The EMBO Meeting

The EMBO Meeting 2012

 

 

 

 

Monday, 18 Nov 2013

Oxygen sensing, vasculogenesis & disease

 

Tuesday, 25 September 14:00-15:30, Apollon Auditorium


Peter Carmeliet

VIB K.U. Leuven

Controlling angiogenesis via endothelial metabolism

Angiogenesis, the growth of new blood vessels, plays a crucial role in numerous diseases, including cancer. Anti-angiogenesis therapies have been developed to deprive the tumor of nutrients. Clinically approved anti-angiogenic drugs offered prolonged survival to numerous cancer patients. However, the success of anti-angiogenic VEGF-targeted therapy is limited in certain cases by intrinsic refractoriness and acquired resistance. New strategies are needed to block tumor angiogenesis via alternative mechanisms.

We are therefore exploring whether targeting endothelial metabolism can be a possible alternative therapeutic strategy. Data will be presented on how Dll4/Notch signaling regulates endothelial metabolism. We will also discuss if  manipulating particular pathways of endothelial metabolism can be a target for anti-angiogenic therapy.

Biography

Peter Carmeliet is Director of the VIB - Vesalius Research Center, at the University of Leuven in Belgium. He graduated as Doctor in Medicine in 1984, and completed his PhD in Medicine in 1989. During his Postdoctoral work at the Whitehead Institute, MIT in Cambridge USA, he acquired the knockout technology.  After his return to Leuven in 1992, Carmeliet started his own research group with a focus on blood vessels and the role of VEGF in angiogenesis. By developing transgenic mice lacking VEGF, he discovered that VEGF is a key player in angiogenesis. Carmeliet has made  contributions to the understanding of how blood vessels grow (angiogenesis) in health and disease. His findings have led to the (pre)clinical development of novel therapeutic strategies for angiogenic diseases. Carmeliet also showed that PlGF is a disease-restricted candidate in many angiogenic disorders and tested the therapeutic potential of anti-PlGF.

In 2001, Carmeliet documented that low VEGF levels in mice and in humans cause motorneuron degeneration, similar to patients suffering the incurable disease amyotrophic lateral sclerosis (ALS). These studies not only provide evidence for a role of VEGF in neurodegeneration, but also opened new research avenues and therapeutic opportunities, which have resulted in clinical tests of VEGF delivery for ALS patients.


Anne Eichmann

Yale School of Medicine/Inserm

Guidance of vascular patterning

My laboratory studies vascular and lymphatic development, with particular interests in mechanisms that direct vascular patterning and guidance. In blood vessels, specialized endothelial cells called tip cells localized at the extremities of growing capillary sprouts mediate guided vascular patterning. Tip cells exhibit characteristic features, including extension of filopodia that explore the tip cell environment, lack of a lumen and a slow proliferation rate. Following behind tip cells, other endothelial cells termed stalk cells form the capillary lumen and proliferate. Tip cell formation is coordinated by the interplay between VEGF and Notch signaling. VEGF promotes tip cell selection, while activation of Notch inhibits tip cells formation and promotes the stalk cell phenotype. Capillary sprouting also shows morphological similarities to axon guidance.Like axonal growth cones, endothelial tip cells extend filopodia that sense and respond to guidance cues provided by soluble, cell- or matrix-bound ligands. We have identified several key molecules regulating capillary and lymphatic guidance, including the netrin receptor UNC5B, Robo4 and the Neuropilin1 and 2 receptors. Molecules regulating capillary patterning and guidance in development also operate during pathological angiogenesis and therefore represent targets for mediating vessel growth in cardiovascular disease.

Biography

Anne Eichmann is Research Director at Inserm, Collège de France, Paris and since 2010 Professor in the Cardiovascular Research Department at Yale University Medical School.
Dr. Eichmann obtained her M.Sc at the Weizmann Institute of Science and her PhD from the University of Paris XIII. During post-doctoral work with Nicole le Douarin in Paris, Dr. Eichmann cloned receptors for vascular endothelial growth factor (VEGF) and used them to isolate the hemangioblast, a common precursor for endothelial and hematopoietic stem cells. Dr. Eichmann went on to establish her group at the Collège de France in Paris in 2001 and explored the molecular basis of the formation of blood and lymphatic vessels, a subject of intense clinical interest because of the roles played by both types of vessel in cancer and ischemia. Dr. Eichmann’s research has notably demonstrated that vessel growth shows anatomical and functional similarities to axon growth and guidance processes.


Kari Alitalo

Molecular/Cancer Biology Program & Finnish Institute for Molecular Medicine, Biomedicum Helsinki, University of Helsinki

Therapeutic Potential of Vascular Endothelial Growth Factor

My laboratory studies vascular growth factors to facilitate therapeutics development for cardiovascular diseases and cancer. – Because of the importance of the growth of new blood vessels, or angiogenesis, in tumor progression, the first anti-angiogenic agents have been approved for clinical use. However, most patients are either refractory or eventually acquire resistance to anti-angiogenic therapeutics. A combination of angiogenesis and lymphangiogenesis inhibitors based on solid knowledge of the major interacting angiogenesis signaling pathways could be used to significantly advance the efficacy of tumor therapy.

The idea of proangiogenic therapy is to grow new functional blood vessels and thus restore blood flow to ischemic tissue. Several attempts have been made to stimulate angiogenesis and arteriogenesis in tissue ischemia, but with limited success. A coronary vascular growth factor has recently stimulated renewed interest in such therapy in cardiac ischemia. The growth of lymphatic vessels, lymphangiogenesis, is actively involved in a number of pathological processes including tissue inflammation and tumor dissemination but is insufficient in patients suffering from lymphedema, a debilitating condition characterized by chronic tissue edema and impaired immunity. Lymphangiogenic growth factors provide possibilities to treat these diseases.

Preclinical studies indicate that there considerable potential for the development of therapeutics based on the biological functions of vascular endothelial growth factors.

Biography

Dr. Kari Alitalo is a tenured Research Professor of the Finnish Academy of Sciences and Director of the Centre of Excellence at the Biomedicum Helsinki research institute of the University of Helsinki in Finland. He obtained his M.D. and Ph.D. from the University of Helsinki and did his postdoctoral studies with Drs. Michael Bishop and Harold Varmus in San Francisco, CA, USA. He has isolated and characterized several tyrosine kinases, growth factor receptors and their ligands. He cloned the first lymphangiogenic growth factor VEGF-C and its receptor VEGFR-3, and isolated lymphatic endothelial cells, showing that this pathway is required for angiogenesis and lymphangiogenesis. Dr. Alitalo also discovered the angiogenic Tie pathway and cloned the VEGF-B growth factor in collaboration with Dr. Ulf Eriksson. In addition, he has devised molecular therapies for lymphedema that are now entering clinical trials. His studies led to the demonstration of VEGF-C induced tumor angiogenesis and lymphangiogenesis, intralymphatic tumor growth, the association of VEGF-C with tumor metastasis and its inhibition by blocking the VEGFR-3 signal transduction pathway. Inhibitors and activators of this pathway have now been approved for clinical trials.

The EMBO Meeting
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