Lymphangiogenomics

 

 
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Control of the lymphatic endothelial differentiation program

 

 

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Last Update: June 23, 2009

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

  

 

 

 

  

 

 

 

 

Our long-term goals are to understand at the molecular level the mechanisms of growth of lymphatic vessels, to identify the key molecules in the lymphatic differentiation program as well as the tissue-specific heterogeneity of LECs. We want to use this knowledge to produce LECs and thier progenitors in vitro with a view to potential clinical applications. In the past two years the laboratories of the University of Helsinki and the Medical University of Vienna have established a method for the isolation of pure populations of primary human BECs and LECs, and carried out gene expression profiling in order to compare their transcriptional programs. Using oligonucleotide microarrays containing sequences form about 12,000 known genes, we have identified 167 BEC-specific and 135 LEC-specific genes. For example, the homeobox transcription factor PROX1 was specifically expressed in LECs consistent with its role in lymphatic endothelial differentiation in vivo. Adenoviral gene transfer of PROX1 into BECs demonstrated that this transcription factor is able to induce the expression of several LEC-specific genes, such as VEGFR-3. More surprisingly, it suppressed the expression of a large number of BEC-sprecific genes, thus validating its essential role in cell differentiation toward the lymphatic phenotype.

 

 

Coordinator of the Lymphangiogenomics program and responsible for this project:

 

 

Dr. Kari Alitalo

Molecular and Cancer Biology Research Program

Faculty of Medicine

University of Helsinki

P.O. Box 63 (Haartmaninkatu 8)

00014 Helsinki, Finland

Phone: +358 9 191 255 11

Fax: +358 9 191 255 10

E-mail: kari.alitalo(at)helsinki.fi

Homepage: http://research.med.helsinki.fi/cancerbio/

 

 

 

Selected recent publications:

  1. 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. 31;454(7204):656-60, 2008.
     
  2. Petrova TV, Nykänen A, Norrmén 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(5):407-19, 2008.
     
  3. 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. Nat Med.13(12):1458-66,2007.
     
  4. Wirzenius M, Tammela T, Uutela M, He Y, Odorisio T, Zambruno G, Nagy JA, Dvorak HF, Ylä-Herttuala S, Shibuya M, Alitalo K. Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting.. J Exp Med. 11;204(6):1431-40, 2007.
     
  5. Heckman CA, Holopainen T, Wirzenius M, Keskitalo S,Jeltsch M, Ylä-Herttuala S, Wedge SR, Jürgensmeier JM, and Alitalo K. The Tyrosine Kinase Inhibitor Cediranib Blocks Ligand-Induced Vascular Endothelial Growth Factor Receptor-3 Activity and Lymphangiogenesis. Cancer Res 68: 4757-4762, 2008.
     

  6. 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. Nat. Med. 13 (12); 1458-66, 2007.
     

  7. Wirzenius M, Tammela T, Uutela M, He Y, Odorisio T, Zambruno G, Nagy JA, Dvorak HF, Ylä-Herttuala S, Shibuya M, Alitalo K. Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting. J. Exp. Med. 204 (6); 1431-40, 2007.
     

  8. Wirzenius M, Tammela T, Uutela M, He Y, Odorisio T, Zambruno G, Nagy J.A, Dvorak H.F., Yla-Herttuala S, Shibuya M, and Alitalo K. Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting. J. Exp. Med., 10.1084/jem.20062642, 2007.
     

  9. Keskitalo S, Tammela T, Lyytikkä J, Kärpänen T, Jeltsch M, Markkanen J, Ylä-Herttuala S, Alitalo K. Enhanced capillary formation stimulated by a chimeric vascular endothelial growth factor/vascular endothelial growth factor-C silk domain fusion protein. Circ. Res. 100; 1460-7, 2007
     

  10. Tammela T, He Y, Lyytikkä J, Jeltsch M, Markkanen J, Pajusola K, Ylä-Herttuala S, Alitalo K. Distinct architecture of lymphatic vessels induced by chimeric vascular endothelial growth factor-C/vascular endothelial growth factor heparin-binding domain fusion proteins. Circ. Res. 100; 1468-75, 2007.
     

  11. Uutela M, Wirzenius M, Paavonen K, Rajantie I, He Y, Karpanen T, Lohela M, Wiig H, Salven P, Pajusola K, Eriksson U, Alitalo K. PDGF-D induces macrophage recruitment, increased interstitial pressure and blood vessel maturation during angiogenesis. Blood Vol. 104, No. 10, pp. 3198-3204, 2004.
     

  12. Paavonen K, Ekman N, Wirzenius M, Rajantie I, Poutanen M, Alitalo K. Bmx Tyrosine Kinase Transgene Induces Skin Hyperplasia, Inflammatory Angiogenesis, and Accelerated Wound Healing. Mol Biol Cell 15(9): 4226–4233, 2004.
     

  13. Wang HW, Trotter MW, Lagos D, Bourboulia D, Henderson S, Makinen T, Elliman S, Flanagan AM, Alitalo K, Boshoff C. Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma. Nat Genet 36:687-693, 2004.
     

  14. Bando H, Brokelmann M, Toi M, Alitalo K, Sleeman JP, Sipos B, Grone HJ, Weich HA. Immunodetection and quantification of vascular endothelial growth factor receptor-3 in human malignant tumor tissues. Int J Cancer 111:184-191, 2004.
     

  15. Rajantie I, Ilmonen M, Alminaite A, Ozerdem U, Alitalo K, Salven P. Adult bone marrow-derived cells recruited during angiogenesis comprise precursors for periendothelial vascular mural cells. Blood 2004, in press.
     

  16. He Y, Rajantie I, Ilmonen M, Makinen T, Karkkainen MJ, Haiko P, Salven P, Alitalo K. Preexisting lymphatic endothelium but not endothelial progenitor cells are essential for tumor lymphangiogenesis and lymphatic metastasis. Cancer Res 64:3737-3740, 2004.
     

  17. Weich HA, Bando H, Brokelmann M, Baumann P, Toi M, Barleon B, Alitalo K, Sipos B, Sleeman J. Quantification of vascular endothelial growth factor-C (VEGF-C) by a novel ELISA. J Immunol Methods 285:145-155, 2004.
     

  18. Wickstrom SA, Alitalo K, Keski-Oja J. An endostatin-derived peptide interacts with integrins and regulates actin cytoskeleton and migration of endothelial cells. J Biol Chem 279:20178-20185, 2004.
     

  19. Cao R, Eriksson A, Kubo H, Alitalo K, Cao Y, Thyberg J. Comparative evaluation of FGF-2-, VEGF-A-, and VEGF-C-induced angiogenesis, lymphangiogenesis, vascular fenestrations, and permeability. Circ Res 94:664-670, 2004.
     

  20. Ober EA, Olofsson B, Makinen T, Jin SW, Shoji W, Koh GY, Alitalo K, Stainier DY. Vegfc is required for vascular development and endoderm morphogenesis in zebrafish. EMBO Rep 5:78-84, 2004.
     

  21. 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. Nat Immunol 5:74-80, 2004.
     

  22. Veikkola T, Lohela M, Ikenberg K, Makinen T, Korff T, Saaristo A, Petrova T, Jeltsch M, Augustin HG, Alitalo K. Intrinsic versus microenvironmental regulation of lymphatic endothelial cell phenotype and function. FASEB J 17:2006-2013, 2003.
     

  23. Dixelius J, Makinen T, Wirzenius M, Karkkainen MJ, Wernstedt C, Alitalo K, Claesson-Welsh L. Ligand-induced vascular endothelial growth factor receptor-3 (VEGFR-3) heterodimerization with VEGFR-2 in primary lymphatic endothelial cells regulates tyrosine phosphorylation sites. J Biol Chem 278:40973-40979, 2003.
     

  24. Iljin K, Petrova TV, Veikkola T, Kumar V, Poutanen M, Alitalo K. A fluorescent Tie1 reporter allows monitoring of vascular development and endothelial cell isolation from transgenic mouse embryos. FASEB J 16:1764-1774, 2002.
     

  25. Veikkola T, Alitalo K. Dual role of Ang2 in postnatal angiogenesis and lymphangiogenesis. Dev Cell 3:302-304, 2002.
     

  26. Saaristo A, Veikkola T, Tammela T, Enholm B, Karkkainen MJ, Pajusola K, Bueler H, Yla-Herttuala S, Alitalo K. Lymphangiogenic gene therapy with minimal blood vascular side effects. J Exp Med 196:719-730, 2002.
     

  27. Petrova TV, Makinen T, Makela TP, Saarela J, Virtanen I, Ferrell RE, Finegold DN, Kerjaschki D, Yla-Herttuala S, Alitalo K. Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. EMBO J 21:4593-4599, 2002.
     

  28. Saaristo A, Veikkola T, Enholm B, Hytonen M, Arola J, Pajusola K, Turunen P, Jeltsch M, Karkkainen MJ, Kerjaschki D, Bueler H, Yla-Herttuala S, Alitalo K. Adenoviral VEGF-C overexpression induces blood vessel enlargement, tortuosity, and leakiness but no sprouting angiogenesis in the skin or mucous membranes. FASEB J 16:1041-1049, 2002.
     

  29. Kubo H, Cao R, Brakenhielm E, Makinen T, Cao Y, Alitalo K. Blockade of vascular endothelial growth factor receptor-3 signaling inhibits fibroblast growth factor-2-induced lymphangiogenesis in mouse cornea. Proc Natl Acad Sci USA 99:8868-8873, 2002.
     

  30. 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 94:819-825, 2002.