The Angiogenesis Program – A Brief History

Angiogenesis1 is the process of forming new blood vessels. Although part of the body’s natural processes (in wound healing and reproduction), angiogenesis is also stimulated by the release of angiogenic growth factors from tumor cells. Without the blood and nutrients that the newly-generated blood vessels supply, it is thought that no tumor would grow to be more than a few millimeters in size. Lymphangiogenesis2 is the related process of forming new lymphatic vessels, and is thought to play a major role in the spread of metastatic cells from a tumor.

Seven years ago, Dr. Ulf Eriksson, an LICR Member, and Head of the Developmental Biology Group at the Stockholm Branch, telephoned the LICR London Office to report that he had discovered, in a mouse library and as part of his study of retinoids, a hitherto unrecognized growth factor. This new molecule showed significant homology to a known vascular endothelial growth factor (VEGF), and thus he termed the new molecule, VEGF-B. Building on established interactions between Dr. Ralf Petersson, LICR Member, and Director of the Stockholm Branch, and Dr. Kari Alitalo, an LICR Affiliate at the University of Helsinki, the Stockholm Branch team then jointly cloned and identified the human form of VEGF-B3.

Dr. Alitalo had previously found a receptor on endothelial cells, which is now called VEGFR-3, and was searching for its ligand. It transpired not to be VEGF-B but the research activities resulted in the identification of another factor called VEGF-C, which did bind to VEGFR-34. Then, quite independently, and as part of another research effort, Drs. Steven Stacker and Mark Achen, both Assistant Members at the Melbourne Branch, identified a fourth vascular endothelial growth factor, that came to be known as VEGF-D5.

Combining all of these related, yet independent studies together to facilitate collaboration was the birth of the LICR Angiogenesis Program.

Meanwhile, Dr. Eriksson, not satisfied with just having found one ligand, went on to identify two new platelet-derived growth factors (PDGF-C and PDGF-D), whose human equivalents have also been cloned and characterized jointly with Dr. Alitalo 6,7. At this juncture, Dr. Carl-Henrik Heldin, LICR Member, and Director of the Uppsala Branch, joined his expertise in biology and biochemistry to study these new factors. The properties of PDGF-C and –D, and the question of whether they work via known or currently unrecognized receptors, are currently being pursued by collaborative interactions between the teams of Drs. Eriksson, Alitalo, and Arne Östman, an LICR Associate Member, and Head of the Growth Regulation Group at the Uppsala Branch, and in conjunction with the team of Dr. Peter Carmeliet, University of Leuven, Belgium.

The research conducted as part of the Angiogenesis Program fits into several different aspects of human disease. For example, VEGF-B has been found to be important with respect to decreasing the extent of damage to the heart following coronary artery occlusion8. Dr. Alitalo found that VEGFR-3 was up-regulated in small blood vessels and the lymphatic system in and around breast and other tumors, with VEGF-C working through it to control angiogenesis and possibly also lymphangiogenesis9. Projects conducted within the Program have since shown that blocking the receptor’s activity using antibodies to the VEGF-D ligand10 can inhibit the development of metastases in model systems.

Excitingly, there is evidence to suggest that the various factors and their receptors discussed herein, may also have roles to play in the mobilization of bone marrow stem cells, in addition to their participation in angiogenesis 11.

The focus of the Program is now shifting towards aspects of intracellular signaling, the inhibition of angiogenesis and lymphangiogenesis, and vascular stem cell biology. The group is frequently in close contact with one another, and its next meeting is scheduled to take place in New York on September 18 this year, when the current status of its activities will be reviewed. Any member of the Institute who wishes to join the Angiogenesis Program is more than welcome.

A. Munro Neville
Angiogenesis Program Co-ordinator

References

1. Saaristo A, Karpanen T, and Alitalo K. Mechanisms of angiogenesis and their use in the inhibition of tumor growth and metastasis. (2000) Oncogene 19(53):6122-6129

2. Stacker SA, Baldwin ME, and Achen MG. The role of tumor lymphangiogenesis in metastatic spread. (2002) FASEB J. 16(9):922-934

3. Olofsson B, Pajusola K, Kaipainen A, von Euler G, Joukov V, Saksela O, Orpana A, Pettersson RF, Alitalo K, and Eriksson U. Vascular endothelial growth factor B, a novel growth factor for endothelial cells. (1996) Proc.Natl.Acad.Sci.U.S.A 93(6):2576-2581

4. Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, and Alitalo K. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. (1996) EMBO J. 15(7):1751

5. Achen MG, Jeltsch M, Kukk E, Makinen T, Vitali A, Wilks AF, Alitalo K, and Stacker SA. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). (1998) Proc.Natl.Acad.Sci.U.S.A 95(2):548-553

6. Bergsten E, Uutela M, Li X, Pietras K, Ostman A, Heldin CH, Alitalo K, and Eriksson U. PDGF-D is a specific, protease-activated ligand for the PDGF beta-receptor. (2001) Nat.Cell Biol. 3(5):512-516

7. Eitner F, Ostendorf T, Van Roeyen C, Kitahara M, Li X, Aase K, Grone HJ, Eriksson U, and Floege J. Expression of a novel PDGF isoform, PDGF-C, in normal and diseased rat kidney. (2002) J.Am.Soc.Nephrol. 13(4):910-917

8. Bellomo D, Headrick JP, Silins GU, Paterson CA, Thomas PS, Gartside M, Mould A, Cahill MM, Tonks ID, Grimmond SM, Townson S, Wells C, Little M, Cummings MC, Hayward NK, and Kay GF. Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. (2000) Circ.Res 86(2):E29-E35

9. Valtola R, Salven P, Heikkila P, Taipale J, Joensuu H, Rehn M, Pihlajaniemi T, Weich H, deWaal R, and Alitalo K. VEGFR-3 and Its Ligand VEGF-C Are Associated with Angiogenesis in Breast Cancer. (1999) American Journal of Pathology 154(5):1381

10. Achen MG, Roufail S, Domagala T, Catimel B, Nice EC, Geleick DM, Murphy R, Scott AM, Caesar C, Makinen T, Alitalo K, and Stacker SA. Monoclonal antibodies to vascular endothelial growth factor-D block its interactions with both VEGF receptor-2 and VEGF receptor-3. (2000) Eur.J.Biochem. 267(9):2505-2515

11. Rappold I, Ziegler BL, Kohler I, Marchetto S, Rosnet O, Birnbaum D, Simmons PJ, Zannettino ACW, Hill B, Neu S, Knapp W, Alitalo R, Alitalo K, Ullrich A, Kanz L, and Buhring HJ. Functional and Phenotypic Characterization of Cord Blood and Bone Marrow Subsets Expressing FLT3 (CD135) Receptor Tyrosine Kinase. (1997) Blood 90(1):111

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