title: Prognostic significance of IL-8-STAT-3 pathway in astrocytomas: correlation with IL-6, VEGF and microvessel morphometry.
abstract: Malignant astrocytomas are highly vascular neoplasms characterized by a potent angiogenic and immunosuppressive phenotype. Th2-cytokines (IL-6/IL-8) are implicated as major regulators of glioma cell growth and invasiveness. STAT-3, a downstream transducer of cytokine signaling is positively associated with tumor angiogenesis. The present study aimed to investigate the expression of IL-8 and p-STAT-3 in 97 diffusely infiltrating astrocytomas of various grades, in relation to IL-6, VEGF, clinicopathological features, microvascular characteristics and patients' survival. IL-8 expression was localized in neoplastic cells, being associated with p-STAT-3 (p = 0.0013), IL-6 (p = 0.0004) and VEGF (p < 0.0001) around areas of necrosis as well as in perivascular inflammatory and endothelial cells. All the molecules under study correlated with tumor grade and degree of necrosis (p < 0.05, respectively). p-STAT-3, IL-8 and VEGF expression was positively associated with microvessel density (p = 0.0491, p < 0.0001 and p = 0.0118, respectively). Univariate analysis indicated that overexpression of IL-8 and IL-6 adversely affected survival in the entire cohort whereas increased p-STAT-3 expression was predictive of improved survival in high grade (III/IV) astrocytomas (p = 0.0032). In multivariate analysis only IL-8 expression (p = 0.043) retained its significance. The prognostic significance of IL-8 expression and its correlation with p-STAT-3 and VEGF implicates this novel signaling pathway in astroglial tumors progression providing new targets for effective immunotherapy.
authors.affiliation: Department of Biological Chemistry, Medical School, University of Athens, Athens, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Piperi
authors.forename: Vassilis
authors.initials: V
authors.lastname: Samaras
authors.forename: Georgia
authors.initials: G
authors.lastname: Levidou
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Kavantzas
authors.forename: Efstathios
authors.initials: E
authors.lastname: Boviatsis
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Petraki
authors.forename: Athanasios
authors.initials: A
authors.lastname: Grivas
authors.forename: Calypso
authors.initials: C
authors.lastname: Barbatis
authors.forename: Vassilis
authors.initials: V
authors.lastname: Varsos
authors.forename: Efstratios
authors.initials: E
authors.lastname: Patsouris
authors.forename: Penelope
authors.initials: P
authors.lastname: Korkolopoulou
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001254:Astrocytoma / Q000098:blood supply / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D014408:Biomarkers, Tumor; D001932:Brain Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007167:Immunotherapy; D015850:Interleukin-6 / Q000096:biosynthesis*; D016209:Interleukin-8 / Q000096:biosynthesis*; D008297:Male; D055806:Microvessels / Q000033:anatomy & histology; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D050796:STAT3 Transcription Factor / Q000096:biosynthesis*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D019043:Vascular Neoplasms
chemical_list: D014408:Biomarkers, Tumor; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A