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British Journal of Cancer (2009) 100, 772 781 & 2009 Cancer Research UK All rights reserved 0007 0920/09 $32.00
http://www.bjcancer.com
Web End =www.bjcancer.com
HIF-1a determines the metastatic potential of gastric cancer cells
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N Rohwer1,2,3, S Lobitz4, K Daskalow1, T Jns5, M Vieth6, PM Schlag7, W Kemmner7, B Wiedenmann1, T Cramer*,1,8 and M Hcker2,8
1Department of Hepatology and Gastroenterology, Charit, Campus Virchow-Klinikum, Berlin 13353, Germany; 2Laboratory for Angiogenesis and Tumour
Metastasis, Charit, Campus Virchow-Klinikum, Berlin 13353, Germany; 3Freie Universitat Berlin, Fachbereich Biologie, Chemie, Pharmazie, Berlin 14195, Germany; 4Department of Pediatric Oncology and Hematology, Charit, Campus Virchow-Klinikum, Berlin 13353, Germany; 5Institute of Integrative Neuroanatomy, Center for Anatomy, Charit, Campus Mitte, Berlin 10115, Germany; 6Institute of Pathology, Klinikum Bayreuth, Bayreuth 95445, Germany; 7Surgical Oncology Research Group, Max Delbrck Center for Molecular Medicine, Berlin 13125, Germany
Gastric adenocarcinoma is characterised by rapid emergence of systemic metastases, resulting in poor prognosis due to vanished curative treatment options. Better understanding of the molecular basis of gastric cancer spread is needed to design innovative treatments. The transcription factor HIF-1a (hypoxia-inducible factor 1a) is frequently overexpressed in human gastric cancer, and inhibition of HIF-1a has proven antitumour efficacy in rodent models, whereas the relevance of HIF-1a for the metastatic phenotype of gastric adenocarcinoma remains elusive. Therefore, we have conducted a comprehensive analysis of the role of HIF-1a for pivotal metastasis-associated processes of human gastric cancer. Immunhistochemistry for HIF-1a showed specific staining at the invading tumour edge in 90% of human gastric cancer samples, whereas normal gastric tissue was negative and only a minority of early gastric cancers (T1 tumours) showed specific staining. Hypoxia-inducible factor 1a-deficient cells showed a significant reduction of migratory, invasive and adhesive properties in vitro. Furthermore, the HIF-1a-inhibitor 2-methoxy-estradiol significantly reduced metastatic properties of gastric cancer cells. The accentuated expression at the invading edge together with the in vitro requirement of HIF-1a for migration, invasion and adherence argues for a pivotal role of HIF-1a in local invasion and, ultimately, systemic tumour spread. These results warrant the exploration of HIF-1a-inhibiting substances in clinical treatment studies of advanced gastric cancer. British Journal of Cancer (2009) 100, 772781. doi:http://dx.doi.org/10.1038/sj.bjc.6604919
Web End =10.1038/sj.bjc.6604919 http://www.bjcancer.com
Web End =www.bjcancer.com Published online 17 February 2009& 2009 Cancer Research UK
Keywords: HIF-1a; hypoxia; metastasis; gastric cancer
MolecularDiagnostics