title: In situ analysis of integrin and growth factor receptor signaling pathways in human glioblastomas suggests overlapping relationships with focal adhesion kinase activation.
abstract: 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 beta8 and alpha5beta1 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.
authors.affiliation: Department of Pathology, Molecular Neuro-Oncology Laboratory, 149-7151, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Riemenschneider
authors.forename: Wolf
authors.initials: W
authors.lastname: Mueller
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Betensky
authors.forename: Gayatry
authors.initials: G
authors.lastname: Mohapatra
authors.forename: David N
authors.initials: DN
authors.lastname: Louis
mesh_terms: D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D020869:Gene Expression Profiling; D018773:Genes, erbB-1; D005909:Glioblastoma / Q000235:genetics / Q000503:physiopathology*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D039641:Integrin beta Chains / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000032:analysis; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D051419:Paxillin / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D039641:Integrin beta Chains; D016023:Integrins; D051419:Paxillin; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; C094865:integrin beta8; D066246:ErbB Receptors; D020796:Receptor, Platelet-Derived Growth Factor alpha; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048052:Mitogen-Activated Protein Kinase 3