Expression of hypoxia-inducible factor 1alpha in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy.

PURPOSE To investigate the impact of expression of hypoxia-inducible factor (HIF)-1alpha on prognosis and on response to chemotherapy in epithelial ovarian tumors. EXPERIMENTAL DESIGN Expression of HIF-1alpha protein was studied by immunohistochemistry in 102 specimens of epithelial ovarian cancers, in 50 borderline tumors, and in 20 cystadenomas. Results were correlated with p53, p21, and bcl-2 expression, microvessel density (MVD), apoptotic rate of tumor cells, and survival. RESULTS In 68.6% of ovarian cancers and 88% of borderline tumors, expression of HIF-1alpha was observed. There was a significant correlation of HIF-1alpha protein expression and MVD (P < 0.001). HIF-1alpha overexpression alone and MVD showed no impact on survival of cancer patients. Furthermore, the response to platinum-based chemotherapy was independent from HIF-1alpha expression. Expression of HIF-1alpha correlated with apoptotic rate in the majority of cases, especially in low malignant potential tumors. In contrast, in cancer patients with strong expression of HIF-1alpha and p53 protein overexpression, not only a significantly increased MVD (P = 0.032, Mann-Whitney test) but also a significantly shorter overall survival was observed (P < 0.0001, Cox regression). The apoptotic rate was very low in these tumors. CONCLUSIONS HIF-1alpha protein overexpression alone has no impact on the prognosis of ovarian cancer. The combination of HIF-1alpha protein overexpression with nonfunctional p53, however, indicates a dismal prognosis.

[1]  M. Schindl,et al.  Impact of human papillomavirus infection on the expression of the KAI1 metastasis suppressor protein in invasive cervical cancer. , 2001, Cancer letters.

[2]  M. Schindl,et al.  Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. , 2000, Cancer research.

[3]  A. Harris,et al.  The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers, and tumor-associated macrophages , 2000 .

[4]  J. M. Arbeit,et al.  Hypoxia-inducible Factor-1α Is a Positive Factor in Solid Tumor Growth , 2000 .

[5]  J. Arends,et al.  Morphological changes in mesothelial cells induced by shed menstrual endometrium in vitro are not primarily due to apoptosis or necrosis. , 2000, Human reproduction.

[6]  G. Semenza,et al.  Expression of hypoxia‐inducible factor 1α in brain tumors , 2000 .

[7]  A. Reles,et al.  p21 (WAF1/CIP1) protein expression is associated with prolonged survival but not with p53 expression in epithelial ovarian carcinoma. , 2000, Gynecologic oncology.

[8]  J. P. Geisler,et al.  p53 and bcl-2 in epithelial ovarian carcinoma: their value as prognostic indicators at a median follow-up of 60 months. , 2000, Gynecologic oncology.

[9]  M. Volm,et al.  Hypoxia-inducible factor (HIF-1) and its relationship to apoptosis and proliferation in lung cancer. , 2000, Anticancer research.

[10]  A. Walch,et al.  Staining patterns of p53 immunohistochemistry and their biological significance in colorectal cancer , 2000, The Journal of pathology.

[11]  G. Semenza,et al.  Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. , 2000, Genes & development.

[12]  A. Freedman,et al.  Prognostic significance of p53 and p21(waf1/cip1) immunoreactivity in epithelial cancers of the ovary. , 1999, Gynecologic oncology.

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

[14]  P. Vaupel,et al.  Hypoxic cervical cancers with low apoptotic index are highly aggressive. , 1999, Cancer research.

[15]  H. Caffier,et al.  Prognostic relevance of the endothelial marker CD 34 in ovarian cancer. , 1999, Anticancer research.

[16]  C. Wykoff,et al.  The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis , 1999, Nature.

[17]  A. Kaider,et al.  Prognostic significance of tumor angiogenesis in epithelial ovarian cancer. , 1999, Cancer letters.

[18]  G. Semenza,et al.  Oncogenic alterations of metabolism. , 1999, Trends in biochemical sciences.

[19]  G. Semenza,et al.  Increased expression of hypoxia inducible factor-1alpha in rat and human prostate cancer. , 1998, Cancer research.

[20]  H. Friess,et al.  bax, but notbcl-2, influences the prognosis of human pancreatic cancer , 1998, Gut.

[21]  B. Werness,et al.  Correlation of TP53 mutations and p53 expression in ovarian tumors. , 1998, Cancer genetics and cytogenetics.

[22]  P. Carmeliet,et al.  Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis , 1998, Nature.

[23]  T. Fojo,et al.  p53 Inhibits Hypoxia-inducible Factor-stimulated Transcription* , 1998, The Journal of Biological Chemistry.

[24]  L. Neckers,et al.  Stabilization of wild-type p53 by hypoxia-inducible factor 1α , 1998, Nature.

[25]  A. Kaider,et al.  Tumor angiogenesis in stage IB cervical cancer: correlation of microvessel density with survival. , 1998, American journal of obstetrics and gynecology.

[26]  H. Lyng,et al.  Oxygen tension in human tumours measured with polarographic needle electrodes and its relationship to vascular density, necrosis and hypoxia. , 1997, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[27]  M. Krasnow,et al.  The Hypoxic Response: Huffing and HIFing , 1997, Cell.

[28]  C. Kainz,et al.  Influence of microvessel density and vascular permeability factor/vascular endothelial growth factor expression on prognosis in vulvar cancer. , 1996, Gynecologic oncology.

[29]  G. Semenza,et al.  Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. , 1996, The American journal of physiology.

[30]  G. Viale,et al.  Prognostic and predictive value of tumour angiogenesis in ovarian carcinomas , 1996, International journal of cancer.

[31]  David E. Housman,et al.  Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours , 1996, Nature.

[32]  C Kurz,et al.  Microvessel density and vessel invasion in lymph‐node‐negative breast cancer: Effect on recurrence‐free survival , 1995, International journal of cancer.

[33]  N. Weidner.  Intratumor microvessel density as a prognostic factor in cancer. , 1995, The American journal of pathology.

[34]  S. Steinberg,et al.  Tumor angiogenesis in advanced stage ovarian carcinoma. , 1995, The American journal of pathology.

[35]  G. Semenza,et al.  Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[36]  T. Graeber,et al.  Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status , 1994, Molecular and cellular biology.

[37]  N. Ferrara.  Vascular endothelial growth factor. , 1993, Trends in cardiovascular medicine.

[38]  J. Folkman,et al.  Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. , 1991, The New England journal of medicine.

[39]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .

[40]  M. Schindl,et al.  Selective immunohistochemical staining of blood and lymphatic vessels reveals independent prognostic influence of blood and lymphatic vessel invasion in early-stage cervical cancer. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[41]  M. Schindl,et al.  Increased microvessel density in adenomyosis uteri. , 2001, Fertility and sterility.

[42]  G. Semenza,et al.  Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. , 1999, Annual review of cell and developmental biology.

[43]  J. Folkman.  Angiogenesis in cancer, vascular, rheumatoid and other disease , 1995, Nature Medicine.

[44]  T. Tong,et al.  Cancer statistics, 1994 , 1994, CA: a cancer journal for clinicians.