Kari Alitalo
    Academy Professor, M.D., Dr. Med.Sci.

    Translational Cancer Biology Research Program
    Institute of Biomedicine
    Biomedicum Helsinki

    Director
    Wihuri Research Institute

    P.O. Box 63 (Haartmaninkatu 8)
    FI-00014 University of Helsinki
    Finland

    Tel. +358 2 941 25511
    Fax +358 2 941 25510

    firstname.surname@helsinki.fi

Affiliations

Alma-intranet Flammaintra

Selected publications

1. Tammela T, Zarkada G, Nurmi H, Jakobsson L, Heinolainen K, Tvorogov D, Zheng W, Franco CA, Murtomäki A, Aranda E, Miura N, Ylä-Herttuala S, Fruttiger M, Mäkinen T, Eichmann A, Pollard JW, Gerhardt H, Alitalo K. VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nature Cell Biol 13: 1202-1213, 2011.

The mechanism of ligand-independent VEGFR-3 function in blood vessel fusions.

2. Tammela T, Saaristo A, Holopainen T, Ylä-Herttuala S, Andersson LC, Virolainen S, Immonen I, Alitalo K. Photodynamic ablation of lymphatic vessels and intralymphatic cancer cells prevents metastasis. Sci Transl Med 3: 69ra11, 2011.

A new method to inhibit in transit/satellite metastasis.

3. Tvorogov D, Anisimov A, Zheng W, Leppänen V-M, Tammela T, Laurinavicius S, Holnthoner W, Heloterä H, Holopainen T, Jeltsch M, Kalkkinen N, Lankinen H, Ojala P, Alitalo K. Effective Suppression of Vascular Network Formation by Combination of Antibodies Blocking VEGFR Ligand Binding and Receptor Dimerization. Cancer Cell 18: 630-40, 2010.

These results indicate that VEGF receptor directed antibodies that inhibit ligand binding and receptor dimerization have additive or even synergistic effects.

4. V-M Leppänen, A Prota, M Jeltsch, A Anisimov, N Kalkkinen, T Strandin, H Lankinen, A Goldman, K Ballmer-Hofer and K Alitalo: Structural determinants of growth factor binding and specificity by VEGF-Receptor 2. Proc Natl Acad Sci USA, 107: 2425-2430, 2010.

The structure of VEGF-C, and its complex with the main angiogenic receptor VEGFR-2.

5. Petrova TV, Nykanen A, Norrmen C, Ivanov KI, Andersson LC, Haglund C, Puolakkainen P, Wempe F, von Melchner H, Gradwohl G, Vanharanta S, Aaltonen LA, Saharinen J, Gentile M, Clarke A, Taipale J, Oliver G, Alitalo K: Transcription factor PROX1 induces colon cancer progression by promoting the transition from benign to highly dysplastic phenotype. Cancer Cell 13: 407-19, 2008.

Discovery of the involvement of a transcription factor and lymphatic marker in the malignant conversion of colonic tumors.

6. Tammela T, Zarkada G, Wallgard E, Murtomäki A, Suchting S, Wirzenius M, Waltari M, Hellström M, Schomber T, Peltonen R, Freitas C, Duarte A, Isoniemi H, Laakkonen P, Christofori G, Ylä-Herttuala S, Shibuya M, Pytowski B, Eichmann A, Betsholtz C, Alitalo K. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454: 656-60, 2008.

This paper reveals a new mechanism involved in blood vessel sprouting and provides an additional target for angiogenesis inhibition.

7. Tammela T, Saaristo A, Holopainen T, Lyytikkä J, Kotronen A, Pitkonen M, Abo-Ramadan U, Ylä-Herttuala S, Petrova TV, Alitalo K. Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation. Nature Medicine 13: 1458-66, 2007.

The first evidence that collecting lymphatic vessels can differentiate from lymphatic capillaries in adults and that VEGF-C gene therapy induces this process.

8. He Y, Rajantie I, Pajusola K, Jeltsch M, Holopainen T, Yla-Herttuala S, Harding T, Jooss K, Takahashi T, Alitalo K. Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. Cancer Res 65: 4739-46, 2005.

The mechanism of VEGF-C induced lymphatic sprouting towards as well as dilation of the draining lymphatic vessels, both contributing to lymphatic metastasis. These processes were blocked dose-dependently by inhibition of VEGFR-3.

9. Petrova TV, Karpanen T, Norrmen C, Mellor R, Tamakoshi T, Finegold D, Ferrell R, Kerjaschki D, Mortimer P, Yla-Herttuala S, Miura N, Alitalo K. Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nature Medicine 10: 974-81, 2004.

Mechanism of development of Lymphedema distichiasis.

10. Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV, Jeltsch M, Jackson DG, Talikka M, Rauvala H, Betsholtz C, Alitalo K. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nature Immunology 5:74-80, 2004.

The results of this paper indicate that VEGF-C is the paracrine factor essential for lymphangiogenesis, and that both Vegfc alleles are required for normal lymphatic development.

11. He Y, Kozaki K, Karpanen T, Koshikawa K, Yla-Herttuala S, Takahashi T, Alitalo K. Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J Natl Cancer Inst 94: 819-25, 2002.

Development of VEGFR-3 signaling inhibitor for suppression of tumor lymphangiogenesis and metastasis to regional lymph nodes.

12. Mäkinen, T., Jussila, L., Veikkola, T., Kärpänen, T., Kettunen, M.I., Pulkkanen, K.J., Kauppinen, R., Jackson, D.G., Kubo, H., Nishikawa, S.-I., Ylä-Herttuala, S. and Alitalo, K.: Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nature Medicine 7: 199-205, 2001.

Demonstration that a soluble form of VEGFR-3 is a potent inhibitor of VEGF-C/VEGF-D signaling and lymphangiogenesis.

13. Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, Banerji S, Huarte J, Montesano R, Jackson DG, Orci L, Alitalo K, ChristoforiG, Pepper MS. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J 20:672-82, 2001.

Demonstration that VEGF-C-induced lymphangiogenesis mediates tumour cell dissemination and the formation of lymph node metastases.
Note the Acknowledgements:" The project presented in this manuscript was conceived and started in Helsinki, and the work is the result of an equal contribution from the laboratories in Helsinki, Vienna and Geneva, together with a major contribution from the Oxford group." This project was thus started in 1995 in Dr. Alitalo's laboratory.

14. Karpanen T, Egeblad M, Karkkainen MJ, Kubo H, Yla-Herttuala S, Jaattela M, Alitalo K. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res 61:1786-90, 2001.

These data show that VEGF-C facilitates tumor metastasis to the lymphatic vessels and that tumor spread is inhibited by blocking the interaction between VEGF-C and its receptor.

15. Karkkainen MJ, Saaristo A, Jussila L, Karila KA, Lawrence EC, Pajusola K, Bueler H, Eichmann A, Kauppinen R, Kettunen MI, Yla-Herttuala S, Finegold DN, Ferrell RE, Alitalo K. A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci USA 98: 12677-82, 2001.

First demonstration that growth factor gene therapy would be applicable to human lymphedema and provide a paradigm for other diseases associated with mutant receptors.

16. Karkkainen, M.J., Ferrell, R.E., Lawrence, E.C., Kimak, M.A., Levinson, K.L., McTigue, M.A., Alitalo, K. and Finegold, D.N.: Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Nature Genetics 25: 153-159, 2000.

Heterozygous missense mutations of VEGFR-3 were shown to inactivate the tyrosine kinase and downstream gene activation in primary lymphedema, indicating that mutations interfering with VEGFR-3 signal transduction are a cause of primary lymphoedema.

17. Dumont DJ, Jussila L, Taipale J, Lymboussaki A, Mustonen T, Pajusola K, Breitman M Alitalo K: Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282: 946-949, 1998.

This paper shows that VEGFR-3 has an essential role in the development of the embryonic cardiovascular system before the emergence of the lymphatic vessels.

18. Cao Y, Linden P, Farnebo J, Cao R, Eriksson A, Kumar V, Qi JH, Claesson-Welsh L, Alitalo K: Vascular endothelial growth factor-C induces angiogenesis in vivo. Proc Natl Acad Sci 95: 14389-14394, 1998.

Demonstration of the angiogenic activity of mature VEGF-C, suggesting that this factor could participate in the development and progression of angiogenic diseases in addition to lymphangiogenesis.

19. Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, Swartz M, Fukumura D, Rakesh KJ, Alitalo K: Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276: 1423-1425, 1997.

Transgenic overexpression of VEGF-C was found to induce lymphatic, but not vascular, endothelial proliferation and vessel growth. VEGF-C was predicted to play a role in disorders involving the lymphatic system.

20. Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, Saksela O, Kalkkinen N, Alitalo K: Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J 16: 3898-3911, 1997.

Effects of post-translational processing in VEGF-C secretion and function, as well as the structure of the mature VEGF-C.