Angiogenesis and its regulation by hypoxia
Previous and Current Research
Endothelial cells constitute the inner lining of all blood vessels and play a central role in the formation of new blood vessels (angiogenesis). We study the cellular and molecular mechanisms of angiogenesis in tumors. It is well known that angiogenesis is efficiently triggered by low tissue oxygen levels (hypoxia), yet the role of oxygen-sensing pathways at the tumor-vessel interface is poorly characterised.
Our initial work addressed the role of vascular endothelial growth factor (VEGF) in blood vessel development and tumor angiogenesis. We then analysed the transciptional regulation of angiogenesis by members of the hypoxia-inducible factor (HIF) family; these proteins are key regulators of the cellular response to hypoxia. Our results established a model in which vascular development is controlled by the combinatorial activity of members of the Ets and HIF families of transcription factors.
Hypoxia has profound impact on tumor progression and patient survival. Therefore, our current studies focus on the role of oxygen-dependent signaling pathways in tumors. The recently discovered HIF hydroxylases function as cellular oxygen sensors and control HIF activity and stability. Our loss-of-function (RNAi, conditional gene targeting in mice) and gain-of function experiments indicate that these enzymes control tumor cell proliferation, angiogenesis and blood vessel maturation.
Future Projects and Goals
Future projects will address the role of HIF hydroxylases in regulating cell-cell interactions at the tumor-vessel interface. By using a combination of in vitro and in vivo models, we will try to understand how these proteins control vessel sprouting, maturation and function as well as the interaction of endothelial cells with perivascular cells and tumor cells. This knowledge might have implications for therapy.
Methodological and Technical Expertise
- In vitro angiogenesis assays
- Endothelial-specific knockout mice
- Genetic manipulation of cancer cells
- Breast cancer models
Ameln KA, Muschter A, Mamlouk S, Kalucka J, Prade I, Franke K, Rezaei M, Poitz DM, Breier G, Wielockx B
Inhibition of HIF prolyl hydroxylase-2 blocks tumor growth in mice through the anti-proliferative activity of transforming growth factor-beta.
Cancer Res 71: 3306–3316. (2011)
Hölscher M, Silter M, Krull S, von Ahlen M, Hesse A, Schwartz P, Wielockx B, Breier G, Katschinski DM, Zieseniss A
Cardiomyocyte-specific prolyl-4-hydroxylase domain 2 knock out protects from acute myocardial ischaemic injury.
J Biol Chem 286: 11185-11194. (2011)
Saito K, Dubreuil V, Arai Y, Wilsch-Bräuninger M, Schwudke D, Saher G, Miyata T, Breier G, Thiele C, Shevchenko A, Nave KA, Huttner WB
Ablation of cholesterol biosynthesis in neural stem cells increases their VEGF expression and angiogenesis but causes neuron apoptosis.
Proc Natl Acad Sci USA 106: 8350-8355. (2009)
Labelle M, Schnittler HJ, Aust DE, Friedrich K, Baretton G, Vestweber D, Breier G
Vascular endothelial cadherin promotes breast cancer progression via transforming growth factor-beta signaling.Cancer Res 68: 1388–1397. (2008)
Licht AH, Muller-Holtkamp F, Flamme I, Breier G
Inhibition of hypoxia-inducible factor activity in endothelial cells disrupts embryonic cardiovascular development.Blood 107: 584-590. (2006)
Elvert G, Kappel A, Heidenreich R, Englmeier U, Lanz S, Acker T, Rauter M, Plate KH, Siewecke M, Breier G, Flamme I
Cooperative interaction of hypoxia-inducible factor-2alpha and Ets-1 in the transcriptional activation of Flk-1.
J Biol Chem 278: 7520-7530. (2003)
Vajkoczy P, Farhadi M, Gaumann A, Heidenreich R, Erber R, Wunder A, Tonn JC, Menger MD, and Breier G
Microtumor growth initiates angiogenic sprouting with simultaneous expression of VEGF, VEGF-receptor-2, and angiopoietin-2.
J Clin Invest 109: 777-785. (2002)