Angiogenesis in Cancer and Cardiovascular Diseases
28-29 August, 2008
Helsinki, Finland

Organiser:

Kari Alitalo: Molecular/Cancer Biology Center of Excellence, University of Helsinki, Finland

Draft Report

Description of the meeting

The meeting focused on the molecular and cellular mechanisms of angiogenesis in cancer and in cardiovascular disease. Insufficient or undesired angiogenesis is involved in a plethora of human diseases, and future pro- or anti-angiogenic therapies are estimated to benefit approximately 500 million people worldwide. The field is rapidly moving forward, as evidenced for example, by the striking connections between the mechanisms regulating cardiac hypertrophy and angiogenesis, as well as the novel discoveries on the hormonal control of angiogenesis. Additional novel insight has been gained in the elucidation of mechanisms governing tumor angiogenesis, as well as the
metastatic spreading of tumor cells via the lymphatic vascular system.

The meeting provided the attendees a comprehensive state-of-the-art overview of the latest advances in the field. The attendees witnessed outstanding presentations from the speakers (see final program below), and had ample time to interact with the speakers during the breaks. All of the talks provoked discussion and questions from the audience. Altogether 119 students registered for the meeting. The Helsinki Biomedical Graduate School (HBGS) awarded the participants study credits, and also contributed to the funding of the meeting. The meeting gave all participants, speakers and students alike, an opportunity to present their unpublished work. We received 18 poster submissions from diverse fields of biomedical research. The poster submissions were of high quality, and instead of the two intended prizes of 300 euros, the jury consisting of Professor Donald McDonald and Professor Kari Alitalo decided to award three prizes of 200 euros each. The prizes were awarded to Hanna Heloterä, Anou Londesborough, and Henrik Sandelin.

Scientific summary

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 cellular mechanisms regulating angiogenesis will constitute the 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 endothelial cells 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.

References

Arras, M., Ito, W. D., Scholz, D., Winkler, B., Schaper, J., and Schaper, W. (1998). Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J Clin Invest 101, 40-50.

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 from hyperplasia to neoplasia. Nature 339, 58-61.

Garcia-Cardena, G., Comander, J., Anderson, K. R., Blackman, B. R., and Gimbrone, M. A., Jr. (2001). Biomechanical activation 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. J Cell Biol 161, 1163-1177.

Hanahan, D., and Weinberg, R. A. (2000). The hallmarks of cancer. Cell 100, 57-70.

Ito, W. D., Arras, M., Winkler, B., Scholz, D., Schaper, J., and Schaper, W. (1997). Monocyte chemotactic protein-1 increases collateral and peripheral conductance after femoral artery occlusion. Circ Res 80, 829-837.

Jain, R. K. (2003). Molecular regulation of vessel maturation. Nat Med 9, 685-693.

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 development and 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 antibody phage 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. Cancer Cell 11, 53-67.

Pipp, F., Heil, M., Issbrucker, K., Ziegelhoeffer, T., Martin, S., van den Heuvel, J., Weich, H., Fernandez, B., Golomb, G., Carmeliet, P., et al. (2003). VEGFR-1-selective VEGF homologue PlGF is arteriogenic: evidence for a monocyte- mediated mechanism. Circ Res 92, 378-385.

Schaper, W., and Scholz, D. (2003). Factors regulating arteriogenesis. Arterioscler Thromb Vasc Biol 23, 1143-1151.

Tirziu, D., Chorianopoulos, E., Moodie, K. L., Palac, R. T., Zhuang, Z. W., Tjwa, M., Roncal, C., Eriksson, U., Fu, Q., Elfenbein, A., et al. (2007). Myocardial hypertrophy in the absence of external stimuli is induced by angiogenesis in mice. J Clin Invest 117, 3188-3197.

Programme

The programme can be viewed as a pdf here.