vascular endothelial growth factor receptor 3


Summary: A vascular endothelial cell growth factor receptor whose expression is restricted primarily to adult lymphatic endothelium. VEGFR-3 preferentially binds the vascular endothelial growth factor C and vascular endothelial growth factor D and may be involved in the control of lymphangiogenesis.

Top Publications

  1. Byzova T, Goldman C, Jankau J, Chen J, Cabrera G, Achen M, et al. Adenovirus encoding vascular endothelial growth factor-D induces tissue-specific vascular patterns in vivo. Blood. 2002;99:4434-42 pubmed
  2. Saharinen P, Tammela T, Karkkainen M, Alitalo K. Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation. Trends Immunol. 2004;25:387-95 pubmed
  3. Goldman J, Rutkowski J, Shields J, Pasquier M, Cui Y, Schmökel H, et al. Cooperative and redundant roles of VEGFR-2 and VEGFR-3 signaling in adult lymphangiogenesis. FASEB J. 2007;21:1003-12 pubmed
    ..Our findings demonstrate that cooperative signaling of VEGFR-2 and -3 is necessary for lymphatic migration and proliferation, but VEGFR-3 is redundant with VEGFR-2 for LEC organization into functional capillaries. ..
  4. Dixelius J, Makinen T, Wirzenius M, Karkkainen M, Wernstedt C, Alitalo K, et al. 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. 2003;278:40973-9 pubmed
  5. Jiang W, Davies G, Martin T, Parr C, Watkins G, Mansel R, et al. The potential lymphangiogenic effects of hepatocyte growth factor/scatter factor in vitro and in vivo. Int J Mol Med. 2005;16:723-8 pubmed
    ..Expression of lymphatic markers, podoplanin, Prox-1, vascular endothelial growth factor receptor 3 (VEGF-R3) and LYVE-1 was determined using reverse transcription polymerase reaction and ..
  6. Pytowski B, Goldman J, Persaud K, Wu Y, Witte L, Hicklin D, et al. Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody. J Natl Cancer Inst. 2005;97:14-21 pubmed
    New lymphatic growth may contribute to tumor metastasis. Activation of vascular endothelial growth factor receptor 3 (VEGFR-3) by its ligands VEGF-C and -D is necessary for embryonic and tumor lymphangiogenesis...
  7. Jüttner S, Wissmann C, Jöns T, Vieth M, Hertel J, Gretschel S, et al. Vascular endothelial growth factor-D and its receptor VEGFR-3: two novel independent prognostic markers in gastric adenocarcinoma. J Clin Oncol. 2006;24:228-40 pubmed
    ..Combined analysis of the VEGF-C/VEGF-D/VEGFR-3 system can be useful to identify patients with unfavorable clinical outcome and thereby may help to refine therapeutic decisions in gastric cancer. ..
  8. Alitalo K, Carmeliet P. Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell. 2002;1:219-27 pubmed
    ..In addition, these studies have opened novel diagnostic and therapeutic avenues for the treatment of lymphedema and metastasis. This overview highlights the recent insights and developments in the field of lymphatic vascular research. ..
  9. Cueni L, Detmar M. New insights into the molecular control of the lymphatic vascular system and its role in disease. J Invest Dermatol. 2006;126:2167-77 pubmed

More Information


  1. Kitadai Y, Amioka T, Haruma K, Tanaka S, Yoshihara M, Sumii K, et al. Clinicopathological significance of vascular endothelial growth factor (VEGF)-C in human esophageal squamous cell carcinomas. Int J Cancer. 2001;93:662-6 pubmed
    ..These results overall suggest that VEGF-C may play a role in tumor progression via lymphangiogenesis and angiogenesis in human esophageal carcinoma. ..
  2. Hughes D. Alternative splicing of the human VEGFGR-3/FLT4 gene as a consequence of an integrated human endogenous retrovirus. J Mol Evol. 2001;53:77-9 pubmed
    The vascular endothelial growth factor receptor 3 (VEGFR-3/FLT4) is a receptor tyrosine kinase that regulates angiogenesis and vasculogenesis in response to the binding of the ligands VEGF-C and VEGF-D...
  3. Kojima H, Shijubo N, Yamada G, Ichimiya S, Abe S, Satoh M, et al. Clinical significance of vascular endothelial growth factor-C and vascular endothelial growth factor receptor 3 in patients with T1 lung adenocarcinoma. Cancer. 2005;104:1668-77 pubmed
    ..0129) as well as N factor (P = 0.0020). VEGF-C and VEGFR-3 status may be indicative of survival rates for patients with T1 lung adenocarcinoma. ..
  4. Baldwin M, Halford M, Roufail S, Williams R, Hibbs M, Grail D, et al. Vascular endothelial growth factor D is dispensable for development of the lymphatic system. Mol Cell Biol. 2005;25:2441-9 pubmed
    b>Vascular endothelial growth factor receptor 3 (Vegfr-3) is a tyrosine kinase that is expressed on the lymphatic endothelium and that signals for the growth of the lymphatic vessels (lymphangiogenesis)...
  5. Burton J, Priceman S, Sung J, Brakenhielm E, An D, Pytowski B, et al. Suppression of prostate cancer nodal and systemic metastasis by blockade of the lymphangiogenic axis. Cancer Res. 2008;68:7828-37 pubmed publisher
    ..Our findings highlight the importance of lymphangiogenic therapies in the control of regional lymph node and systemic metastasis. ..
  6. Wilting J, Papoutsi M, Christ B, Nicolaides K, Von Kaisenberg C, Borges J, et al. The transcription factor Prox1 is a marker for lymphatic endothelial cells in normal and diseased human tissues. FASEB J. 2002;16:1271-3 pubmed
    ..VEGFR-3 and CD34 are less reliable markers for LECs and BECs, respectively, because exceptions from their normal expression patterns are found in pathologic tissues...
  7. Paavonen K, Mandelin J, Partanen T, Jussila L, Li T, Ristimaki A, et al. Vascular endothelial growth factors C and D and their VEGFR-2 and 3 receptors in blood and lymphatic vessels in healthy and arthritic synovium. J Rheumatol. 2002;29:39-45 pubmed
    ..The relatively few lymphatic vessels along with increased vascular permeability in RA may contribute to the development of tissue edema and joint stiffness. ..
  8. Bierer S, Herrmann E, Köpke T, Neumann J, Eltze E, Hertle L, et al. Lymphangiogenesis in kidney cancer: expression of VEGF-C, VEGF-D and VEGFR-3 in clear cell and papillary renal cell carcinoma. Oncol Rep. 2008;20:721-5 pubmed
    ..Further studies are necessary to confirm these results and to determine whether the VEGF-C/VEGF-D/VEGFR-3-axis can play a role as a prognostic tool or a target for therapeutic intervention in renal cell carcinoma. ..
  9. Li Q, Dong X, Gu W, Qiu X, Wang E. Clinical significance of co-expression of VEGF-C and VEGFR-3 in non-small cell lung cancer. Chin Med J (Engl). 2003;116:727-30 pubmed
    ..01). In NSCLC, VEGF-C and VEGFR-3 are related to the lymphangiogenesis, angiogenesis, and occurrence and development of lung cancers. VEGF-C expression could be a useful predictor of poor prognosis in NSCLC. ..
  10. Lin J, Lalani A, Harding T, Gonzalez M, Wu W, Luan B, et al. Inhibition of lymphogenous metastasis using adeno-associated virus-mediated gene transfer of a soluble VEGFR-3 decoy receptor. Cancer Res. 2005;65:6901-9 pubmed
    ..Recombinant adeno-associated virus-mediated gene transfer of sVEGFR3-Fc may represent a feasible therapeutic strategy for blockade of lymphogenous metastasis. ..
  11. Gunningham S, Currie M, Han C, Turner K, Scott P, Robinson B, et al. Vascular endothelial growth factor-B and vascular endothelial growth factor-C expression in renal cell carcinomas: regulation by the von Hippel-Lindau gene and hypoxia. Cancer Res. 2001;61:3206-11 pubmed
  12. Huang H, Ho C, Huang P, Hsu S. Co-expression of VEGF-C and its receptors, VEGFR-2 and VEGFR-3, in endothelial cells of lymphangioma. Implication in autocrine or paracrine regulation of lymphangioma. Lab Invest. 2001;81:1729-34 pubmed
    ..The results suggest that VEGF-C and its receptors may take active parts in the formation of lymphangioma by autocrine or paracrine regulation...
  13. Kitadai Y, Kodama M, Cho S, Kuroda T, Ochiumi T, Kimura S, et al. Quantitative analysis of lymphangiogenic markers for predicting metastasis of human gastric carcinoma to lymph nodes. Int J Cancer. 2005;115:388-92 pubmed
    ..These results indicate that quantitative analysis of lymphangiogenic markers in gastric biopsy specimens may be useful in predicting metastasis of gastric cancer to regional lymph nodes. ..
  14. Roberts N, Kloos B, Cassella M, Podgrabinska S, Persaud K, Wu Y, et al. Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. Cancer Res. 2006;66:2650-7 pubmed
  15. Su J, Yang P, Shih J, Yang C, Wei L, Hsieh C, et al. The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells. Cancer Cell. 2006;9:209-23 pubmed
    ..The VEGF-C/Flt-4 axis, through upregulation of contactin-1, may regulate the invasive capacity in different types of cancer cells. ..
  16. Von Marschall Z, Scholz A, Stacker S, Achen M, Jackson D, Alves F, et al. Vascular endothelial growth factor-D induces lymphangiogenesis and lymphatic metastasis in models of ductal pancreatic cancer. Int J Oncol. 2005;27:669-79 pubmed
    ..Our results suggest that VEGF-D plays a pivotal role in stimulating lymphangiogenesis and lymphatic metastasis in human ductal pancreatic cancer, and therefore represents a novel therapeutic target for this devastating disease. ..
  17. Saaristo A, Karkkainen M, Alitalo K. Insights into the molecular pathogenesis and targeted treatment of lymphedema. Ann N Y Acad Sci. 2002;979:94-110 pubmed
    ..Strategies to avoid these side-effects have also been developed. This new field of reseach has important implications for the development of new therapies for human lymphedema. ..
  18. Yuan L, Moyon D, Pardanaud L, Breant C, Karkkainen M, Alitalo K, et al. Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development. 2002;129:4797-806 pubmed
    ..Arteries, veins and larger, collecting lymphatic vessels developed normally, suggesting that neuropilin 2 is selectively required for the formation of small lymphatic vessels and capillaries. ..
  19. Matsuura M, Onimaru M, Yonemitsu Y, Suzuki H, Nakano T, Ishibashi H, et al. Autocrine loop between vascular endothelial growth factor (VEGF)-C and VEGF receptor-3 positively regulates tumor-associated lymphangiogenesis in oral squamoid cancer cells. Am J Pathol. 2009;175:1709-21 pubmed publisher
    ..These findings together suggested that the VEGF-C/FLT-4 autocrine loop in tumor cells was a potential enhancer system to promote cancer progression, and FLT-4 in tumor tissue might become an effective target for cancer therapy. ..
  20. Jeltsch M, Karpanen T, Strandin T, Aho K, Lankinen H, Alitalo K. Vascular endothelial growth factor (VEGF)/VEGF-C mosaic molecules reveal specificity determinants and feature novel receptor binding patterns. J Biol Chem. 2006;281:12187-95 pubmed
    ..VEGFR-2 and VEGFR-3 showed striking differences in their requirements for VEGF-C binding; extracellular domain 2 of VEGFR-2 was sufficient, whereas in VEGFR-3, both domains 1 and 2 were necessary. ..
  21. Tang R, Itakura J, Aikawa T, Matsuda K, Fujii H, Korc M, et al. Overexpression of lymphangiogenic growth factor VEGF-C in human pancreatic cancer. Pancreas. 2001;22:285-92 pubmed
    ..These findings indicate that VEGF-C and its receptor are commonly overexpressed in human pancreatic cancers and that this factor may contribute to the lymphangiogenic process and metastasis in this disorder. ..
  22. Guo R, Zhou Q, Proulx S, Wood R, Ji R, Ritchlin C, et al. Inhibition of lymphangiogenesis and lymphatic drainage via vascular endothelial growth factor receptor 3 blockade increases the severity of inflammation in a mouse model of chronic inflammatory arthritis. Arthritis Rheum. 2009;60:2666-76 pubmed publisher
    ..synovial volumes and draining popliteal LN volumes before and after 8 weeks of treatment with vascular endothelial growth factor receptor 3 (VEGFR-3) neutralizing antibody, VEGFR-2 neutralizing antibody, or isotype IgG...
  23. Karkkainen M, Jussila L, Ferrell R, Finegold D, Alitalo K. Molecular regulation of lymphangiogenesis and targets for tissue oedema. Trends Mol Med. 2001;7:18-22 pubmed
    ..These data suggest that it may become possible to stimulate lymphatic growth and function and to treat tissue oedema involved in many diseases. ..
  24. Kivivuori S, Siitonen S, Porkka K, Vettenranta K, Alitalo R, Saarinen Pihkala U. Expression of vascular endothelial growth factor receptor 3 and Tie1 tyrosine kinase receptor on acute leukemia cells. Pediatr Blood Cancer. 2007;48:387-92 pubmed
    ..Activation of vascular endothelial growth factor receptor 3 (VEGFR-3) and Tie1 tyrosine kinase receptor are known to promote leukemia cell survival...
  25. Saaristo A, Veikkola T, Tammela T, Enholm B, Karkkainen M, Pajusola K, et al. Lymphangiogenic gene therapy with minimal blood vascular side effects. J Exp Med. 2002;196:719-30 pubmed
    ..These results have important implications for the development of gene therapy for human lymphedema. ..
  26. Clarijs R, Schalkwijk L, Hofmann U, Ruiter D, de Waal R. Induction of vascular endothelial growth factor receptor-3 expression on tumor microvasculature as a new progression marker in human cutaneous melanoma. Cancer Res. 2002;62:7059-65 pubmed
    ..In addition, we propose VEGFR-3 expression as a new microvascular progression marker in cutaneous melanoma. ..
  27. Björndahl M, Cao R, Burton J, Brakenhielm E, Religa P, Galter D, et al. Vascular endothelial growth factor-a promotes peritumoral lymphangiogenesis and lymphatic metastasis. Cancer Res. 2005;65:9261-8 pubmed
    ..Our data show that VEGF-A contributes to lymphatic mestastasis. Thus, blockage of VEGF-A-induced lymphangiogenesis may provide a novel approach for prevention and treatment of lymphatic metastasis. ..
  28. Yang J, Wu H, Qian L, Zhang W, Hua L, Yu M, et al. Increased expressions of vascular endothelial growth factor (VEGF), VEGF-C and VEGF receptor-3 in prostate cancer tissue are associated with tumor progression. Asian J Androl. 2006;8:169-75 pubmed
    ..However, the chief role of increased expressions of VEGF-C and VEGFR-3 was to enhance lymphangiogenesis and provide a main pathway for cancer cells to disseminate. ..
  29. Shida A, Fujioka S, Kobayashi K, Ishibashi Y, Nimura H, Mitsumori N, et al. Expression of vascular endothelial growth factor (VEGF)-C and -D in gastric carcinoma. Int J Clin Oncol. 2006;11:38-43 pubmed
    ..Our study suggests that both VEGF-C and VEGF-D are involved in lymphatic spreading of gastric cancer cells, which is clinically useful for the evaluation of lymphatic invasion in patients with gastric carcinoma. ..
  30. Saintigny P, Kambouchner M, Ly M, Gomes N, Sainte Catherine O, Vassy R, et al. Vascular endothelial growth factor-C and its receptor VEGFR-3 in non-small-cell lung cancer: concurrent expression in cancer cells from primary tumour and metastatic lymph node. Lung Cancer. 2007;58:205-13 pubmed
    ..As VEGF-C/VEGFR-3 coexpression is very frequent in metastatic LN tumour cells, it can be hypothesised that this coexpression participates in the growth of LN metastasis. ..
  31. Kajita T, Ohta Y, Kimura K, Tamura M, Tanaka Y, Tsunezuka Y, et al. The expression of vascular endothelial growth factor C and its receptors in non-small cell lung cancer. Br J Cancer. 2001;85:255-60 pubmed
    ..In light of these findings, we conclude that VEGF-C plays an important role in lymphatic invasion/metastasis and tumour progression in non-small cell lung cancer. ..
  32. McColl B, Baldwin M, Roufail S, Freeman C, Moritz R, Simpson R, et al. Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D. J Exp Med. 2003;198:863-8 pubmed
    ..Identification of an enzyme that activates the lymphangiogenic growth factors will facilitate development of inhibitors of metastasis. ..
  33. White J, Hewett P, Kosuge D, McCulloch T, Enholm B, Carmichael J, et al. Vascular endothelial growth factor-D expression is an independent prognostic marker for survival in colorectal carcinoma. Cancer Res. 2002;62:1669-75 pubmed
    ..We conclude that VEGF-D expression, but not that of its receptor VEGFR-3, is an independent prognostic indicator in CRC. VEGF-D expression may be associated with disease outcome through the promotion of lymphatic involvement/metastases. ..
  34. Kawakami M, Furuhata T, Kimura Y, Yamaguchi K, Hata F, Sasaki K, et al. Quantification of vascular endothelial growth factor-C and its receptor-3 messenger RNA with real-time quantitative polymerase chain reaction as a predictor of lymph node metastasis in human colorectal cancer. Surgery. 2003;133:300-8 pubmed
    ..Furthermore, the expression levels of VEGF-C mRNA and protein in colorectal cancer are correlated with lymph node metastasis and lymphatic invasion. ..
  35. Yokoyama Y, Charnock Jones D, Licence D, Yanaihara A, Hastings J, Holland C, et al. Vascular endothelial growth factor-D is an independent prognostic factor in epithelial ovarian carcinoma. Br J Cancer. 2003;88:237-44 pubmed
    ..Since VEGF-D was found to be an independent predictor of poor outcome, its measurement, together with other prognostic markers may improve prospective identification of patients with a poor prognosis. ..
  36. Krishnan J, Kirkin V, Steffen A, Hegen M, Weih D, Tomarev S, et al. Differential in vivo and in vitro expression of vascular endothelial growth factor (VEGF)-C and VEGF-D in tumors and its relationship to lymphatic metastasis in immunocompetent rats. Cancer Res. 2003;63:713-22 pubmed
  37. Leppänen V, Prota A, Jeltsch M, Anisimov A, Kalkkinen N, Strandin T, et al. Structural determinants of growth factor binding and specificity by VEGF receptor 2. Proc Natl Acad Sci U S A. 2010;107:2425-30 pubmed publisher
    ..Our results provide significant insights into the structural features that determine the high affinity and specificity of VEGF/VEGFR interactions. ..
  38. Padera T, Jain R. VEGFR3: a new target for antiangiogenesis therapy?. Dev Cell. 2008;15:178-9 pubmed publisher
    ..Tammela et al. in Nature show that VEGFR-3, via Notch regulation, is present on endothelial tip cells and is critical to sprouting angiogenesis. ..
  39. Sorensen E, Gerber S, Frelinger J, Lord E. IL-12 suppresses vascular endothelial growth factor receptor 3 expression on tumor vessels by two distinct IFN-gamma-dependent mechanisms. J Immunol. 2010;184:1858-66 pubmed publisher
    ..Vessels found within B16 tumors are chaotic and poorly formed and express vascular endothelial growth factor receptor 3 (VEGFR3), a growth factor receptor not expressed on normal adult vessels...
  40. Achen M, Mann G, Stacker S. Targeting lymphangiogenesis to prevent tumour metastasis. Br J Cancer. 2006;94:1355-60 pubmed
    ..In this review, we discuss the evidence supporting a role for this signalling system in the spread of cancer and potential approaches for blocking this system to prevent tumour metastasis. ..
  41. Hoshida T, Isaka N, Hagendoorn J, di Tomaso E, Chen Y, Pytowski B, et al. Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications. Cancer Res. 2006;66:8065-75 pubmed
  42. Kodama M, Kitadai Y, Tanaka M, Kuwai T, Tanaka S, Oue N, et al. Vascular endothelial growth factor C stimulates progression of human gastric cancer via both autocrine and paracrine mechanisms. Clin Cancer Res. 2008;14:7205-14 pubmed publisher
    ..Gastric carcinoma cells express VEGF-C and VEGFR-3. VEGF-C may play a role in the progressive growth of human gastric carcinoma through both autocrine and paracrine mechanisms. ..
  43. Laakkonen P, Waltari M, Holopainen T, Takahashi T, Pytowski B, Steiner P, et al. Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. Cancer Res. 2007;67:593-9 pubmed
    b>Vascular endothelial growth factor receptor 3 (VEGFR-3) binds VEGF-C and VEGF-D and is essential for the development of the lymphatic vasculature...
  44. Lian Z, Liu J, Wu M, Wang H, Arbuthnot P, Kew M, et al. Hepatitis B x antigen up-regulates vascular endothelial growth factor receptor 3 in hepatocarcinogenesis. Hepatology. 2007;45:1390-9 pubmed publisher
    ..In conclusion, HBxAg may short circuit VEGFR-3(S) signaling in liver cancer. Blocking VEGFR-3(S) signaling may be effective in preventing tumor development and/or prolonging survival in tumor bearing patients...
  45. Yonemura Y, Fushida S, Bando E, Kinoshita K, Miwa K, Endo Y, et al. Lymphangiogenesis and the vascular endothelial growth factor receptor (VEGFR)-3 in gastric cancer. Eur J Cancer. 2001;37:918-23 pubmed
    ..In these circumstances, cancer cells can easily invade the lymphatic vessel, because of the increase of the contact points of cancer cells with the lymphatic vessels. ..
  46. Kirkin V, Mazitschek R, Krishnan J, Steffen A, Waltenberger J, Pepper M, et al. Characterization of indolinones which preferentially inhibit VEGF-C- and VEGF-D-induced activation of VEGFR-3 rather than VEGFR-2. Eur J Biochem. 2001;268:5530-40 pubmed
    ..These tools should be useful in analysing the different activities and roles of VEGF-C, VEGF-D and their ligands, and in blocking VEGFR-3-mediated lymphangiogenesis. ..
  47. Takahashi M, Yoshimoto T, Kubo H. Molecular mechanisms of lymphangiogenesis. Int J Hematol. 2004;80:29-34 pubmed
    ..This review describes the main players in lymphangiogenesis that have been identified so far and the attempts to shed some light on the mysteries surrounding this process. ..
  48. Shimizu K, Kubo H, Yamaguchi K, Kawashima K, Ueda Y, Matsuo K, et al. Suppression of VEGFR-3 signaling inhibits lymph node metastasis in gastric cancer. Cancer Sci. 2004;95:328-33 pubmed
    ..Antilymphangiogenesis by inhibiting VEGFR-3 signaling could provide a potential strategy for the prevention of lymph node metastasis in gastric cancer. ..
  49. Witte D, Thomas A, Ali N, Carlson N, Younes M. Expression of the vascular endothelial growth factor receptor-3 (VEGFR-3) and its ligand VEGF-C in human colorectal adenocarcinoma. Anticancer Res. 2002;22:1463-6 pubmed
    ..05), but not with lymph node metastasis or depth of tumor invasion. Our results suggest that VEGFs promote cancer growth not only by stimulating angiogenesis, but also by acting on receptors present on the cancer cells themselves. ..
  50. Tomanek R, Holifield J, Reiter R, Sandra A, Lin J. Role of VEGF family members and receptors in coronary vessel formation. Dev Dyn. 2002;225:233-40 pubmed
    ..In summary, these experiments document a role for multiple members of the VEGF family and their receptors in formation of the coronary vascular bed. ..
  51. Podgrabinska S, Braun P, Velasco P, Kloos B, Pepper M, Skobe M. Molecular characterization of lymphatic endothelial cells. Proc Natl Acad Sci U S A. 2002;99:16069-74 pubmed
  52. Yokoyama Y, Charnock Jones D, Licence D, Yanaihara A, Hastings J, Holland C, et al. Expression of vascular endothelial growth factor (VEGF)-D and its receptor, VEGF receptor 3, as a prognostic factor in endometrial carcinoma. Clin Cancer Res. 2003;9:1361-9 pubmed
    ..In addition, VEGF-D and VEGFR-3 may be promising targets for new therapeutic strategies in endometrial carcinoma. ..
  53. Kriehuber E, Breiteneder Geleff S, Groeger M, Soleiman A, Schoppmann S, Stingl G, et al. Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages. J Exp Med. 2001;194:797-808 pubmed
    ..These results demonstrate that LECs and BECs constitute stable and specialized EC lineages equipped with the potential to navigate leukocytes and, perhaps also, tumor cells into and out of the tissues. ..
  54. Dias S, Choy M, Alitalo K, Rafii S. Vascular endothelial growth factor (VEGF)-C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy. Blood. 2002;99:2179-84 pubmed
    ..These results identify the VEGF-C/FLT-4 pathway as a novel therapeutic target for the treatment of subsets of acute leukemia. ..
  55. Amioka T, Kitadai Y, Tanaka S, Haruma K, Yoshihara M, Yasui W, et al. Vascular endothelial growth factor-C expression predicts lymph node metastasis of human gastric carcinomas invading the submucosa. Eur J Cancer. 2002;38:1413-9 pubmed
    ..VEGF-C expression at the invading edge of a gastric carcinoma may be a sensitive marker for metastasis to the lymph nodes. ..
  56. Tammela T, Zarkada G, Wallgard E, Murtomäki A, Suchting S, Wirzenius M, et al. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature. 2008;454:656-60 pubmed publisher
    ..Our results implicate VEGFR-3 as a regulator of vascular network formation. Targeting VEGFR-3 may provide additional efficacy for anti-angiogenic therapies, especially towards vessels that are resistant to VEGF or VEGFR-2 inhibitors. ..
  57. Jennbacken K, Vallbo C, Wang W, Damber J. Expression of vascular endothelial growth factor C (VEGF-C) and VEGF receptor-3 in human prostate cancer is associated with regional lymph node metastasis. Prostate. 2005;65:110-6 pubmed
    ..The results of the present study indicate that increased expression of VEGF-C and VEGFR-3 play a role in prostate cancer progression and in metastasis to regional lymph nodes. ..
  58. Veikkola T, Lohela M, Ikenberg K, Makinen T, Korff T, Saaristo A, et al. Intrinsic versus microenvironmental regulation of lymphatic endothelial cell phenotype and function. FASEB J. 2003;17:2006-13 pubmed
    ..Collectively, these data show intrinsic cell-specific differences of BEC and LEC responses to VEGFs and identify a pericellular regulatory mechanism for VEGFR-3 down-regulation in endothelial cells. ..
  59. Li R, Younes M, Wheeler T, Scardino P, Ohori M, Frolov A, et al. Expression of vascular endothelial growth factor receptor-3 (VEGFR-3) in human prostate. Prostate. 2004;58:193-9 pubmed
  60. He Y, Karpanen T, Alitalo K. Role of lymphangiogenic factors in tumor metastasis. Biochim Biophys Acta. 2004;1654:3-12 pubmed
    ..This review examines some of these issues and provides a brief summary of the recent developments in this field of research. ..
  61. Persaud K, Tille J, Liu M, Zhu Z, Jimenez X, Pereira D, et al. 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. 2004;117:2745-56 pubmed
    ..Similar results were obtained with HUVECs. Together, these findings point to a role for VEGFR-3 in vascular tubular morphogenesis and highlight the utility of hF4-3C5 as a tool for the investigation of the biology of VEGFR-3. ..
  62. Zeng Y, Opeskin K, Baldwin M, Horvath L, Achen M, Stacker S, et al. Expression of vascular endothelial growth factor receptor-3 by lymphatic endothelial cells is associated with lymph node metastasis in prostate cancer. Clin Cancer Res. 2004;10:5137-44 pubmed
    ..Thus the VEGF-C/VEGF-D/VEGF receptor-3 signaling pathway may provide a target for antilymphangiogenic therapy in prostate cancer. ..
  63. Chen F, Takenaka K, Ogawa E, Yanagihara K, Otake Y, Wada H, et al. Flt-4-positive endothelial cell density and its clinical significance in non-small cell lung cancer. Clin Cancer Res. 2004;10:8548-53 pubmed
    ..019). CD34-positive vessel density or Flt-4 status in tumor cells was not a significant prognostic factor. Flt-4-positive endothelial cell density, not Flt-4 status in tumor cells, was a significant prognostic factor in NSCLC. ..
  64. Nakamura Y, Yasuoka H, Tsujimoto M, Yang Q, Imabun S, Nakahara M, et al. Flt-4-positive vessel density correlates with vascular endothelial growth factor-d expression, nodal status, and prognosis in breast cancer. Clin Cancer Res. 2003;9:5313-7 pubmed
    ..High FVD may be a significant unfavorable prognostic factor for long-term survival in breast cancer. It is possible that Flt-4 becomes a target for antiangiogenic therapy to breast cancer. ..
  65. Masood R, Kundra A, Zhu S, Xia G, Scalia P, Smith D, et al. Malignant mesothelioma growth inhibition by agents that target the VEGF and VEGF-C autocrine loops. Int J Cancer. 2003;104:603-10 pubmed
    ..These results indicate that targeting VEGF and VEGF-C simultaneously may be an effective therapeutic approach for malignant mesothelioma. ..
  66. Orlandini M, Spreafico A, Bardelli M, Rocchigiani M, Salameh A, Nucciotti S, et al. Vascular endothelial growth factor-D activates VEGFR-3 expressed in osteoblasts inducing their differentiation. J Biol Chem. 2006;281:17961-7 pubmed
    ..These experiments establish that VEGF-D/VEGFR-3 signaling plays a critical role in osteoblast maturation and suggest that VEGF-D is a downstream effector of VEGF in osteogenesis. ..
  67. Favier B, Alam A, Barron P, Bonnin J, Laboudie P, Fons P, et al. Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration. Blood. 2006;108:1243-50 pubmed
    ..Thus, our data indicate that NRP2 acts as a coreceptor that enhances human endothelial cell biological responses induced by VEGF-A and VEGF-C. ..
  68. He Y, Kozaki K, Karpanen T, Koshikawa K, Yla Herttuala S, Takahashi T, et al. Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J Natl Cancer Inst. 2002;94:819-25 pubmed
    ..Lymph node metastasis appears to be regulated by additional factors besides VEGF-C. Inhibition of VEGFR-3 signaling can suppress tumor lymphangiogenesis and metastasis to regional lymph nodes but not to lungs. ..
  69. Francois M, Caprini A, Hosking B, Orsenigo F, Wilhelm D, Browne C, et al. Sox18 induces development of the lymphatic vasculature in mice. Nature. 2008;456:643-7 pubmed publisher
    ..Our findings demonstrate a critical role for Sox18 in developmental lymphangiogenesis, and suggest new avenues to investigate for therapeutic management of human lymphangiopathies. ..
  70. Karkkainen M, Saaristo A, Jussila L, Karila K, Lawrence E, Pajusola K, et al. A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci U S A. 2001;98:12677-82 pubmed
    ..Our results suggest that growth factor gene therapy is applicable to human lymphedema and provide a paradigm for other diseases associated with mutant receptors. ..
  71. Bono P, Wasenius V, Heikkila P, Lundin J, Jackson D, Joensuu H. High LYVE-1-positive lymphatic vessel numbers are associated with poor outcome in breast cancer. Clin Cancer Res. 2004;10:7144-9 pubmed
    ..Lymph vessel density was not an independent prognostic factor in a multivariate survival analysis. A high peritumoral lymph vessel density is associated with a poor outcome in ductal breast cancer. ..