title: Expression of HIF-1alpha, CA IX, VEGF, and MMP-9 in surgically resected non-small cell lung cancer.
abstract: Endogenous hypoxia markers have been studied as prognostic indicators because they appear to be associated with tumor aggressiveness. This study was undertaken to compare the expression of two endogenous hypoxia markers, Hypoxia-inducible factor-1alpha (HIF-1alpha) and carbonic anhydrase IX (CA IX), with regard to their prognostic significance. We also compared spatial distribution of HIF-1alpha and CA IX and examined their relationship with expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9, which may be regulated by hypoxia. We studied 74 resected stage I/II non-small cell lung cancers (NSCLCs) for expression of HIF-1alpha, CA IX, VEGF, and MMP-9 by immunohistochemistry, and the extent of tumor necrosis. Univariate and multivariate analyses were performed to assess prognostic implications of these markers for disease free survival. HIF-1alpha expression was strongly correlated with CA IX (r=0.667, p<0.001) and was co-localized with CA IX in corresponding areas. HIF-1alpha and CA IX expression were higher in areas with moderate to severe tumor necrosis relative to areas with minimal necrosis, suggesting their relationship with hypoxia. VEGF expression also showed a modest relationship with HIF-1alpha (p=0.07); however, there was no relationship between HIF-1alpha and MMP-9 expression (p>0.99). Expression of HIF-1alpha and CA IX above the median value was significantly associated with shorter disease free survival in univariate analysis (p<0.05). However, only high CA IX expression and pathologic stage were independent prognostic indicators in a multivariate analysis. Of the markers considered in this study, CA IX expression status was the most reliable hypoxia marker for predicting tumor aggressiveness.
authors.affiliation: Department of Medicine, Duke University Medical Center and Durham Veterans Affairs Hospital, Durham, NC 27705, USA.
authors.forename: Seok Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Zahid N
authors.initials: ZN
authors.lastname: Rabbani
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.forename: Zeljko
authors.initials: Z
authors.lastname: Vujaskovic
authors.forename: Robin T
authors.initials: RT
authors.lastname: Vollmer
authors.forename: Ernst-Gilbert
authors.initials: EG
authors.lastname: Schreiber
authors.forename: Egbert
authors.initials: E
authors.lastname: Oosterwijk
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kelley
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000096:biosynthesis*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000096:biosynthesis*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000601:surgery*; D018572:Disease-Free Survival; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000378:metabolism* / Q000601:surgery*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D008875:Middle Aged; D015999:Multivariate Analysis; D009336:Necrosis; D011379:Prognosis; D016016:Proportional Hazards Models; D012044:Regression Analysis; D013997:Time Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
chemical_list: D000951:Antigens, Neoplasm; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D020780:Matrix Metalloproteinase 9; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases