Prognostic Relevance of the Expression of CA IX, GLUT-1, and VEGF in Ovarian Epithelial Cancers

Background Tumor hypoxia is associated with malignant progression and treatment resistance. Hypoxia-related factors, such as carbonic anhydrase IX (CA IX), glucose transporter-1 (GLUT-1), and vascular endothelial growth factor (VEGF) permit tumor cell adaptation to hypoxia. We attempted to elucidate the correlation of these markers with variable clinicopathological factors and overall prognosis. Methods Immunohistochemistry for CA IX, GLUT-1, and VEGF was performed on formalin-fixed, paraffin-embedded tissues from 125 cases of ovarian epithelial cancer (OEC). Results CA IX expression was significantly associated with an endometrioid and mucinous histology, nuclear grade, tumor necrosis, and mitosis. GLUT-1 expression was associated with tumor necrosis and mitosis. VEGF expression was correlated only with disease recurrence. Expression of each marker was not significant in terms of overall survival in OECs; however, there was a significant correlation between poor overall survival rate and high coexpression of these markers. Conclusions The present study suggests that it is questionable whether CA IX, GLUT-1, or VEGF can be used alone as independent prognostic factors in OECs. Using at least two markers helps to predict patient outcomes in total OECs. Moreover, the inhibition of two target gene combinations might prove to be a novel anticancer therapy.

[1]  K. Jung,et al.  Cancer Statistics in Korea: Incidence, Mortality, Survival and Prevalence in 2010 , 2013, Cancer research and treatment : official journal of Korean Cancer Association.

[2]  A. Jemal,et al.  Cancer statistics, 2011 , 2011, CA: a cancer journal for clinicians.

[3]  H. Moch,et al.  Overexpression of carbonic anhydrase IX (CAIX) is an independent unfavorable prognostic marker in endometrioid ovarian cancer , 2011, Virchows Archiv.

[4]  Sohee Park,et al.  Cancer Statistics in Korea: Incidence, Mortality, Survival, and Prevalence in 2008 , 2011, Cancer research and treatment : official journal of Korean Cancer Association.

[5]  G. Song,et al.  Role of hypoxia in the hallmarks of human cancer , 2009, Journal of cellular biochemistry.

[6]  M. Lerman,et al.  Transcriptional control of the tumor- and hypoxia-marker carbonic anhydrase 9: A one transcription factor (HIF-1) show? , 2009, Biochimica et biophysica acta.

[7]  I. Ishiwata,et al.  Therapeutic strategy targeting the mTOR–HIF‐1α–VEGF pathway in ovarian clear cell adenocarcinoma , 2009, Pathology international.

[8]  A. Al-Attar,et al.  Vascular Endothelial Growth Factor Expression in Ovarian Cancer: A Model for Targeted Use of Novel Therapies? , 2008, Clinical Cancer Research.

[9]  A. Mobasheri,et al.  Hypoxic Regulation of Glucose Transport, Anaerobic Metabolism and Angiogenesis in Cancer: Novel Pathways and Targets for Anticancer Therapeutics , 2007, Chemotherapy.

[10]  C. Dang,et al.  Effects of hypoxia on tumor metabolism , 2007, Cancer and Metastasis Reviews.

[11]  G. Semenza,et al.  Up‐regulation of gene expression by hypoxia is mediated predominantly by hypoxia‐inducible factor 1 (HIF‐1) , 2005, The Journal of pathology.

[12]  K. Blackwell,et al.  Hypoxia and anemia: factors in decreased sensitivity to radiation therapy and chemotherapy? , 2004, The oncologist.

[13]  A. Giaccia,et al.  Hypoxic gene expression and metastasis , 2004, Cancer and Metastasis Reviews.

[14]  F. Peale,et al.  Expression of vascular endothelial growth factor, hypoxia inducible factor 1α, and carbonic anhydrase IX in human tumours , 2004, Journal of Clinical Pathology.

[15]  W. Murdoch,et al.  Roles of the ovarian surface epithelium in ovulation and carcinogenesis. , 2002, Reproduction.

[16]  A. Harris,et al.  Expression of hypoxia-inducible carbonic anhydrase-9 relates to angiogenic pathways and independently to poor outcome in non-small cell lung cancer. , 2001, Cancer research.

[17]  A. Harris,et al.  Tumour hypoxia, hypoxia signaling pathways and hypoxia inducible factor expression in human cancer. , 2001, Anticancer research.

[18]  R. Angioli,et al.  GLUT‐1 expression in ovarian carcinoma , 2001, Cancer.

[19]  A. Harris,et al.  Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix. , 2001, Cancer research.

[20]  W. Sly,et al.  Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. , 2001, The American journal of pathology.

[21]  Y. Sugisaki,et al.  Prognostic significance of vascular endothelial growth factor expression in human ovarian carcinoma , 2000, British Journal of Cancer.

[22]  G. Semenza HIF-1: mediator of physiological and pathophysiological responses to hypoxia. , 2000, Journal of applied physiology.

[23]  G. Semenza,et al.  Hypoxia, Clonal Selection, and the Role of HIF-1 in Tumor Progression , 2000, Critical reviews in biochemistry and molecular biology.

[24]  D A Hilton,et al.  Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. , 1999, Cancer research.

[25]  F. Ismail-Beigi,et al.  Dual Control of glut1 Glucose Transporter Gene Expression by Hypoxia and by Inhibition of Oxidative Phosphorylation* , 1997, The Journal of Biological Chemistry.

[26]  G. Semenza,et al.  A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation , 1992, Molecular and cellular biology.

[27]  M. Shimizu,et al.  Expression of hypoxia inducible factor-1alpha (HIF-1alpha) and glucose transporter-1 (GLUT-1) in ovarian adenocarcinomas: difference in hypoxic status depending on histological character. , 2008, Oncology reports.

[28]  Napoleone Ferrara,et al.  The role of vascular endothelial growth factor in pathological angiogenesis , 2004, Breast Cancer Research and Treatment.

[29]  S. Silverberg Histopathologic grading of ovarian carcinoma: a review and proposal. , 2000, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[30]  N. Dubrawsky Cancer statistics , 1989, CA: a cancer journal for clinicians.