The EMBO Meeting 2012

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.

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

Therapeutic Potential of Vascular Endothelial Growth Factors

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. – Thus, there is still 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.

Yale School of Medicine

Guidance of vascular patterning: lessons from the nervous system

Anatomical parallels between the nervous and the vascular system are readily apparent in peripheral body tissues, where blood vessels and nerves ramify throughout nearly all domains of the body and are usually aligned. Alignment of nerves and blood vessels allows the establishment of a physical relationship between them, as larger nerves are vascularized by vasa nervorum to ensure their oxygen and nutriment supply, while arteries are innervated by autonomic nerve fibers that control vascular tone. To orchestrate the formation of their highly branched, exquisitely wired networks, nerves and blood vessels have developed shared cellular and molecular principles.

Biography

My laboratory studies vascular and lymphatic development, with particular interests in mechanisms that direct vascular patterning and guidance. We have shown that in blood vessels, specialized endothelial cells called tip cells located 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 selection is induced by VEGF signaling through VEGFR2 and is suppressed in stalk cells by Delta-Notch signaling. Capillary sprouting also shows morphological similarities to axon guidance. Like endothelial tip cells, axonal growth cones extend filopodia that sense and respond to extracellular guidance cues. We have identified several key molecules regulating capillary and lymphatic guidance, including the Netrin receptor UNC5B, Robo4 and the Neuropilin 1 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.