Priority Research Program of the German Research Foundation (DFG)
SPP 1190 - THE TUMOR - VESSEL INTERFACE

SPP 1190 - Projects
 
A. Abdollahi / P. Huber/
J. Debus

A. Acker-Palmer
T. Acker
R. Adams
F. Alves
H. Augustin
H. Beck / M. Conrad
G. Breier / B. Wielockx
P. Friedl
C. Bruns / P. Nelson
B. Homey / A. Müller-Homey
Ch. Klein
V. Orian-Rousseau / H. Ponta
K.T. Preissner
B. Sipos
J. Sleeman
P. Vajkoczy
 

 

Prof. Dr. Till Acker

 

Institute of Neuropathology
Universitätsklinikum Giessen und Marburg GmbH
Arndtstr. 16
D-35392 Giessen, Germany
Tel.: +49- (0)641-99-41180
Fax: +49-(0)641-99-41189

Lab Homepage

Till.Acker(at)patho.med.uni-giessen.de

   
 
The role of HIF-1/2alpha in regulating the switch between the angiogenic and invasive phenotype in malignant brain tumors
The ability to initiate homeostatic responses and adapt to hypoxia represents a central aspect in solid tumor growth, crucially governed by the key transcriptional regulators hypoxia inducible transcription factor (HIF)-1lapha and HIF-2alpha. Thus, a low PO2 may via activation of the HIF system trigger the tumor cell to cover its oxygen and nutrient supply by inducing angiogenesis (angiogenic phenotype) or by migrating away from hypoxic areas into the well oxygenated host tissue and organs (invasive phenotype). Preexisting or newly formed vessels serve as migration scaffolds to support tumor spread. Interestingly, current anti-angiogenic therapies seem to be counteracted by a similar switch to a more invasive phenotype that renders tumor cells independent of new blood vessel growth. We propose that such a qualitative change in the signaling response (angiogenic vs. invasive) may be governed by oxygen levels being reflected at the molecular level by HIF protein quantities (moderate vs. high). To test this hypothesis, we will analyze the distinct role and contribution of HIF-1alpha and/or HIF-2alpha and, with regard to their protein levels, the qualitative response changes in the induction of angiogenesis and (or) migration/invasion by modulating HIF-1alpha and HIF-2alpha protein levels in glioblastomas by overexpression and siRNA mediated knock-down.
 
- Relevant recent publications -

Acker T, Diez A-J, Aragones J, Tjwa M, Brusselmans K, Moons L, , Fukumura D, Moreno-Murciano MP, Herbert JM, Burger A, Riedel J, Elvert G, Flamme I, Maxwell PH, Collen D, Dewerchin M, Jain RK, Plate KH, Carmeliet P: Genetic evidence for tumor suppressor role of HIF-2alpha. Cancer Cell 8: 131-41, 2005

Preusser M, Wolfsberger S, Haberler C, Breitschopf H, Czech T, Slavc I, Harris AL, Acker T, Budka H, Hainfellner JA: Vascularization and expression of hypoxia-related tissue factors in intracranial ependymoma and their impact on patient survival. Acta Neuropathol 109: 211-6, 2005

Birner P, Preusser M, Gelpi E, Berger J, Gatterbauer B, Ambros IM, Acker T, Plate KH, Harris AL, Hainfellner JA: Expression of hypoxia-related tissue factors correlates with diminished survival of adjuvantly treated patients with chromosome 1p-aberrant oligodendroglial neoplasms: therapeutic implications. Clin Cancer Res 10: 6567-71, 2004

Acker T, Acker H: Cellular oxygen sensing need in CNS function - physiological and pathological implications. J Exp Biol 207: 3171-88, 2004

Elvert G, Kappel A, Heidenreich R, Englmeier U, Lanz S, Acker T, Rauter M, Plate KH, Sieweke M, Breier G, Flamme I: Cooperative interaction of hypoxia inducible factor (HIF)-2a and Ets-1 in the transcriptional activation of vascular endothelial growth factor receptor-2 (Flk-1). J Biol Chem 278: 7520-30, 2003

Acker T, Plate KH: Role of hypoxia in tumor angiogenesis – molecular and cellular angiogenic crosstalk. Cell Tissue Res 314: 145-55, 2003

Compernolle V, Brusselmans K, Acker T, Hoet P, Tjwa M, Beck H, Plaisance S, Dor Y, Keshet E, Lupu F, Nemery B, Dewerchin M, Van Veldhoven P, Plate KH, Moons L, Collen D, Carmeliet P: Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat Med 8: 702-710, 2002

 

 
 
 
 
 
 
 
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Impressum | Last update: 04/24/2009