Hypoxia inducible factor-1alpha correlates with VEGF-C expression and lymphangiogenesis in breast cancer.
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.
Schoppmann
Sebastian F
SF
Department of Surgery, University of Vienna, Waehringer, Vienna, Austria. sebastian.schoppmann@meduniwien.ac.at
Fenzl
Alexandra
A
Schindl
Monika
M
Bachleitner-Hofmann
Thomas
T
Nagy
Katalin
K
Gnant
Michael
M
Horvat
Reinhard
R
Jakesz
Raimund
R
Birner
Peter
P
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000556:secondary; D018275:Carcinoma, Lobular / Q000378:metabolism / Q000556:secondary; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis / Q000473:pathology; D042601:Lymphatic Vessels / Q000473:pathology*; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C