title: Differential expression of HIF-1 in glioblastoma multiforme and anaplastic astrocytoma.
abstract: Hypoxia is an important factor mediating tumor progression and therapeutic resistance, in part through proteome changes mediated by the transcription factor hypoxia-inducible factor (HIF)-1. Since glioblastoma multiforme is the epitome of a highly aggressive tumor entity, while lower-grade astrocytomas often show a prolonged clinical course, a profound difference in the extent of hypoxic tissue areas and corresponding magnitude of HIF-1 activity may exist between these entities. In this study, to address this question, serial sections of 11 glioblastomas and 10 anaplastic astrocytomas were immunostained for HIF-1α, glucose transporter (GLUT)-1, carbonic anhydrase (CA) IX (i.e., hypoxia-related markers), Ki67 (proliferation), phosphorylated ribosomal protein S6 [p-rpS6; mammalian target of rapamycin (mTOR) activity] and CD34 (microvascular endothelium). Digital scans of whole tumor sections were registered to achieve geometric correspondence for subsequent morphometric operations. HIF-1α-, GLUT-1- and CA IX-positive staining was found in all 11 glioblastomas, showing a preferential expression in tissue areas adjacent to necroses. A considerable spatial overlap between GLUT-1 and CA IX, and a colocalization of these proteins with areas of enlarged mean diffusion distances were observed. Conversely, 8 of the 10 anaplastic astrocytomas were completely negative for hypoxia-related markers. The glioblastomas also showed significantly greater heterogeneity of intercapillary distances, larger diffusion-limited tissue fractions, significantly higher mTOR activity and a trend for higher proliferation rates. Microregionally, mTOR and proliferation showed a significant spatial overlap with areas of shorter mean diffusion distances. In conclusion, diffusion-limited hypoxia, leading to the expression of hypoxia-related markers is a pivotal element of the glioblastoma phenotype and may be driven by dysregulated growth and proliferation in normoxic subregions.
authors: Department of Radiooncology and Radiotherapy, University Medical Center, D-55131 Mainz, Germany. arnmayer@uni-mainz.de
authors: Arnulf
authors: A
authors: Mayer
authors: Fabienne
authors: F
authors: Schneider
authors: Peter
authors: P
authors: Vaupel
authors: Clemens
authors: C
authors: Sommer
authors: Heinz
authors: H
authors: Schmidberger
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D000951:Antigens, Neoplasm / Q000096:biosynthesis; D001254:Astrocytoma / Q000235:genetics* / Q000473:pathology; D014408:Biomarkers, Tumor; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D019394:Ki-67 Antigen / Q000096:biosynthesis; D038601:Ribosomal Protein S6 / Q000096:biosynthesis; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis
chemical_list: D018952:Antigens, CD34; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019394:Ki-67 Antigen; D038601:Ribosomal Protein S6; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases