title: Expression of hypoxia-related tissue factors in astrocytic gliomas. A multivariate survival study with emphasis upon carbonic anhydrase IX.
abstract: Carbonic anhydrase IX (CAIX) is a transmembrane enzyme involved in the reversible metabolism of carbon dioxide to carbonic acid and, hence, in physiological pH regulation. It also participates in cellular differentiation and proliferation, its expression being absent in most normal tissues. It has been recently postulated that the hypoxia-inducible factor (HIF-1) pathway up-regulated by hypoxia accounts for CAIX overexpression in most human tumors. In the present study, we examined the expression of this enzyme in diffuse gliomas of astrocytic origin in relation to vascular endothelial growth factor (VEGF) and HIF-1alpha expression, proliferation rate (as assessed with Ki-67 antigen), microvessel morphology, and survival. Of 84 cases analyzed, 61 cases (72.6%) displayed strong membrane and/or cytoplasmic expression of CAIX and were grouped as positive. Immunoreactivity tended to have a perinecrotic distribution and increased in parallel with the extent of necrosis (P < .001) and histologic grade (P < .001). A positive correlation was also noted with HIF-1alpha and VEGF expression (P < .001), proliferation rate (P = .010), microvessel density (P = .004), and microvessel caliber parameters (P = .014-.038). In univariate survival analysis, increased CAIX expression was associated with shortened survival in the entire cohort (P < .0001), along with VEGF (P = .0205) and HIF-1alpha levels (P = .0190). Multivariate analysis selected the interaction model of CAIX, with grade and age as the only parameters independently affecting survival. CAIX expression was also the only significant parameter for the survival of patients with grades II/III. We conclude that CAIX may be used as a prognostic indicator in diffuse astrocytomas to refine the information provided by grade. Given the role of CAIX in the acidification of tumor environment and its up-regulation by hypoxia, it is thought that CAIX expression may be linked to resistance of tumor cells to radiotherapy by allowing them to acclimatize to a hypoxic and acidic microenvironment.
authors: Department of Pathology, National and Kapodistrian University of Athens, GR 115 27 Athens, Greece. pkorkol@cc.uoa.gr
authors: Penelope
authors: P
authors: Korkolopoulou
authors: Marina
authors: M
authors: Perdiki
authors: Irini
authors: I
authors: Thymara
authors: Efstathios
authors: E
authors: Boviatsis
authors: George
authors: G
authors: Agrogiannis
authors: Xenophon
authors: X
authors: Kotsiakis
authors: Dimitrios
authors: D
authors: Angelidakis
authors: Dimitrios
authors: D
authors: Rologis
authors: Kalliopi
authors: K
authors: Diamantopoulou
authors: Euphemia
authors: E
authors: Thomas-Tsagli
authors: Loukas
authors: L
authors: Kaklamanis
authors: Kevin
authors: K
authors: Gatter
authors: Efstratios
authors: E
authors: Patsouris
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000096:biosynthesis*; D001254:Astrocytoma / Q000098:blood supply / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000096:biosynthesis*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D000951:Antigens, Neoplasm; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019394:Ki-67 Antigen; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases