Organiser

Kari Alitalo, University of Helsinki, Finland

Introduction

Angiogenesis, the growth of new blood vessels from pre-existing vasculature, is uncontrolled in tumor growth and insufficient in tissue ischemia. Neoplastic lesions are unable to grow beyond a small size without engaging a gene expression program that initiates angiogenesis, termed “the angiogenic switch” (Ferrara and Kerbel, 2005; Folkman et al., 1989). Blood vessels in tumors lack hierarchial organization and are leaky, leading to sluggish blood flow and high interstitial fluid pressure within the tumor (reviewed in (Jain, 2003; Jain, 2005; McDonald and Choyke, 2003). Hypoperfusion within the tumor perpetuates hypoxia and VEGF production, while high intratumoral fluid pressure hampers the delivery of therapeutic agents (Jain, 2003; Jain, 2005). As tumor growth is dependent on angiogenesis, and as vascular cells, unlike tumor cells, are less likely to become resistant to therapeutics, targeting the tumor vasculature is an attractive strategy to treat cancer patients (Folkman, 1971; Hanahan and Weinberg, 2000). On the other hand, it is conceivable that anti-angiogenic therapies promote the dedifferentiation of tumor cells by increasing hypoxic stress (Axelson et al., 2005), and considering therapeutic possibilities to avoid hypoxic cellular responses is at the heart of current research efforts. The emerging approaches to study tumor-specific hypoxic responses include chromatin modifications and miRNA profiling. The epgenetic and ”traditional” cellular mechanisms regulating angiogenesis will be a key focus of the meeting.

Conversely, angiogenesis is frequently insufficient in ischemic tissues e.g. following arterial occlusion in the heart or the lower limb. Strategies to induce therapeutic growth of microvessels and, in particular, arteries are being developed to efficiently revascularize ischemic tissues. Interestingly, recent work has elucidated a link between vascular growth and myocardial hypertrophy, suggesting that intersecting pathways regulating both angiogenesis and cardiomyocyte growth exist (Tirziu et al., 2007). Arteriogenesis, or remodeling of angiogenic blood vascular capillaries or small arterioles into larger caliber vessels that acquire a thick smooth muscle cell coating, is known to occur in ischemic conditions (reviewed in (Schaper and Scholz, 2003)). Circumferentially directed stress and shear stress acting on the endothelium are key forces that drive arteriogenesis, and changes in fluid flow have been shown to regulate gene expression in blood endothelial cells (Garcia-Cardena et al., 2001; Schaper and Scholz, 2003). Furthermore, reactive inflammation of the vessel wall and recruitment of monocytes/macrophages are important for arteriogenesis (Arras et al., 1998; Ito et al., 1997; Pipp et al., 2003). The molecular mechanisms of
arteriogenesis and myocardial hypertrophy in the context of angiogenesis constitute another focus of the meeting.

Far from being passive bystanders, endothelial cells have multiple functions: They regulate blood flow by releasing nitric oxide to relax smooth muscle that constricts vessels; act as gatekeepers for cells and macromolecules in between the blood and the interstitium; and respond to growth factors that stimulate the formation of new blood vessels. Endothelial cell biology is therefore at the heart of all molecular processes regulating angiogenesis. Angiogenic sprouting involves specification of
subpopulations of ECs into tip cells, that respond to guidance cues in the surrounding microenvironment, and stalk cells that follow the tip cells and proliferate to form a lumenized vascular network (Gerhardt et al., 2003). This is followed by stabilization and remodeling of the nascent vasculature (reviewed in (Coultas et al., 2005)). The recent years have seen considerable advances in understanding endothelial cell guidance, specification, and stabilization, and molecular mechanisms regulating these processes, including VEGF/VEGFR-2, Notch, angiopoietin/Tie, and VEGF-C/VEGFR-3 will be covered by leading experts in the meeting.

The analogy between axon guidance and endothelial tip cell migration has various neural guidance molecules has recently been implicated as an attractive strategy to target angiogenesis. Most importantly, neuropilin-1 was recently shown to be important for tumor angiogenesis (Liang et al., 2007; Pan et al., 2007). Other neural guidance ligand/receptor systems that have been implicated in the growth and angiogenesis of experimental tumors include Robo1/Slit-2, netrin-1/Unc5b, and
ephrinB2/EphB4 (reviewed in (Carmeliet and Tessier-Lavigne, 2005; Klagsbrun and Eichmann, 2005)). These mechanisms will be addressed by one or two specialists in the field.

References
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Axelson, H., Fredlund, E., Ovenberger, M., Landberg, G., and Pahlman, S. (2005). Hypoxia-induced dedifferentiation of tumor cells--a mechanism behind heterogeneity and aggressiveness of solid tumors. Semin Cell Dev Biol 16, 554-563.
Carmeliet, P., and Tessier-Lavigne, M. (2005). Common mechanisms of nerve and blood vessel wiring. Nature 436,193-200.
Coultas, L., Chawengsaksophak, K., and Rossant, J. (2005). Endothelial cells and VEGF in vascular development.Nature 438, 937-945.
Ferrara, N., and Kerbel, R. S. (2005). Angiogenesis as a therapeutic target. Nature 438, 967-974.
Folkman, J. (1971). Tumour angiogenesis: therapeutic implications. N Engl J Med 285, 1182-1186.
Folkman, J., Watson, K., Ingber, D., and Hanahan, D. (1989). Induction of angiogenesis during the transition fromhyperplasia to neoplasia. Nature 339, 58-61.
Garcia-Cardena, G., Comander, J., Anderson, K. R., Blackman, B. R., and Gimbrone, M. A., Jr. (2001). Biomechanicalactivation of vascular endothelium as a determinant of its functional phenotype. Proc Natl Acad Sci U S A 98, 44784485.
Gerhardt, H., Golding, M., Fruttiger, M., Ruhrberg, C., Lundkvist, A., Abramsson, A., Jeltsch, M., Mitchell, C., Alitalo,K., Shima, D., and Betsholtz, C. (2003). VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. JCell Biol 161, 1163-1177.
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Ito, W. D., Arras, M., Winkler, B., Scholz, D., Schaper, J., and Schaper, W. (1997). Monocyte chemotactic protein-1increases collateral and peripheral conductance after femoral artery occlusion. Circ Res 80, 829-837.
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Jain, R. K. (2005). Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307,58-62.
Klagsbrun, M., and Eichmann, A. (2005). A role for axon guidance receptors and ligands in blood vessel developmentand tumor angiogenesis. Cytokine Growth Factor Rev 16, 535-548.
Liang, W. C., Dennis, M. S., Stawicki, S., Chanthery, Y., Pan, Q., Chen, Y., Eigenbrot, C., Yin, J., Koch, A. W., Wu,X., et al. (2007). Function blocking antibodies to neuropilin-1 generated from a designed human synthetic antibodyphage library. J Mol Biol 366, 815-829.
McDonald, D. M., and Choyke, P. L. (2003). Imaging of angiogenesis: from microscope to clinic. Nat Med 9, 713-725.
Pan, Q., Chanthery, Y., Liang, W. C., Stawicki, S., Mak, J., Rathore, N., Tong, R. K., Kowalski, J., Yee, S. F., Pacheco,G., et al. (2007). Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. CancerCell 11, 53-67.
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Preliminary Programme

28.8.2008

Session I Chairman: Tuomas Tammela

13:00-13:45 Marc Tessier-Lavigne, Genentech Inc, USA
Keynote presentation: “Neural guidance molecules in angiogenesis”
13:45-14:30 Peter Staller, BRIC, Copenhagen, Denmark
“Cellular metabolism and epigenetics in hypoxia”
14:30-15:00 Coffee break

15:00 -15:45 Michael Simons, Dartmouth Medical School, USA
“Intersecting pathways regulating angiogenesis and cardiac hypertrophy”
15:45-16:30 Andras Nagy, Samuel Lunenfeld Research Institute, Toronto, Canada
“Manipulation of the mouse genome for the discovery of genes
regulating angiogenesis”

19:00- Speakers’ dinner

29.8.2008

Session II Chairman: Kari Alitalo

9:30-10:15 Christer Betsholtz, Karoliska Instittutet, Sweden
” Tip and stalk cell specification in the formation of vascular networks”

10:15-11:00 Tuomas Tammela, University of Helsinki, Finland
“The VEGF-C/VEGFR-3 pathway in lymphangiogenesis and
angiogenesis”

11:00-11:15 Coffee break

11:15-12:00 Dietmar Vestweber, University of Münster, Germany
” Adhesion and signaling molecules controlling the transmigration of
leukocytes through endothelium”

12:00-12:45 Pipsa Saharinen, University of Helsinki, Finland
“Novel concepts in angiopoietin/Tie signaling”
12:45-13:45 Lunch

Session III Chairman: Pipsa Saharinen

13:45-14:30 Mark Kahn, University of Pennsylvania, Philadelphia, USA
“Mechanisms of blood and lymphatic vessel separation”
14:30-15:15 Sirpa Jalkanen, University of Turku, Finland

”Endothelial adhesion molecules in leukocyte trafficking and cancer”
15:15-15:30 Coffee break
15:30-16:15 Seppo Ylä-Herttuala, University of Kuopio, Finland

“Gene therapy of peripheral vascular disease”
16:15-17:00 Heikki Ruskoaho, University of Oulu, Finland
”Hypertension and remodeling of the heart”
17:00-Poster session, wine & cheese

Venue

The conference will be held at the Biomedicum Helsinki.
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Registration

Registration is closed.