gms | German Medical Science

27th German Cancer Congress Berlin 2006

German Cancer Society (Frankfurt/M.)

22. - 26.03.2006, Berlin

Inhibition of Heat-shock Protein 90 (Hsp90) with 17DMAG impairs multiple angiogenic signaling pathways in gastric cancers cells in vitro and reduces tumor growth and angiogenesis in vivo

Meeting Abstract

  • corresponding author presenting/speaker Oliver Stöltzing - Chirurgische Klinik, Universität Regensburg, Deutschland
  • Sven Lang - Chirurgische Klinik, Universität Regensburg
  • Dagmar Klein - Chirurgische Klinik, Universität Regensburg
  • Ulrich Bolder - Chirurgische Klinik, Universität Regensburg
  • Aiman Obed - Chirurgische Klinik, Universität Regensburg
  • Andreas Gaumann - Institut für Pathologie, Universität Regensburg
  • Hans-Jürgen Schlitt - Chirurgische Klinik, Universität Regensburg
  • Edward Geissler - Chirurgische Klinik, Universität Regensburg

27. Deutscher Krebskongress. Berlin, 22.-26.03.2006. Düsseldorf, Köln: German Medical Science; 2006. DocOP430

The electronic version of this article is the complete one and can be found online at:

Published: March 20, 2006

© 2006 Stöltzing et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.



Introduction: Various oncogenic signaling pathways, such as hypoxia-inducible-factor 1 (HIF-1), epidermal growth factor receptor (EGFR) and HER-2/neu, have been implicated in gastric cancer growth and angiogenesis by up-regulating angiogenic molecules, predominantly vascular endothelial growth factor (VEGF). Recently, heat-shock protein 90 (Hsp90) has been shown to be critical for activation of intracellular signaling cascades (MAPK) and oncogenic proteins (HIF-1alpha, HER-2). We hypothesized that specific inhibitors to Hsp90 (17AAG, 17DMAG) would impair EGF mediated angiogenic signaling in gastric cancer cells in vitro and therefore inhibit angiogenesis and tumor growth in vivo.

Methods: Human gastric cancer cells (TMK-1, KKLS, MKN45) were used for experiments. Effects of 17AAG on EGF-induced activation of signaling intermediates were investigated by Western blotting. Expression of VEGF upon 17AAG treatment was determined by PCR and ELISA. Changes in cell migration and invasion were evaluated in in vitro assays. For in vivo experiments, the water soluble compound 17DMAG was used (25mg/kg; 3x/wk). Effects of Hsp90 inhibition on tumor growth and angiogenesis were investigated in a xenogenic tumor model with subcutaneously implanted cancer cells. Mice received either 17DMAG or vehicle by i.p. injection.

Results: Western blotting showed that 17AAG inhibited constitutive and inducible activation of MAPK/Erk, PI-3K/Akt and HIF-1, and disrupted HER-2 and STAT3 activation. 17AAG treatment significantly reduced basal and EGF- induced VEGF secretion (P<0.05). In addition, phosphorylation ofEGFR and FAK were decreased and migratory and invasive properties of gastric cancer cells were abrogated in vitro(P<0.01). In vivo, treatment with 17DMAG led to a significant reduction in tumor growth rates (P<0.05) and final tumor weights (P<0.05). Tumoral vessel area (CD31) and numbers of proliferating tumor cells were significantly lower in 17DMAG treated tumors (P<0.05), as determined by immunohistochemistry. Metronomic low-dose regimens for 17DAMG are currently being investigated.

Conclusions: Blockade of Hsp90 disrupted multiple pro-angiogenic signaling pathways in gastric cancer cells in vitro and decreased tumor growth and angiogenesis in vivo. Thus, inhibitors of Hsp90 could prove to be a valuable addition to antiangiogenic/antineoplastic therapy regimens for the treatment of gastric cancer.