In situ analysis of integrin and growth factor receptor signaling pathways in human glioblastomas suggests overlapping relationships with focal adhesion kinase activation

Am J Pathol. 2005 Nov;167(5):1379-87. doi: 10.1016/S0002-9440(10)61225-4.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzyme Activation
  • ErbB Receptors / metabolism
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism*
  • Gene Expression Profiling
  • Genes, erbB-1
  • Glioblastoma / genetics
  • Glioblastoma / physiopathology*
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Integrin beta Chains / metabolism
  • Integrins / metabolism*
  • Male
  • Mitogen-Activated Protein Kinase 3 / analysis
  • Models, Biological
  • Oligonucleotide Array Sequence Analysis
  • Paxillin / analysis
  • RNA, Messenger / analysis
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Receptors, Growth Factor / genetics
  • Receptors, Growth Factor / metabolism*
  • Signal Transduction*
  • Up-Regulation


  • Integrin beta Chains
  • Integrins
  • Paxillin
  • RNA, Messenger
  • Receptors, Growth Factor
  • integrin beta8
  • ErbB Receptors
  • Receptor, Platelet-Derived Growth Factor alpha
  • Focal Adhesion Protein-Tyrosine Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase 3