305
Views
27
CrossRef citations to date
0
Altmetric
Articles

Vascular endothelial growth factor-D: signaling mechanisms, biology, and clinical relevance

&
Pages 283-296 | Received 27 Apr 2012, Accepted 18 Jun 2012, Published online: 20 Jul 2012

References

  • Achen MG, Stacker SA. 2008. Molecular control of lymphatic metastasis. Ann NY Acad Sci. 1131:225–234.
  • Achen MG, Jeltsch M, Kukk E, Makinen T, Vitali A, Wilks AF, Alitalo K, Stacker SA. 1998. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci USA. 95:548–553.
  • Achen MG, Roufail S, Domagala T, Catimel B, Nice EC, Geleick DM, Murphy R, Scott AM, Caesar C, Makinen T, Alitalo K, Stacker SA. 2000. Monoclonal antibodies to vascular endothelial growth factor-D block interactions with both VEGF receptor-2 and VEGF receptor-3. Eur J Biochem. 267:2505–2515.
  • Achen MG, Williams RA, Minekus MP, Thornton GE, Stenvers K, Rogers PA, Lederman F, Roufail S, Stacker SA. 2001. Localization of vascular endothelial growth factor-D in malignant melanoma suggests a role in tumour angiogenesis. J Pathol. 193:147–154.
  • Achen MG, McColl BK, Stacker SA. 2005. Focus on lymphangiogenesis in tumor metastasis. Cancer Cell. 7:121–127.
  • Adams RH, Alitalo K. 2007. Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol. 8:464–478.
  • Alam A, Herault JP, Barron P, Favier B, Fons P, Delesque-Touchard N, Senegas I, Laboudie P, Bonnin J, Cassan C, Savi P, Ruggeri B, Carmeliet P, Bono F, Herbert JM. 2004. Heterodimerization with vascular endothelial growth factor receptor-2 (VEGFR-2) is necessary for VEGFR-3 activity. Biochem Biophys Res Commun. 324:909–915.
  • Algra AM, Rothwell PM. 2012. Effects of regular aspirin on long-term cancer incidence and metastasis: A systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncol. 13:518–527.
  • Anisimov A, Alitalo A, Korpisalo P, Soronen J, Kaijalainen S, Leppanen VM, Jeltsch M, Yla-Herttuala S, Alitalo K. 2009. Activated forms of VEGF-C and VEGF-D provide improved vascular function in skeletal muscle. Circ Res. 104:1302–1312.
  • Artenstein AW, Opal SM. 2011. Proprotein convertases in health and disease. New Engl J Med. 365:2507–2518.
  • Avantaggiato V, Orlandini M, Acampora D, Oliviero S, Simeone A. 1998. Embryonic expression pattern of the murine figf gene, a growth factor belonging to platelet-derived growth factor/vascular endothelial growth factor family. Mech Dev. 73:221–224.
  • Baldwin ME, Catimel B, Nice EC, Roufail S, Hall NE, Stenvers KL, Karkkainen MJ, Alitalo K, Stacker SA, Achen MG. The specificity of receptor binding by vascular endothelial growth factor-D is different in mouse and man. J Biol Chem. 2001a; 276:19166–19171.
  • Baldwin ME, Roufail S, Halford MM, Alitalo K, Stacker SA, Achen MG. Multiple forms of mouse vascular endothelial growth factor-D are generated by RNA splicing and proteolysis. J Biol Chem. 2001b; 276:44307–44314.
  • Baldwin ME, Stacker SA, Achen MG. 2002. Molecular control of lymphangiogenesis. Bioessays. 24:1030–1040.
  • Baldwin ME, Halford MM, Roufail S, Williams RA, Hibbs ML, Grail D, Kubo H, Stacker SA, Achen MG. 2005. Vascular endothelial growth factor D is dispensable for development of the lymphatic system. Mol Cell Biol. 25:2441–2449.
  • Baluk P, Tammela T, Ator E, Lyubynska N, Achen MG, Hicklin DJ, Jeltsch M, Petrova TV, Pytowski B, Stacker SA, Yla-Herttuala S, Jackson DG, Alitalo K, McDonald DM. 2005. Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation. J Clin Invest. 115:247–257.
  • Bazigou E, Xie S, Chen C, Weston A, Miura N, Sorokin L, Adams R, Muro AF, Sheppard D, Makinen T. 2009. Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis. Dev Cell. 17:175–186.
  • Benedito R, Rocha SF, Woeste M, Zamykal M, Radtke F, Casanovas O, Duarte A, Pytowski B, Adams RH. 2012. Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling. Nature. 484:110–114.
  • Bhardwaj S, Roy H, Gruchala M, Viita H, Kholova I, Kokina I, Achen MG, Stacker SA, Hedman M, Alitalo K, Yla-Herttuala S. 2003. Angiogenic responses of vascular endothelial growth factors in periadventitial tissue. Hum Gene Ther. 14:1451–1562.
  • Byzova TV, Goldman CK, Jankau J, Chen J, Cabrera G, Achen MG, Stacker SA, Carnevale KA, Siemionow M, Deitcher SR, DiCorleto PE. 2002. Adenovirus encoding vascular endothelial growth factor-D induces tissue-specific vascular patterns in vivo. Blood. 99:4434–4442.
  • Cao Y, Linden P, Farnebo J, Cao R, Eriksson A, Kumar V, Qi JH, Claesson-Welsh L, Alitalo K. 1998. Vascular endothelial growth factor C induces angiogenesis in vivo. Proc Natl Acad Sci USA. 95:14389–14394.
  • Caunt M, Mak J, Liang WC, Stawicki S, Pan Q, Tong RK, Kowalski J, Ho C, Reslan HB, Ross J, Berry L, Kasman I, Zlot C, Cheng Z, Le Couter J, Filvaroff EH, Plowman G, Peale F, French D, Carano R, Koch AW, Wu Y, Watts RJ, Tessier-Lavigne M, Bagri A. 2008. Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell. 13:331–342.
  • Chretien M, Seidah NG, Basak A, Mbikay M. 2008. Proprotein convertases as therapeutic targets. Expert Opin Ther Targets. 12:1289–1300.
  • Crawford Y, Ferrara N. 2009. VEGF inhibition: Insights from preclinical and clinical studies. Cell Tissue Res. 335:261–269.
  • Davydova N, Roufail S, Streltsov VA, Stacker SA, Achen MG. 2011. The VD1 neutralizing antibody to vascular endothelial growth factor-D: Binding epitope and relationship to receptor binding. J Mol Biol. 407:581–593.
  • Davydova N, Streltsov VA, Roufail S, Lovrecz GO, Stacker SA, Adams TE, Achen MG. 2012. Preparation of human vascular endothelial growth factor-D for structural and preclinical therapeutic studies. Protein Expr Purif. 82:232–239.
  • Debinski W, Slagle-Webb B, Achen MG, Stacker SA, Tulchinsky E, Gillespie GY, Gibo DM. 2001. VEGF-D is an X-linked/AP-1 regulated putative onco-angiogen in human glioblastoma multiforme. Mol Med. 7:598–608.
  • Dignam SS, Case ST. 1990. Balbiani ring 3 in Chironomus tentans encodes a 185-kDa secretory protein which is synthesized throughout the fourth larval instar. Gene. 88:133–140.
  • Farnsworth RH, Karnezis T, Shayan R, Matsumoto M, Nowell CJ, Achen MG, Stacker SA. 2011. A role for bone morphogenic protein-4 in vascular endothelial growth factor-D mediated tumor growth, metastasis and vessel remodelling. Cancer Res. 71:6547–6557.
  • Fuster V, Charlton P, Boyd A. 2001. Clinical protocol. A phase IIb, randomized, multicenter, double-blind study of the efficacy and safety of Trinam (EG004) in stenosis prevention at the graft-vein anastomosis site in dialysis patients. Hum Gene Ther. 12:2025–2027.
  • Girling JE, Donoghue JF, Lederman FL, Cann LM, Achen MG, Stacker SA, Rogers PA. 2010. Vascular endothelial growth factor-D over-expressing tumor cells induce differential effects on uterine vasculature in a mouse model of endometrial cancer. Reprod Biol Endocrinol. 8:84.
  • Glasgow CG, Avila NA, Lin JP, Stylianou MP, Moss J. 2009. Serum vascular endothelial growth factor-D levels in patients with lymphangioleiomyomatosis reflect lymphatic involvement. Chest. 135:1293–1300.
  • Haiko P, Makinen T, Keskitalo S, Taipale J, Karkkainen MJ, Baldwin ME, Stacker SA, Achen MG, Alitalo K. 2008. Deletion of vascular endothelial growth factor C (VEGF-C) and VEGF-D is not equivalent to VEGF receptor 3 deletion in mouse embryos. Mol Cell Biol. 28:4843–4850.
  • Hajrasouliha AR, Funaki T, Sadrai Z, Hattori T, Chauhan SK, Dana R. 2012. Vascular endothelial growth factor-C promotes alloimmunity by amplifying antigen-presenting cell maturation and lymphangiogenesis. Invest Ophthalmol Vis Sci. 53:1244–1250.
  • Halford MM, Tebbutt NC, Desai J, Achen MG, Stacker SA. 2012. Towards the biomarker-guided rational use of anti-angiogenic agents in the treatment of metastatic colorectal cancer. Colorectal Cancer. 1:149–161.
  • Harris NC, Paavonen K, Davydova N, Roufail S, Sato T, Zhang YF, Karnezis T, Stacker SA, Achen MG. 2011. Proteolytic processing of vascular endothelial growth factor-D is essential for its capacity to promote the growth and spread of cancer. FASEB J. 25:2615–2625.
  • He Y, Kozaki K, Karpanen T, Koshikawa K, Yla-Herttuala S, Takahashi T, Alitalo K. 2002. Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J Natl Cancer Inst. 94:819–825.
  • He Y, Rajantie I, Pajusola K, Jeltsch M, Holopainen T, Yla-Herttuala S, Harding T, Jooss K, Takahashi T, Alitalo K. 2005. 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. 65:4739–4746.
  • Holmes MD, Chen WY, Li L, Hertzmark E, Spiegelman D, Hankinson SE. 2010. Aspirin intake and survival after breast cancer. J Clin Oncol. 28:1467–1472.
  • Huggenberger R, Ullmann S, Proulx ST, Pytowski B, Alitalo K, Detmar M. 2010. Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation. J Exp Med. 207:2255–2269.
  • Huggenberger R, Siddiqui SS, Brander D, Ullmann S, Zimmermann K, Antsiferova M, Werner S, Alitalo K, Detmar M. 2011. An important role of lymphatic vessel activation in limiting acute inflammation. Blood. 117:4667–4678.
  • Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. 2004. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New Engl J Med. 350:2335–2342.
  • Jenkins NA, Woollatt E, Crawford J, Gilbert DJ, Baldwin ME, Sutherland GR, Copeland NG, Achen MG. 1997. Mapping of the gene for vascular endothelial growth factor-D in mouse and man to the X chromosome. Chromosome Res. 5:502–505.
  • Jia H, Bagherzadeh A, Bicknell R, Duchen MR, Liu D, Zachary I. 2004. Vascular endothelial growth factor (VEGF)-D and VEGF-A differentially regulate KDR-mediated signaling and biological function in vascular endothelial cells. J Biol Chem. 279:36148–36157.
  • Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K. 1996. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt-4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J. 15:290–298.
  • Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, Saksela O, Kalkkinen N, Alitalo K. 1997. Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J. 16:3898–3911.
  • Kabbinavar FF, Hambleton J, Mass RD, Hurwitz HI, Bergsland E, Sarkar S. 2005. Combined analysis of efficacy: The addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol. 23:3706–3712.
  • Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV, Jeltsch M, Jackson DG, Talikka M, Rauvala H, Betsholtz C, Alitalo K. 2004. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol. 5:74–80.
  • Karnezis T, Shayan R, Caesar C, Roufail S, Harris NC, Ardipradja K, Zhang YF, Williams SP, Farnsworth RH, Chai MG, Rupasinghe TW, Tull DL, Baldwin ME, Sloan EK, Fox SB, Achen MG, Stacker SA. 2012. VEGF-D promotes tumor metastasis by regulating prostaglandins produced by the collecting lymphatic endothelium. Cancer Cell. 21:181–195.
  • Karpanen T, Egeblad M, Karkkainen MJ, Kubo H, Yla-Herttuala S, Jaattela M, Alitalo K. 2001. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res. 61:1786–1790.
  • Karpanen T, Heckman CA, Keskitalo S, Jeltsch M, Ollila H, Neufeld G, Tamagnone L, Alitalo K. Functional interaction of VEGF-C and VEGF-D with neuropilin receptors. FASEB J. 2006a; 20:1462–1472.
  • Karpanen T, Wirzenius M, Makinen T, Veikkola T, Haisma HJ, Achen MG, Stacker SA, Pytowski B, Yla-Herttuala S, Alitalo K. Lymphangiogenic growth factor responsiveness is modulated by postnatal lymphatic vessel maturation. Am J Pathol. 2006b; 169:708–718.
  • Kholova I, Koota S, Kaskenpaa N, Leppanen P, Narvainen J, Kavec M, Rissanen TT, Hazes T, Korpisalo P, Grohn O, Yla-Herttuala S. 2007. Adenovirus-mediated gene transfer of human vascular endothelial growth factor-D induces transient angiogenic effects in mouse hind limb muscle. Hum Gene Ther. 18:232–244.
  • Koch M, Dettori D, Van Nuffelen A, Souffreau J, Marconcini L, Wallays G, Moons L, Bruyere F, Oliviero S, Noel A, Foidart JM, Carmeliet P, Dewerchin M. 2009. VEGF-D deficiency in mice does not affect embryonic or postnatal lymphangiogenesis but reduces lymphatic metastasis. J Pathol. 219:356–364.
  • Koch S, Tugues S, Li X, Gualandi L, Claesson-Welsh L. 2011. Signal transduction by vascular endothelial growth factor receptors. Biochem J. 437:169–183.
  • Kopfstein L, Veikkola T, Djonov VG, Baeriswyl V, Schomber T, Strittmatter K, Stacker SA, Achen MG, Alitalo K, Christofori G. 2007. Distinct roles of vascular endothelial growth factor-D in lymphangiogenesis and metastasis. Am J Pathol. 170:1348–1361.
  • Kumasaka T, Seyama K, Mitani K, Sato T, Souma S, Kondo T, Hayashi S, Minami M, Uekusa T, Fukuchi Y, Suda K. 2004. Lymphangiogenesis in lymphangioleiomyomatosis: Its implication in the progression of lymphangioleiomyomatosis. Am J Surg Pathol. 28:1007–1016.
  • Kumasaka T, Seyama K, Mitani K, Souma S, Kashiwagi S, Hebisawa A, Sato T, Kubo H, Gomi K, Shibuya K, Fukuchi Y, Suda K. 2005. Lymphangiogenesis-mediated shedding of LAM cell clusters as a mechanism for dissemination in lymphangioleiomyomatosis. Am J Surg Pathol. 29:1356–1366.
  • Laakkonen P, Waltari M, Holopainen T, Takahashi T, Pytowski B, Steiner P, Hicklin D, Persaud K, Tonra JR, Witte L, Alitalo K. 2007. Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. Cancer Res. 67:593–599.
  • Lahteenvuo M, Honkonen K, Tervala T, Tammela T, Suominen E, Lahteenvuo J, Kholova I, Alitalo K, Yla-Herttuala S, Saaristo A. 2011. Growth factor therapy and autologous lymph node transfer in lymphedema. Circulation. 123:613–620.
  • Leppanen P, Koota S, Kholova I, Koponen J, Fieber C, Eriksson U, Alitalo K, Yla-Herttuala S. 2005. Gene transfers of vascular endothelial growth factor-A, vascular endothelial growth factor-B, vascular endothelial growth factor-C, and vascular endothelial growth factor-D have no effects on atherosclerosis in hypercholesterolemic low-density lipoprotein-receptor/apolipoprotein B48-deficient mice. Circulation. 112:1347–1352.
  • Leppanen VM, Prota AE, Jeltsch M, Anisimov A, Kalkkinen N, Strandin T, Lankinen H, Goldman A, Ballmer-Hofer K, Alitalo K. 2010. Structural determinants of growth factor binding and specificity by VEGF receptor 2. Proc Natl Acad Sci USA. 107:2425–2430.
  • Leppanen VM, Jeltsch M, Anisimov A, Tvorogov D, Aho K, Kalkkinen N, Toivanen P, Yla-Herttuala S, Ballmer-Hofer K, Alitalo K. 2011. Structural determinants of vascular endothelial growth factor-D receptor binding and specificity. Blood. 117:1507–1515.
  • Liang WC, Dennis MS, Stawicki S, Chanthery Y, Pan Q, Chen Y, Eigenbrot C, Yin J, Koch AW, Wu X, Ferrara N, Bagri A, Tessier-Lavigne M, Watts RJ, Wu Y. 2007. Function blocking antibodies to neuropilin-1 generated from a designed human synthetic antibody phage library. J Mol Biol. 366:815–829.
  • Lin J, Lalani AS, Harding TC, Gonzalez M, Wu WW, Luan B, Tu GH, Koprivnikar K, VanRoey MJ, He Y, Alitalo K, Jooss K. 2005. Inhibition of lymphogenous metastasis using adeno-associated virus-mediated gene transfer of a soluble VEGFR-3 decoy receptor. Cancer Res. 65:6901–6909.
  • Makinen T, Jussila L, Veikkola T, Karpanen T, Kettunen MI, Pulkkanen KJ, Kauppinen R, Jackson DG, Kubo H, Nishikawa S, Yla-Herttuala S, Alitalo K. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med.. 2001a; 7:199–205.
  • Makinen T, Veikkola T, Mustjoki S, Karpanen T, Catimel B, Nice EC, Wise L, Mercer A, Kowalski H, Kerjaschki D, Stacker SA, Achen MG, Alitalo K. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J. 2001b; 20:4762–4773.
  • Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, Banerji S, Huarte J, Montesano R, Jackson DG, Orci L, Alitalo K, Christofori G, Pepper MS. 2001. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J. 20:672–682.
  • Marconcini L, Marchio S, Morbidelli L, Cartocci E, Albini A, Ziche M, Bussolino F, Oliviero S. 1999. c-fos-induced growth factor/vascular endothelial growth factor D induces angiogenesis in vivo and in vitro. Proc Natl Acad Sci USA. 96:9671–9676.
  • McColl BK, Baldwin ME, Roufail S, Freeman C, Moritz RL, Simpson RJ, Alitalo K, Stacker SA, Achen MG. 2003. Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D. J Exp Med. 198:863–868.
  • McColl BK, Paavonen K, Karnezis T, Harris NC, Davydova N, Rothacker J, Nice EC, Harder KW, Roufail S, Hibbs ML, Rogers PA, Alitalo K, Stacker SA, Achen MG. 2007. Proprotein convertases promote processing of VEGF-D, a critical step for binding the angiogenic receptor VEGFR-2. FASEB J. 21:1088–1098.
  • McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC. 2011. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. New Engl J Med. 364:1595–1606.
  • McDonald NQ, Hendrickson WA. 1993. A structural superfamily of growth factors containing a cystine knot motif. Cell. 73:421–424.
  • Millauer B, Wizigmann-Voos S, Schnurch H, Martinez R, Moller NP, Risau W, Ullrich A. 1993. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell. 72:835–846.
  • Mitani K, Kumasaka T, Takemura H, Hayashi T, Gunji Y, Kunogi M, Akiyoshi T, Takahashi K, Suda K, Seyama K. 2009. Cytologic, immunocytochemical and ultrastructural characterization of lymphangioleiomyomatosis cell clusters in chylous effusions of patients with lymphangioleiomyomatosis. Acta Cytol. 53:402–409.
  • Ny A, Koch M, Vandevelde W, Schneider M, Fischer C, Diez-Juan A, Neven E, Geudens I, Maity S, Moons L, Plaisance S, Lambrechts D, Carmeliet P, Dewerchin M. 2008. Role of VEGF-D and VEGFR-3 in developmental lymphangiogenesis, a chemicogenetic study in Xenopus tadpoles. Blood. 112:1740–1749.
  • Orlandini M, Oliviero S. 2001. In fibroblasts Vegf-D expression is induced by cell-cell contact mediated by cadherin-11. J Biol Chem. 276:6576–6581.
  • Orlandini M, Marconcini L, Ferruzzi R, Oliviero S. 1996. Identification of a c-fos-induced gene that is related to the platelet-derived growth factor/vascular endothelial growth factor family. Proc Natl Acad Sci USA. 93:11675–11680.
  • Orlandini M, Semboloni S, Oliviero S. 2003. Beta-catenin inversely regulates vascular endothelial growth factor-D mRNA stability. J Biol Chem. 278:44650–44656.
  • Orlandini M, Spreafico A, Bardelli M, Rocchigiani M, Salameh A, Nucciotti S, Capperucci C, Frediani B, Oliviero S. 2006. Vascular endothelial growth factor-D activates VEGFR-3 expressed in osteoblasts inducing their differentiation. J Biol Chem. 281:17961–17967.
  • Pan Q, Chanthery Y, Liang WC, Stawicki S, Mak J, Rathore N, Tong RK, Kowalski J, Yee SF, Pacheco G, Ross S, Cheng Z, Le Couter J, Plowman G, Peale F, Koch AW, Wu Y, Bagri A, Tessier-Lavigne M, Watts RJ. 2007. Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell. 11:53–67.
  • Partanen TA, Arola J, Saaristo A, Jussila L, Ora A, Miettinen M, Stacker SA, Achen MG, Alitalo K. 2000. VEGF-C and VEGF-D expression in neuroendocrine cells and their receptor, VEGFR-3, in fenestrated blood vessels in human tissues. FASEB J. 14:2087–2096.
  • Persaud K, Tille JC, Liu M, Zhu Z, Jimenez X, Pereira DS, Miao HQ, Brennan LA, Witte L, Pepper MS, Pytowski B. 2004. Involvement of the VEGF receptor 3 in tubular morphogenesis demonstrated with a human anti-human VEGFR-3 monoclonal antibody that antagonizes receptor activation by VEGF-C. J Cell Sci. 117:2745–2756.
  • Pytowski B, Goldman J, Persaud K, Wu Y, Witte L, Hicklin DJ, Skobe M, Boardman KC, Swartz MA. 2005. Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody. J Natl Cancer Inst. 97:14–21.
  • Rinderknecht M, Villa A, Ballmer-Hofer K, Neri D, Detmar M. 2010. Phage-derived fully human monoclonal antibody fragments to human vascular endothelial growth factor-C block its interaction with VEGF receptor-2 and 3. PLoS One. 5:e11941.
  • Rissanen TT, Markkanen JE, Gruchala M, Heikura T, Puranen A, Kettunen MI, Kholova I, Kauppinen RA, Achen MG, Stacker SA, Alitalo K, Yla-Herttuala S. 2003. VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Circ Res. 92:1098–1106.
  • Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, Warlow CP, Meade TW. 2010. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 376:1741–1750.
  • Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. 2011. Effect of daily aspirin on long-term risk of death due to cancer: Analysis of individual patient data from randomised trials. Lancet. 377:31–41.
  • Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z. 2012. Effect of daily aspirin on risk of cancer metastasis: A study of incident cancers during randomised controlled trials. Lancet. 379:1591–1601.
  • Roy H, Bhardwaj S, Babu M, Lahteenvuo JE, Yla-Herttuala S. 2010. VEGF-DdeltaNdeltaC mediated angiogenesis in skeletal muscles of diabetic WHHL rabbits. Eur J Clin Invest. 40:422–432.
  • Rutanen J, Leppanen P, Tuomisto TT, Rissanen TT, Hiltunen MO, Vajanto I, Niemi M, Hakkinen T, Karkola K, Stacker SA, Achen MG, Alitalo K, Yla-Herttuala S. 2003. Vascular endothelial growth factor-D expression in human atherosclerotic lesions. Cardiovasc Res. 59:971–979.
  • Rutanen J, Rissanen TT, Markkanen JE, Gruchala M, Silvennoinen P, Kivela A, Hedman A, Hedman M, Heikura T, Orden MR, Stacker SA, Achen MG, Hartikainen J, Yla-Herttuala S. 2004. Adenoviral catheter-mediated intramyocardial gene transfer using the mature form of vascular endothelial growth factor-D induces transmural angiogenesis in porcine heart. Circulation. 109:1029–1035.
  • Rutanen J, Turunen AM, Teittinen M, Rissanen TT, Heikura T, Koponen JK, Gruchala M, Inkala M, Jauhiainen S, Hiltunen MO, Turunen MP, Stacker SA, Achen MG, Yla-Herttuala S. 2005. Gene transfer using the mature form of VEGF-D reduces neointimal thickening through nitric oxide-dependent mechanism. Gene Ther. 12:980–987.
  • Schafer G, Wissmann C, Hertel J, Lunyak V, Hocker M. 2008. Regulation of vascular endothelial growth factor D by orphan receptors hepatocyte nuclear factor-4 alpha and chicken ovalbumin upstream promoter transcription factors 1 and 2. Cancer Res. 68:457–466.
  • Schoppmann SF, Birner P, Stockl J, Kalt R, Ullrich R, Caucig C, Kriehuber E, Nagy K, Alitalo K, Kerjaschki D. 2002. Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol. 161:947–956.
  • Seyama K, Kumasaka T, Souma S, Sato T, Kurihara M, Mitani K, Tominaga S, Fukuchi Y. 2006. Vascular endothelial growth factor-D is increased in serum of patients with lymphangioleiomyomatosis. Lymphat Res Biol. 4:143–152.
  • Seyama K, Kumasaka T, Kurihara M, Mitani K, Sato T. 2010. Lymphangioleiomyomatosis: A disease involving the lymphatic system. Lymphat Res Biol. 8:21–31.
  • Shayan R, Achen MG, Stacker SA. 2006. Lymphatic vessels in cancer metastasis: Bridging the gaps. Carcinogenesis. 27:1729–1738.
  • Shayan R, Karnezis T, Tsantikos E, Williams SP, Runting A, Ashton MW, Achen MG, Hibbs ML, Stacker SA. 2007. A system for quantifying the patterning of the lymphatic vasculature. Growth Factors. 25:417–425.
  • Siegfried G, Basak A, Cromlish JA, Benjannet S, Marcinkiewicz J, Chretien M, Seidah NG, Khatib AM. 2003. The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis. J Clin Invest. 111:1723–1732.
  • Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M. 1998. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell. 92:735–745.
  • Song M, Yang H, Yao S, Ma F, Li Z, Deng Y, Deng H, Zhou Q, Lin S, Wei Y. 2007. A critical role of vascular endothelial growth factor D in zebrafish embryonic vasculogenesis and angiogenesis. Biochem Biophys Res Commun. 357:924–930.
  • Stacker SA, Achen MG. 2008. From anti-angiogenesis to anti-lymphangiogenesis: Emerging trends in cancer therapy. Lymphat Res Biol. 6:165–172.
  • Stacker SA, Stenvers K, Caesar C, Vitali A, Domagala T, Nice E, Roufail S, Simpson RJ, Moritz R, Karpanen T, Alitalo K, Achen MG. Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers. J Biol Chem. 1999a; 274:32127–32136.
  • Stacker SA, Vitali A, Caesar C, Domagala T, Groenen LC, Nice E, Achen MG, Wilks AF. A mutant form of vascular endothelial growth factor (VEGF) that lacks VEGF receptor-2 activation retains the ability to induce vascular permeability. J Biol Chem. 1999b; 274:34884–34892.
  • Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R, Jackson DG, Nishikawa S, Kubo H, Achen MG. 2001. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med.. 7:186–191.
  • Stacker SA, Williams RA, Achen MG. 2004. Lymphangiogenic growth factors as markers of tumor metastasis. APMIS. 112:539–549.
  • Tammela T, Alitalo K. 2010. Lymphangiogenesis: Molecular mechanisms and future promise. Cell. 140:460–476.
  • Tammela T, Saaristo A, Holopainen T, Lyytikka J, Kotronen A, Pitkonen M, Abo-Ramadan U, Yla-Herttuala S, Petrova TV, Alitalo K. 2007. Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation. Nat Med. 13:1458–1466.
  • Tammela T, Zarkada G, Wallgard E, Murtomaki A, Suchting S, Wirzenius M, Waltari M, Hellstrom M, Schomber T, Peltonen R, Freitas C, Duarte A, Isoniemi H, Laakkonen P, Christofori G, Yla-Herttuala S, Shibuya M, Pytowski B, Eichmann A, Betsholtz C, Alitalo K. 2008. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature. 454:656–660.
  • Tammela T, Zarkada G, Nurmi H, Jakobsson L, Heinolainen K, Tvorogov D, Zheng W, Franco CA, Murtomaki A, Aranda E, Miura N, Yla-Herttuala S, Fruttiger M, Makinen T, Eichmann A, Pollard JW, Gerhardt H, Alitalo K. 2011. VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nat Cell Biol. 13:1202–1213.
  • Thelen A, Scholz A, Benckert C, von Marschall Z, Schroder M, Wiedenmann B, Neuhaus P, Rosewicz S, Jonas S. 2008. VEGF-D promotes tumor growth and lymphatic spread in a mouse model of hepatocellular carcinoma. Int J Cancer. 122:2471–2481.
  • Toivanen PI, Nieminen T, Viitanen L, Alitalo A, Roschier M, Jauhiainen S, Markkanen JE, Laitinen OH, Airenne TT, Salminen TA, Johnson MS, Airenne KJ, Yla-Herttuala S. 2009. Novel vascular endothelial growth factor D variants with increased biological activity. J Biol Chem. 284:16037–16048.
  • Veikkola T, Jussila L, Makinen T, Karpanen T, Jeltsch M, Petrova TV, Kubo H, Thurston G, McDonald DM, Achen MG, Stacker SA, Alitalo K. 2001. Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. EMBO J. 20:1223–1231.
  • Vlahakis NE, Young BA, Atakilit A, Sheppard D. 2005. The lymphangiogenic vascular endothelial growth factors VEGF-C and -D are ligands for the integrin alpha9beta1. J Biol Chem. 280:4544–4552.
  • Von Marschall Z, Scholz A, Stacker SA, Achen MG, Jackson DG, Alves F, Schirner M, Haberey M, Thierauch KH, Wiedenmann B, Rosewicz S. 2005. Vascular endothelial growth factor-D induces lymphangiogenesis and lymphatic metastasis in models of ductal pancreatic cancer. Int J Oncol. 27:669–679.
  • Wang JF, Zhang XF, Groopman JE. 2001. Stimulation of beta1 integrin induces tyrosine phosphorylation of vascular endothelial growth factor receptor-3 and modulates cell migration. J Biol Chem. 276:41950–41957.
  • Weickhardt AJ, Williams D, Lee C, Simes J, Murone C, Wilson K, Cummins M, Asadi K, Price TJ, Mariadason J, Tebbutt NC. 2011. Vascular endothelial growth factors (VEGF) and VEGF receptor expression as predictive biomarkers for benefit with bevacizumab in metastatic colorectal cancer (mCRC): Analysis of the phase III MAX study. In: 2011 ASCO Annual Meeting. J Clin Oncol. 29 2011 (Suppl abstr 3531).
  • White JD, Hewett PW, Kosuge D, McCulloch T, Enholm BC, Carmichael J, Murray JC. 2002. Vascular endothelial growth factor-D expression is an independent prognostic marker for survival in colorectal carcinoma. Cancer Res. 62:1669–1675.
  • Wiesmann C, Fuh G, Christinger HW, Eigenbrot C, Wells JA, de Vos AM. 1997. Crystal structure at 1.7 A resolution of VEGF in complex with domain 2 of the Flt-1 receptor. Cell. 91:695–704.
  • Wirzenius M, Tammela T, Uutela M, He Y, Odorisio T, Zambruno G, Nagy JA, Dvorak HF, Yla-Herttuala S, Shibuya M, Alitalo K. 2007. Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting. J Exp Med. 204:1431–1440.
  • Wise LM, Ueda N, Dryden NH, Fleming SB, Caesar C, Roufail S, Achen MG, Stacker SA, Mercer AA. 2003. Viral vascular endothelial growth factors vary extensively in amino acid sequence, receptor-binding specificities, and the ability to induce vascular permeability yet are uniformly active mitogens. J Biol Chem. 278:38004–38014.
  • Witte L, Hicklin DJ, Zhu Z, Pytowski B, Kotanides H, Rockwell P, Bohlen P. 1998. Monoclonal antibodies targeting the VEGF receptor-2 (Flk1/KDR) as an anti-angiogenic therapeutic strategy. Cancer Metastasis Rev. 17:155–161.
  • Xu Y, Yuan L, Mak J, Pardanaud L, Caunt M, Kasman I, Larrivee B, Del Toro R, Suchting S, Medvinsky A, Silva J, Yang J, Thomas JL, Koch AW, Alitalo K, Eichmann A, Bagri A. 2010. Neuropilin-2 mediates VEGF-C-induced lymphatic sprouting together with VEGFR3. J Cell Biol. 188:115–130.
  • Yamada Y, Nezu JI, Shimane M, Hirata Y. 1997. Molecular cloning of a novel vascular endothelial growth factor, VEGF-D. Genomics. 42:483–488.
  • Yokoyama Y, Charnock-Jones DS, Licence D, Yanaihara A, Hastings JM, Holland CM, Emoto M, Umemoto M, Sakamoto T, Sato S, Mizunuma H, Smith SK. 2003. Vascular endothelial growth factor-D is an independent prognostic factor in epithelial ovarian carcinoma. Br J Cancer. 88:237–244.
  • Yonemura Y, Endo Y, Tabata K, Kawamura T, Yun HY, Bandou E, Sasaki T, Miura M. 2005. Role of VEGF-C and VEGF-D in lymphangiogenesis in gastric cancer. Int J Clin Oncol. 10:318–327.
  • Young LR, Vandyke R, Gulleman PM, Inoue Y, Brown KK, Schmidt LS, Linehan WM, Hajjar F, Kinder BW, Trapnell BC, Bissler JJ, Franz DN, McCormack FX. 2010. Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases. Chest. 138:674–681.
  • Zhang H, Li Y, Li H, Bassi R, Jimenez X, Witte L, Bohlen P, Hicklin D, Zhu Z. 2004. Inhibition of both the autocrine and the paracrine growth of human leukemia with a fully human antibody directed against vascular endothelial growth factor receptor 2. Leuk Lymphoma. 45:1887–1897.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.