Angiogenesis and its Regulation by Hypoxia
Angiogenesis, the formation of new blood vessels, plays a critical role in physiological and pathological processes, for example in embryonic development, tumor growth and metastasis, and diabetic retinopathy. The goal of our research is to understand the mechanisms that control blood vessel formation in healthy and diseased tissue. The knowledge of these mechanisms will be valuable for the development of novel therapeutic strategies aimed at fighting cancer, or promoting tissue regeneration.
Our research group is located at the Department of Pathology of the University Hospital. We are part of the Medical Faculty Carl Gustav Carus, the DFG Center for Regenerative Therapies (CRTD), and the University Cancer Center (UCC). We are closely linked to the Biotechnology Center of Dresden University (BIOTEC), the Max Planck Institute for Molecular Cell Biology and Genetics (MPI-CBG), and the Dresden International Graduate School for Biomedicine and Bioengineering (DIGS-BB).
Past and current research
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 Induction of angiogenesis in microtumors by VEGF and Ang-2 (see paper by Vajkoczy et al., Journal of Clinical Investigation 109: 2002) |
Angiogenesis involves complex communication between endothelial cells and the surrounding tissue. At the heart of regulatory network that controls blood vessel formation in physiology and pathology is the angiogenic growth factor, VEGF. VEGF is required for the formation of the primitive vascular network in the embryo and for the vascularisation of developing organs, such as the brain. Because VEGF is also a potent tumor angiogenesis factor, it represents an attractive target for anti-angiogenic therapy. However, not all patients and not all tumors respond to anti-VEGF treatment, and it appears necessary to target additional angiogenic pathways in tumors.
One of the most critical environmental factors involved in the progression of solid tumors is hypoxia. The cellular hypoxia response is controlled by the transcription factor HIF-1, which stimulates, among other genes, the expression of VEGF and Ang-2. Recent evidence shows that hypoxia signaling is relevant not only in tumor cells, but also in vascular endothelial cells: HIF family members control the expression of the receptors for VEGF and the angiopoietins in endothelial cells, and the inhibition of HIF activity in endothelial cells disrupts murine cardiovascular development and influences tumor angiogenesis and growth.
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 Inhibition of HIF activity in endothelial cells disrupts cardiovascular development (left: normal mouse embryo; right: transgenic mouse embryo; see paper by Licht et al., Blood 2006) |
We are studying currently the role of cellular oxygen sensors in physiological and pathological processes. Changes in oxygen tension are monitored by hydroxylases that modify the HIF protein and thus affect its activity and stability. We are using gene targeting approaches in mice and various in vitro angiogenesis assays to identify the function of such enzymes. Our results indicate that HIF prolyl hydroxylases (PHDs) play an important role in tumor progression and that modulation of their expression might be a promising strategy for the treatment of cancer.
Another line of research in our laboratory is addressing the role of VE-cadherin in tumor cells. We observed that the endothelial cell selective VE-cadherin is induced in breast cancer cells during their transition into an aggressive and invasive state. Unexpectedly, VE-cadherin enhances characteristics of cancer cells that contribute to their increased malignancy and metastatic potential. Analysis of the signaling mechanisms involved revealed that VE-cadherin expression cross-talks to the TGF-beta pathway which is known to contribute to malignant tumor cell proliferation. These findings provide evidence for a novel function of VE-cadherin in tumor progression and reveal a previously unknown molecular link between VE-cadherin and TGF-beta signaling which may be of relevance for therapy.
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Expression of VE-cadherin in tumor vessels (arrows) and in tumor cells of human breast cancer (see paper by Labelle et al., Cancer Research 2008) |
Future prospects
In the future, we will try to understand how oxygen-sensitive signaling pathways control angiogenesis and coordinate the interaction between vascular endothelial cells and tumor cells. Using the transgenic and knockout models that we have developed in collaboration with groups at the Biotec, the CRTD, and the MPI-CBG, we will study the function of cellular oxygen sensors in angiogenesis in healthy and diseased tissue, and study their potential to prevent tissue degeneration, and enhance tissue regeneration.
General Contact Information
Prof. Dr. Georg Breier
Department of Pathology
University Hospital / Faculty of Medicine Carl Gustav Carus
Technische Universität Dresden
Fetscherstr. 74
01307 Dresden, Germany
Email: georg.breier(at)uniklinikum-dresden(dot)de
Phone: +49 (0)351 458-5278
Fax: +49 (0)351 458-5814
Mail Address
Prof. Dr. Georg Breier
Institut für Pathologie
Universitätsklinikum Carl Gustav Carus
Fetscherstr. 74
01307 Dresden, Germany
Visitor Address
Institut für Pathologie
Schubertstr. 15
01307 Dresden, Germany