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  • Title: Hypoxia inducible factor-1alpha correlates with VEGF-C expression and lymphangiogenesis in breast cancer.
    Author: Schoppmann SF, Fenzl A, Schindl M, Bachleitner-Hofmann T, Nagy K, Gnant M, Horvat R, Jakesz R, Birner P.
    Journal: Breast Cancer Res Treat; 2006 Sep; 99(2):135-41. PubMed ID: 16555123.
    Abstract:
    The transcription factor Hypoxia inducible factor-1alpha (HIF-1alpha) plays a crucial role in tumor progression by regulating angiogenesis, cell survival and drug resistance. HIF-1alpha is also implicated in biological functions under normoxic conditions and recent data provide evidence for a possible role in tumor lymphangiogenesis by regulating the lymphatic vascular endothelial growth factor-C (VEGF-C). In breast cancer, lymphatic vessel invasion (LVI) by tumor cells and subsequent metastasis to axillary lymph nodes is a critical point in progression of the disease with severe therapeutical and prognostic implications. Aim of this study is to investigate the role of HIF-1alpha in VEGF-C expression, lymphangiogenesis, and LVI in lymph node positive breast cancer. Lymphatic microvessel density (LMVD), LVI, HIF-1alpha and VEGF-C protein-expression were evaluated by immunohistochemistry in 119 cases of lymph node positive invasive breast cancer. There was a significant correlation between HIF-1alpha and VEGF-C (p = 0.026, r = 0.204, Spearman's coefficient of correlation). Further a significant association between HIF-1alpha-expression and the amount of peritumoral lymphangiogenesis LMVD was seen (p = 0.014, Mann-Whitney test). LMVD correlated significantly with LVI (p<0.001, Mann-Whitney test). HIF-1alpha was an independent prognostic factor for overall and disease free survival in uni- and multivariate analysis (p = 0.027, 0.029, 0.025, respectively, Cox regression). Our data provide evidence for a possible role of HIF-1alpha as regulator of tumor-associated lymphangiogenesis in human breast cancer and emphasizes the promising status of HIF-1alpha as a therapeutical target against tumor progression and metastasis.
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