a panel of 30 glioblastomas and gene expression arrays, immunohistochemistry, and fluorescence in situ hybridization, emphasizing the histological distribution of molecular changes. Within individual tumors, increased expression of FAK, p-FAK, paxillin, ERK-1/2, and p-ERK-1/2 occurred in regions of elevated EGFR and/or PDGFRA expression. Moreover, FAK activation levels correlated with EGFR and PDGFRA expression, and p-FAK and EGFR expression co-localized at the single-cell level. In addition, integrin expression was enriched in EGFR/PDGFRA-overexpressing areas but was more regionally confined than FAK, p-FAK, and paxillin. Integrins ß8 and 5ß1 were most commonly expressed, often in a perinecrotic or perivascular pattern. Taken together, our data suggest that growth factor receptor overexpression facilitates alterations in the integrin signaling pathway. Thus, FAK may act in glioblastoma as a downstream target of growth factor signaling, with integrins enhancing the impact of such signaling in the tumor microenvironment.

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