vascular endothelial growth factor d


Summary: A vascular endothelial growth factor that specifically binds to VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2 and VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-3. In addition to being an angiogenic factor it can act on LYMPHATIC VESSELS to stimulate LYMPHANGIOGENESIS. It is similar in structure to VASCULAR ENDOTHELIAL GROWTH FACTOR C in that they both contain N- and C-terminal extensions that were not found in other VEGF family members.

Top Publications

  1. Thelen A, Scholz A, Benckert C, Von Marschall Z, Schröder M, Wiedenmann B, et al. VEGF-D promotes tumor growth and lymphatic spread in a mouse model of hepatocellular carcinoma. Int J Cancer. 2008;122:2471-81 pubmed publisher
    ..In conclusion, our study suggests that expression of VEGF-D is involved in growth and lymphatic spread of HCC. Therefore, VEGF-D might represent a therapeutic target in HCC. ..
  2. Miyata Y, Kanda S, Ohba K, Nomata K, Hayashida Y, Eguchi J, et al. Lymphangiogenesis and angiogenesis in bladder cancer: prognostic implications and regulation by vascular endothelial growth factors-A, -C, and -D. Clin Cancer Res. 2006;12:800-6 pubmed
    ..Our results suggest that LVD and MVD are useful tools for the selection of postoperative management and treatment strategies in patients with bladder cancer. ..
  3. Nakazato T, Shingaki S, Kitamura N, Saito C, Kuwano R, Tachibana M. Expression level of vascular endothelial growth factor-C and -A in cultured human oral squamous cell carcinoma correlates respectively with lymphatic metastasis and angiogenesis when transplanted into nude mouse oral cavity. Oncol Rep. 2006;15:825-30 pubmed
    ..Since VEGF-C is a lymphangiogenic factor, these results suggest that expression of VEGF-C is a useful predictor for LN metastasis. ..
  4. Seyama K, Kumasaka T, Souma S, Sato T, Kurihara M, Mitani K, et al. Vascular endothelial growth factor-D is increased in serum of patients with lymphangioleiomyomatosis. Lymphat Res Biol. 2006;4:143-52 pubmed
    ..Immunohistochemical examination of lung specimens demonstrated the positive immunoreactivity of LAM cells for VEGF-D. Serum VEGF-D levels may be a valuable surrogate marker for evaluating the disease severity in LAM. ..
  5. Donoghue J, Lederman F, Susil B, Rogers P. Lymphangiogenesis of normal endometrium and endometrial adenocarcinoma. Hum Reprod. 2007;22:1705-13 pubmed
    ..Endometrial lymphatics are significantly reduced in the functionalis, and increases in endometrial adenocarcinoma peri-tumoural lymphatics are associated with increases in VEGF-C and VEGF-D peptides. ..
  6. Shida A, Fujioka S, Ishibashi Y, Kobayashi K, Nimura H, Mitsumori N, et al. Prognostic significance of vascular endothelial growth factor D in gastric carcinoma. World J Surg. 2005;29:1600-7 pubmed
    ..Our data indicate the involvement of VEGF-D in tumor progression via lymphoangiogenic pathways. Practically, VEGF-D expression can be useful for predicting RFS and OS in patients with gastric carcinoma. ..
  7. Farnsworth R, Karnezis T, Shayan R, Matsumoto M, Nowell C, Achen M, et al. A role for bone morphogenetic protein-4 in lymph node vascular remodeling and primary tumor growth. Cancer Res. 2011;71:6547-57 pubmed publisher
    ..Furthermore, they implicate BMP-4 as a negative regulator of this process, suggesting its potential utility as a prognostic marker or antitumor agent. ..
  8. Issaka R, Oommen S, Gupta S, Liu G, Myers J, Ryu J, et al. Vascular endothelial growth factors C and D induces proliferation of lymphangioleiomyomatosis cells through autocrine crosstalk with endothelium. Am J Pathol. 2009;175:1410-20 pubmed publisher
  9. Ming J, Zhang Q, Qiu X, Wang E. Interleukin 7/interleukin 7 receptor induce c-Fos/c-Jun-dependent vascular endothelial growth factor-D up-regulation: a mechanism of lymphangiogenesis in lung cancer. Eur J Cancer. 2009;45:866-73 pubmed publisher
    ..Taken together, our results provide evidence that IL-7/IL-7R induce VEGF-D up-regulation and promote lymphangiogenesis via c-Fos/c-Jun pathway in lung cancer. ..

More Information


  1. 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. ..
  2. Song M, Yang H, Yao S, Ma F, Li Z, Deng Y, et al. A critical role of vascular endothelial growth factor D in zebrafish embryonic vasculogenesis and angiogenesis. Biochem Biophys Res Commun. 2007;357:924-30 pubmed
  3. van der Schaft D, Pauwels P, Hulsmans S, Zimmermann M, van de Poll Franse L, Griffioen A. Absence of lymphangiogenesis in ductal breast cancer at the primary tumor site. Cancer Lett. 2007;254:128-36 pubmed
    ..This parameter did predict survival in patients with an age below 63 only. Interestingly, expression of VEGF-D was found to be related to the presence of intralymphatic tumor cells. ..
  4. Kopfstein L, Veikkola T, Djonov V, Baeriswyl V, Schomber T, Strittmatter K, et al. Distinct roles of vascular endothelial growth factor-D in lymphangiogenesis and metastasis. Am J Pathol. 2007;170:1348-61 pubmed
  5. Kholova I, Koota S, Kaskenpää N, Leppänen P, Narvainen J, Kavec M, et al. Adenovirus-mediated gene transfer of human vascular endothelial growth factor-d induces transient angiogenic effects in mouse hind limb muscle. Hum Gene Ther. 2007;18:232-44 pubmed
    ..VEGF-D also increases the presence of pericytes/smooth muscle cells in neovessels. AdhVEGF-D is a potential new agent for the induction of therapeutic vascular growth in skeletal muscle. ..
  6. Cursiefen C, Chen L, Saint Geniez M, Hamrah P, Jin Y, Rashid S, et al. Nonvascular VEGF receptor 3 expression by corneal epithelium maintains avascularity and vision. Proc Natl Acad Sci U S A. 2006;103:11405-10 pubmed
  7. 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. ..
  8. Achen M, Jeltsch M, Kukk E, Makinen T, Vitali A, Wilks A, et al. 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 U S A. 1998;95:548-53 pubmed
    ..In addition, VEGF-D is a mitogen for endothelial cells. The structural and functional similarities between VEGF-D and VEGF-C define a subfamily of the VEGFs. ..
  9. Bjorndahl M, Cao R, Nissen L, Clasper S, Johnson L, Xue Y, et al. Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo. Proc Natl Acad Sci U S A. 2005;102:15593-8 pubmed
    ..Because members of the IGF ligand and receptor families are widely expressed in various types of solid tumors, our findings suggest that these factors are likely to contribute to lymphatic metastasis. ..
  10. Van Trappen P, Pepper M. Lymphangiogenesis in human gynaecological cancers. Angiogenesis. 2005;8:137-45 pubmed
    ..Potential anti-lymphangiogenic strategies are also discussed. ..
  11. 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. ..
  12. Sipos B, Klapper W, Kruse M, Kalthoff H, Kerjaschki D, Kloppel G. Expression of lymphangiogenic factors and evidence of intratumoral lymphangiogenesis in pancreatic endocrine tumors. Am J Pathol. 2004;165:1187-97 pubmed
    ..PET is the first human tumor entity in which VEGF-C-related intratumoral lymphangiogenesis has been demonstrated. ..
  13. Choi W, Lewis M, Lawson D, Yin Goen Q, Birdsong G, Cotsonis G, et al. Angiogenic and lymphangiogenic microvessel density in breast carcinoma: correlation with clinicopathologic parameters and VEGF-family gene expression. Mod Pathol. 2005;18:143-52 pubmed
    ..Thus, measurements of angiogenesis and lymphangiogenesis may have utility for breast cancer pathology, particularly for estimation of metastatic risk. ..
  14. 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. ..
  15. 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
  16. Koyama Y, Kaneko K, Akazawa K, Kanbayashi C, Kanda T, Hatakeyama K. Vascular endothelial growth factor-C and vascular endothelial growth factor-d messenger RNA expression in breast cancer: association with lymph node metastasis. Clin Breast Cancer. 2003;4:354-60 pubmed
    ..Our results suggest that a decrease in VEGF-D mRNA or an increase in the VEGF-C/VEGF-D ratio may have an association with tumorigenesis and/or lymph node metastasis in breast cancer. ..
  17. Funaki H, Nishimura G, Harada S, Ninomiya I, Terada I, Fushida S, et al. Expression of vascular endothelial growth factor D is associated with lymph node metastasis in human colorectal carcinoma. Oncology. 2003;64:416-22 pubmed
    ..15). These results suggest that the expression of VEGF-D protein could be useful in predicting the nodal status of colorectal carcinoma patients. ..
  18. 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. ..
  19. Ishikawa M, Kitayama J, Kazama S, Nagawa H. Expression of vascular endothelial growth factor C and D (VEGF-C and -D) is an important risk factor for lymphatic metastasis in undifferentiated early gastric carcinoma. Jpn J Clin Oncol. 2003;33:21-7 pubmed
    ..These observations are based only on retrospective analysis of a small case series and further evaluation with a larger number of cases is necessary. ..
  20. Schoppmann S, Birner P, Stockl J, Kalt R, Ullrich R, Caucig C, et al. Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol. 2002;161:947-56 pubmed
    ..In conclusion VEGF-C-expressing TAMs play a novel role in peritumoral lymphangiogenesis and subsequent dissemination in human cancer. ..
  21. Yang W, Klos K, Yang Y, Smith T, Shi D, Yu D. ErbB2 overexpression correlates with increased expression of vascular endothelial growth factors A, C, and D in human breast carcinoma. Cancer. 2002;94:2855-61 pubmed
    ..e., VEGFs) might be regulated at least in part by ErbB2. In addition, the combination of VEGF-A and VEGF-C status may better predict prognosis of patients with breast carcinoma than VEGF-A alone. ..
  22. 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. ..
  23. Stacker S, Caesar C, Baldwin M, Thornton G, Williams R, Prevo R, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med. 2001;7:186-91 pubmed
    ..This study demonstrates that lymphatics can be established in solid tumors and implicates VEGF family members in determining the route of metastatic spread. ..