Immunohistochemical expression and prognostic significance of HIF-1α and VEGF-C in neuroendocrine breast cancer.

AIM To determine the predictive value of HIF-1α and VEGF-C in primary neuroendocrine breast cancers (NEBC) and their correlation with other clinico-pathological characteristics of NEBC. MATERIALS AND METHODS HIF-1α and VEGF-C were determined immunohistochemically in tissue samples from 31 cases of NEBC. RESULTS The HIF-1α expression in NEBC was predominantly negative, with only 5 (16.1%) cases showing strong reaction to HIF-1α. Eighteen (58.0%) NEBC cases showed moderate-to-strong VEGF-C expression. VEGF-C expression negatively correlated with progesterone receptor positivity (p=0.014) and duration of follow-up (p=0.021). A multivariate Cox proportional hazard regression analysis showed that HIF-1α (p=0.019) was a significant predictor of disease-free survival, whereas VEGF-C (p=0.099) showed no such association. CONCLUSION HIF-1α overexpression indicated unfavourable prognosis and could serve as an additional prognostic factor in NEBC. Moreover, patients with NEBC exhibiting moderate or strong VEGF-C expression could be candidates for a specific VEGF-C antibody therapy.

[1]  John M S Bartlett,et al.  Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. , 2014, Archives of pathology & laboratory medicine.

[2]  Philip S Rosenberg,et al.  Incidence of breast cancer in the United States: current and future trends. , 2011, Journal of the National Cancer Institute.

[3]  B. Monk,et al.  Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): A Gynecologic Oncology Group study. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  Kan Wang,et al.  Anti-HIF-1alpha antibody-conjugated pluronic triblock copolymers encapsulated with Paclitaxel for tumor targeting therapy. , 2010, Biomaterials.

[5]  T. Stępień,et al.  Inhibition of proliferation, VEGF secretion of human neuroendocrine tumor cell line NCI-H727 by an antagonist of growth hormone-releasing hormone (GH-RH) in vitro. , 2008, Cancer letters.

[6]  M. Saif New developments in the treatment of pancreatic cancer. Highlights from the "44th ASCO Annual Meeting". Chicago, IL, USA. May 30 - June 3, 2008. , 2008, JOP : Journal of the pancreas.

[7]  S. Påhlman,et al.  Localization of immunoreactive HIF‐1α and HIF‐2α in neuroendocrine cells of both benign and malignant prostate glands , 2007 .

[8]  R. Matkowski,et al.  Evaluation of prognostic value of VEGF-C and VEGF-D in breast cancer--10 years follow-up analysis. , 2007, Anticancer research.

[9]  C. Kirwan,et al.  Vascular endothelial growth factor-C in patients with breast cancer. , 2007, In vivo.

[10]  I. Ellis,et al.  Prognostic significance of vascular endothelial cell growth factors -A, -C and -D in breast cancer and their relationship with angio- and lymphangiogenesis , 2007, British Journal of Cancer.

[11]  B. Rini Vascular Endothelial Growth Factor–Targeted Therapy in Renal Cell Carcinoma: Current Status and Future Directions , 2007, Clinical Cancer Research.

[12]  R. Govindan,et al.  The proportion of patients with metastatic non-small cell lung cancer potentially eligible for treatment with bevacizumab: a single institutional survey. , 2006, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[13]  M. Schindl,et al.  Hypoxia inducible factor-1α correlates with VEGF-C expression and lymphangiogenesis in breast cancer , 2006, Breast Cancer Research and Treatment.

[14]  P. Bonnier,et al.  Overexpression of hypoxia‐inducible factor HIF‐1α predicts early relapse in breast cancer: Retrospective study in a series of 745 patients , 2005, International journal of cancer.

[15]  R. Mayer,et al.  Two steps forward in the treatment of colorectal cancer. , 2004, The New England journal of medicine.

[16]  H. Katoh,et al.  Overexpression of hypoxia-inducible-factor 1α(HIF-1α) in oesophageal squamous cell carcinoma correlates with lymph node metastasis and pathologic stage , 2003, British Journal of Cancer.

[17]  P. V. van Diest,et al.  Levels of hypoxia‐inducible factor‐1α independently predict prognosis in patients with lymph node negative breast carcinoma , 2003, Cancer.

[18]  A. Harris,et al.  Coexpression of hypoxia-inducible factors 1alpha and 2alpha, carbonic anhydrase IX, and vascular endothelial growth factor in nasopharyngeal carcinoma and relationship to survival. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[19]  A. Harris,et al.  Hypoxia-inducible factors HIF-1alpha and HIF-2alpha in head and neck cancer: relationship to tumor biology and treatment outcome in surgically resected patients. , 2002, Cancer research.

[20]  I. Ellis,et al.  Neuroendocrine differentiation and prognosis in breast adenocarcinoma , 2002, Histopathology.

[21]  D. Parkin,et al.  Global cancer statistics in the year 2000. , 2001, The Lancet. Oncology.

[22]  A. Harris,et al.  Relation of hypoxia inducible factor 1α and 2α in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival , 2001, British Journal of Cancer.

[23]  M. Papotti,et al.  Expression of Apocrine Differentiation Markers in Neuroendocrine Breast Carcinomas of Aged Women , 2001, Modern Pathology.

[24]  M. Schindl,et al.  Expression of hypoxia‐inducible factor–1α in oligodendrogliomas , 2001 .

[25]  M. Schindl,et al.  Expression of hypoxia-inducible factor 1alpha in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[26]  K. Alitalo,et al.  VEGF‐C and VEGF‐D expression in neuroendocrine cells and their receptor, VEGFR‐3, in fenestrated blood vessels in human tissues , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[27]  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.

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

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

[30]  C. W. Spalding Glands , 1888, The Homoeopathic physician.

[31]  C. Hofstetter,et al.  Intra-arterial delivery of bevacizumab after blood-brain barrier disruption for the treatment of recurrent glioblastoma: progression-free survival and overall survival. , 2012, World neurosurgery.

[32]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[33]  M. Saif New Developments in the Treatment of Pancreatic Cancer , 2008 .

[34]  Anthony Rhodes,et al.  American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. , 2007, Archives of pathology & laboratory medicine.

[35]  A. Harris,et al.  Advances in Brief Hypoxia-inducible Factors HIF-1 and HIF-2 in Head and Neck Cancer : Relationship to Tumor Biology and Treatment Outcome in Surgically Resected Patients , 2002 .

[36]  G. Semenza,et al.  Expression of Hypoxia-inducible Factor-1 a : A Novel Predictive and Prognostic Parameter in the Radiotherapy of Oropharyngeal Cancer 1 , 2001 .

[37]  M. Schindl,et al.  Expression of Hypoxia-inducible Factor 1 a in Epithelial Ovarian Tumors: Its Impact on Prognosis and on Response to Chemotherapy 1 , 2001 .

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