Expression of hypoxia-related tissue factors in astrocytic gliomas. A multivariate survival study with emphasis upon carbonic anhydrase IX.
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.
Korkolopoulou
Penelope
P
Department of Pathology, National and Kapodistrian University of Athens, GR 115 27 Athens, Greece. pkorkol@cc.uoa.gr
Perdiki
Marina
M
Thymara
Irini
I
Boviatsis
Efstathios
E
Agrogiannis
George
G
Kotsiakis
Xenophon
X
Angelidakis
Dimitrios
D
Rologis
Dimitrios
D
Diamantopoulou
Kalliopi
K
Thomas-Tsagli
Euphemia
E
Kaklamanis
Loukas
L
Gatter
Kevin
K
Patsouris
Efstratios
E
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
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