, Volume 17, Issue 2, pp 407–418 | Cite as

Src contributes to IL6-induced vascular endothelial growth factor-C expression in lymphatic endothelial cells

  • Yu-Han Huang
  • Hung-Yu Yang
  • Ya-Fen Hsu
  • Pei-Ting Chiu
  • George Ou
  • Ming-Jen HsuEmail author
Original Paper


Formation of lymphatic capillaries by lymphatic endothelial cells (LECs) occurs both in normal tissues as well as in pathological processes including tumor metastasis. Interleukin-6 (IL-6), a potent pro-inflammatory cytokine, has been shown to be highly elevated in various cancers. IL-6 has also been shown to increase tumor lymphangiogenesis through vascular endothelial growth factor-C (VEGF-C) induction in tumor cells. Although lymphangiogenesis is associated with lymph node metastasis and also resistance to conventional therapy in various cancers, the precise mechanisms of lymphangiogenesis in LECs remain unclear. This study aimed to investigate the signaling cascade involved in IL-6-induced VEGF-C expression in murine LECs (SV-LEC). The VEGF-C mRNA and protein levels were increased in SV-LECs exposed to IL-6. IL-6 time-dependently induced Src phosphorylation and downstream phosphorylation of ERK1/2 and p38MAPK. In contrast, PP2, an inhibitor of Src signaling, abrogated IL-6′s effects on ERK1/2 and p38MAPK phosphorylation. IL-6 exposure also led to increase in VEGF-C promoter-luciferase activity as well as C/EBPβ- and κB-luciferase activities. VEGF-C promoter-, C/EBPβ- and κB-luciferase activities were all suppressed by Src, ERK1/2 or p38MAPK signaling blockades despite presence of IL-6. Finally, C/EBPβ and p65 binding to the VEGF-C promoter region were increased after IL-6 exposure in SV-LECs. Taken together, we report a Src-mediated ERK1/2 and p38MAPK activation resulting in C/EBPβ and p65 binding to the promoter region of VEGF-C, leading to VEGF-C expression in IL-6-exposed SV-LECs.


Lymphatic endothelial cells (LECs) Interleukin-6 (IL-6) Vascular endothelial growth factor-C (VEGF-C) Lymphangiogenesis Src 



We would like to thank Dr. Kjetil Tasken for the kind gift of the p/T81 C/EBP-luc reporter construct and Dr. J.S. Alexander (Shreveport, LA, USA) for the kind gift of the mouse LEC line SV-LEC. This work was supported by grant from the National Science Council of Taiwan [NSC98-2320-B-038-007]; Grant [100TMU-WFH-01-4] from the Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan; and Grant [LSH-2012-04] from the Landseed Hospital, Taoyuan, Taiwan.

Conflicts of interest



  1. 1.
    Chiang AC, Massague J (2008) Molecular basis of metastasis. N Engl J Med 359(26):2814–2823PubMedCrossRefGoogle Scholar
  2. 2.
    Achen MG, Stacker SA (2008) Molecular control of lymphatic metastasis. Ann N Y Acad Sci 1131:225–234PubMedCrossRefGoogle Scholar
  3. 3.
    Alitalo K, Tammela T, Petrova TV (2005) Lymphangiogenesis in development and human disease. Nature 438(7070):946–953PubMedCrossRefGoogle Scholar
  4. 4.
    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(4):331–342PubMedCrossRefGoogle Scholar
  5. 5.
    Mumprecht V, Detmar M (2009) Lymphangiogenesis and cancer metastasis. J Cell Mol Med 13(8A):1405–1416PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Szczepanik AM, Scislo L, Scully T, Walewska E, Siedlar M, Kolodziejczyk P, Lenart M, Rutkowska M, Galas A, Czupryna A, Kulig J (2011) IL-6 serum levels predict postoperative morbidity in gastric cancer patients. Gastric Cancer 14(3):266–273 Google Scholar
  7. 7.
    Kallio JP, Tammela TL, Marttinen AT, Kellokumpu-Lehtinen PL (2001) Soluble immunological parameters and early prognosis of renal cell cancer patients. J Exp Clin Cancer Res 20(4):523–528PubMedGoogle Scholar
  8. 8.
    Trikha M, Corringham R, Klein B, Rossi JF (2003) Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. Clin Cancer Res 9(13):4653–4665PubMedCentralPubMedGoogle Scholar
  9. 9.
    Hong DS, Angelo LS, Kurzrock R (2007) Interleukin-6 and its receptor in cancer: implications for translational therapeutics. Cancer 110(9):1911–1928PubMedCrossRefGoogle Scholar
  10. 10.
    Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454(7203):436–444PubMedCrossRefGoogle Scholar
  11. 11.
    Ara T, Song L, Shimada H, Keshelava N, Russell HV, Metelitsa LS, Groshen SG, Seeger RC, DeClerck YA (2009) Interleukin-6 in the bone marrow microenvironment promotes the growth and survival of neuroblastoma cells. Cancer Res 69(1):329–337PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Duffy SA, Taylor JM, Terrell JE, Islam M, Li Y, Fowler KE, Wolf GT, Teknos TN (2008) Interleukin-6 predicts recurrence and survival among head and neck cancer patients. Cancer 113(4):750–757PubMedCrossRefGoogle Scholar
  13. 13.
    Lee YJ, Heo JS, Suh HN, Lee MY, Han HJ (2007) Interleukin-6 stimulates alpha-MG uptake in renal proximal tubule cells: involvement of STAT3, PI3 K/Akt, MAPKs, and NF-kappaB. Am J Physiol Renal Physiol 293(4):F1036–F1046PubMedCrossRefGoogle Scholar
  14. 14.
    Smith PC, Hobisch A, Lin DL, Culig Z, Keller ET (2001) Interleukin-6 and prostate cancer progression. Cytokine Growth Factor Rev 12(1):33–40PubMedCrossRefGoogle Scholar
  15. 15.
    Hibi M, Murakami M, Saito M, Hirano T, Taga T, Kishimoto T (1990) Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell 63(6):1149–1157PubMedCrossRefGoogle Scholar
  16. 16.
    Jones SA, Horiuchi S, Topley N, Yamamoto N, Fuller GM (2001) The soluble interleukin 6 receptor: mechanisms of production and implications in disease. Faseb J 15(1):43–58PubMedCrossRefGoogle Scholar
  17. 17.
    Hirano T, Nakajima K, Hibi M (1997) Signaling mechanisms through gp130: a model of the cytokine system. Cytokine Growth Factor Rev 8(4):241–252PubMedCrossRefGoogle Scholar
  18. 18.
    Makinen T, Norrmen C, Petrova TV (2007) Molecular mechanisms of lymphatic vascular development. Cell Mol Life Sci 64(15):1915–1929PubMedCrossRefGoogle Scholar
  19. 19.
    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 (2001) Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J 20(17):4762–4773PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    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(6):1223–1231PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    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(5):1786–1790PubMedGoogle Scholar
  22. 22.
    Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, Riccardi L, Alitalo K, Claffey K, Detmar M (2001) Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 7(2):192–198PubMedCrossRefGoogle Scholar
  23. 23.
    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(2):186–191PubMedCrossRefGoogle Scholar
  24. 24.
    Kataru RP, Jung K, Jang C, Yang H, Schwendener RA, Baik JE, Han SH, Alitalo K, Koh GY (2009) Critical role of CD11b + macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution. Blood 113(22):5650–5659PubMedCrossRefGoogle Scholar
  25. 25.
    Iwata C, Kano MR, Komuro A, Oka M, Kiyono K, Johansson E, Morishita Y, Yashiro M, Hirakawa K, Kaminishi M, Miyazono K (2007) Inhibition of cyclooxygenase-2 suppresses lymph node metastasis via reduction of lymphangiogenesis. Cancer Res 67(21):10181–10189PubMedCrossRefGoogle Scholar
  26. 26.
    Brideau G, Makinen MJ, Elamaa H, Tu H, Nilsson G, Alitalo K, Pihlajaniemi T, Heljasvaara R (2007) Endostatin overexpression inhibits lymphangiogenesis and lymph node metastasis in mice. Cancer Res 67(24):11528–11535PubMedCrossRefGoogle Scholar
  27. 27.
    Kishimoto T (2005) Interleukin-6: from basic science to medicine—40 years in immunology. Annu Rev Immunol 23:1–21PubMedCrossRefGoogle Scholar
  28. 28.
    Shinriki S, Jono H, Ueda M, Ota K, Ota T, Sueyoshi T, Oike Y, Ibusuki M, Hiraki A, Nakayama H, Shinohara M, Ando Y (2011) Interleukin-6 signalling regulates vascular endothelial growth factor-C synthesis and lymphangiogenesis in human oral squamous cell carcinoma. J Pathol 225(1):142–150PubMedCrossRefGoogle Scholar
  29. 29.
    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 (2001) Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med 7(2):199–205PubMedCrossRefGoogle Scholar
  30. 30.
    Nisato RE, Harrison JA, Buser R, Orci L, Rinsch C, Montesano R, Dupraz P, Pepper MS (2004) Generation and characterization of telomerase-transfected human lymphatic endothelial cells with an extended life span. Am J Pathol 165(1):11–24PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Ando T, Jordan P, Joh T, Wang Y, Jennings MH, Houghton J, Alexander JS (2005) Isolation and characterization of a novel mouse lymphatic endothelial cell line: SV-LEC. Lymphat Res Biol 3(3):105–115PubMedCrossRefGoogle Scholar
  32. 32.
    Luo Y, Zhou H, Liu L, Shen T, Chen W, Xu B, Han X, Zhang F, Scott RS, Alexander JS, Alam A, Huang S (2011) The fungicide ciclopirox inhibits lymphatic endothelial cell tube formation by suppressing VEGFR-3-mediated ERK signaling pathway. Oncogene 30(18):2098–2107PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Hsu YF, Sheu JR, Lin CH, Yang DS, Hsiao G, Ou G, Chiu PT, Huang YH, Kuo WH (1820) Hsu MJ Trichostatin A and sirtinol suppressed survivin expression through AMPK and p38MAPK in HT29 colon cancer cells. Biochim Biophys Acta 2:104–115Google Scholar
  34. 34.
    Novick D, Rubinstein M (2007) The tale of soluble receptors and binding proteins: from bench to bedside. Cytokine Growth Factor Rev 18(5–6):525–533PubMedCrossRefGoogle Scholar
  35. 35.
    Zhang P, Chebath J, Lonai P, Revel M (2004) Enhancement of oligodendrocyte differentiation from murine embryonic stem cells by an activator of gp130 signaling. Stem Cells 22(3):344–354PubMedCrossRefGoogle Scholar
  36. 36.
    Patel A, Zhu Y, Kuzhikandathil EV, Banks WA, Siegel A, Zalcman SS (2012) Soluble interleukin-6 receptor induces motor stereotypies and co-localizes with gp130 in regions linked to cortico-striato-thalamo-cortical circuits. PLoS One 7(7):e41623PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Yamashita M, Iwama N, Date F, Shibata N, Miki H, Yamauchi K, Sawai T, Sato S, Takahashi T, Ono M (2009) Macrophages participate in lymphangiogenesis in idiopathic diffuse alveolar damage through CCL19-CCR7 signal. Hum Pathol 40(11):1553–1563PubMedCrossRefGoogle Scholar
  38. 38.
    Su JL, Shih JY, Yen ML, Jeng YM, Chang CC, Hsieh CY, Wei LH, Yang PC, Kuo ML (2004) Cyclooxygenase-2 induces EP1- and HER-2/Neu-dependent vascular endothelial growth factor-C up-regulation: a novel mechanism of lymphangiogenesis in lung adenocarcinoma. Cancer Res 64(2):554–564PubMedCrossRefGoogle Scholar
  39. 39.
    Timoshenko AV, Chakraborty C, Wagner GF, Lala PK (2006) COX-2-mediated stimulation of the lymphangiogenic factor VEGF-C in human breast cancer. Br J Cancer 94(8):1154–1163PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Turkson J, Bowman T, Garcia R, Caldenhoven E, De Groot RP, Jove R (1998) Stat3 activation by Src induces specific gene regulation and is required for cell transformation. Mol Cell Biol 18(5):2545–2552PubMedCentralPubMedGoogle Scholar
  41. 41.
    Calalb MB, Polte TR, Hanks SK (1995) Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases. Mol Cell Biol 15(2):954–963PubMedCentralPubMedGoogle Scholar
  42. 42.
    Heinemeyer T, Wingender E, Reuter I, Hermjakob H, Kel AE, Kel OV, Ignatieva EV, Ananko EA, Podkolodnaya OA, Kolpakov FA, Podkolodny NL, Kolchanov NA (1998) Databases on transcriptional regulation: TRANSFAC, TRRD and COMPEL. Nucleic Acids Res 26(1):362–367PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Mukundan L, Milhorn DM, Matta B, Suttles J (2004) CD40-mediated activation of vascular smooth muscle cell chemokine production through a Src-initiated, MAPK-dependent pathway. Cell Signal 16(3):375–384PubMedCrossRefGoogle Scholar
  44. 44.
    Touyz RM, He G, El Mabrouk M, Diep Q, Mardigyan V, Schiffrin EL (2001) Differential activation of extracellular signal-regulated protein kinase 1/2 and p38 mitogen activated-protein kinase by AT1 receptors in vascular smooth muscle cells from Wistar-Kyoto rats and spontaneously hypertensive rats. J Hypertens 19(3 Pt 2):553–559PubMedCrossRefGoogle Scholar
  45. 45.
    Abu-Ghazaleh R, Kabir J, Jia H, Lobo M, Zachary I (2001) Src mediates stimulation by vascular endothelial growth factor of the phosphorylation of focal adhesion kinase at tyrosine 861, and migration and anti-apoptosis in endothelial cells. Biochem J 360(Pt 1):255–264PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Min J, Reznichenko M, Poythress RH, Gallant CM, Vetterkind S, Li Y, Morgan KG (2012) Src modulates contractile vascular smooth muscle function via regulation of focal adhesions. J Cell Physiol 227(11):3585–3592Google Scholar
  47. 47.
    Thamilselvan V, Craig DH, Basson MD (2007) FAK association with multiple signal proteins mediates pressure-induced colon cancer cell adhesion via a Src-dependent PI3 K/Akt pathway. Faseb J 21(8):1730–1741PubMedCrossRefGoogle Scholar
  48. 48.
    Gu Y, Qi X, Guo S (2008) Lymphangiogenesis induced by VEGF-C and VEGF-D promotes metastasis and a poor outcome in breast carcinoma: a retrospective study of 61 cases. Clin Exp Metastasis 25(7):717–725PubMedCrossRefGoogle Scholar
  49. 49.
    Yamashita T, Uramoto H, Onitsuka T, Ono K, Baba T, So T, Takenoyama M, Hanagiri T, Oyama T, Yasumoto K (2010) Association between lymphangiogenesis-/micrometastasis- and adhesion-related molecules in resected stage I NSCLC. Lung Cancer 70(3):320–328PubMedCrossRefGoogle Scholar
  50. 50.
    Hoshida T, Isaka N, Hagendoorn J, di Tomaso E, Chen YL, Pytowski B, Fukumura D, Padera TP, Jain RK (2006) 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 66(16):8065–8075PubMedCrossRefGoogle Scholar
  51. 51.
    Saharinen P, Tammela T, Karkkainen MJ, Alitalo K (2004) Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation. Trends Immunol 25(7):387–395PubMedCrossRefGoogle Scholar
  52. 52.
    Mihara M, Hashizume M, Yoshida H, Suzuki M, Shiina M (2012) IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clin Sci 122(4):143–159PubMedCrossRefGoogle Scholar
  53. 53.
    Johnson GL, Lapadat R (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298(5600):1911–1912PubMedCrossRefGoogle Scholar
  54. 54.
    Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9(11):798–809PubMedCrossRefGoogle Scholar
  55. 55.
    Olayioye MA, Beuvink I, Horsch K, Daly JM, Hynes NE (1999) ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases. J Biol Chem 274(24):17209–17218PubMedCrossRefGoogle Scholar
  56. 56.
    Silva CM (2004) Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis. Oncogene 23(48):8017–8023PubMedCrossRefGoogle Scholar
  57. 57.
    De Martin R, Hoeth M, Hofer-Warbinek R, Schmid JA (2000) The transcription factor NF-kappa B and the regulation of vascular cell function. Arterioscler Thromb Vasc Biol 20(11):E83–E88PubMedCrossRefGoogle Scholar
  58. 58.
    Aoki T, Kataoka H, Shimamura M, Nakagami H, Wakayama K, Moriwaki T, Ishibashi R, Nozaki K, Morishita R, Hashimoto N (2007) NF-kappaB is a key mediator of cerebral aneurysm formation. Circulation 116(24):2830–2840PubMedCrossRefGoogle Scholar
  59. 59.
    DeBusk LM, Massion PP, Lin PC (2008) IkappaB kinase-alpha regulates endothelial cell motility and tumor angiogenesis. Cancer Res 68(24):10223–10228PubMedCrossRefGoogle Scholar
  60. 60.
    Sakamoto K, Maeda S, Hikiba Y, Nakagawa H, Hayakawa Y, Shibata W, Yanai A, Ogura K, Omata M (2009) Constitutive NF-kappaB activation in colorectal carcinoma plays a key role in angiogenesis, promoting tumor growth. Clin Cancer Res 15(7):2248–2258PubMedCrossRefGoogle Scholar
  61. 61.
    Karin M (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441(7092):431–436PubMedCrossRefGoogle Scholar
  62. 62.
    Nizamutdinova IT, Oh HM, Min YN, Park SH, Lee MJ, Kim JS, Yean MH, Kang SS, Kim YS, Chang KC, Kim HJ (2007) Paeonol suppresses intercellular adhesion molecule-1 expression in tumor necrosis factor-alpha-stimulated human umbilical vein endothelial cells by blocking p38, ERK and nuclear factor-kappaB signaling pathways. Int Immunopharmacol 7(3):343–350PubMedCrossRefGoogle Scholar
  63. 63.
    Barbier D, Garcia-Verdugo I, Pothlichet J, Khazen R, Descamps D, Rousseau K, Thornton D, Si-Tahar M, Touqui L, Chignard M, Sallenave JM (2012) Influenza A induces the major secreted airway mucin MUC5AC in a protease-EGFR-ERK-Sp1 dependent pathway. Am J Respir Cell Mol Biol 47(2):149–157PubMedCrossRefGoogle Scholar
  64. 64.
    Lin HH, Lai SC, Chau LY (2011) Heme oxygenase-1/carbon monoxide induces vascular endothelial growth factor expression via p38 kinase-dependent activation of Sp1. J Biol Chem 286(5):3829–3838PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Kinoshita S, Akira S, Kishimoto T (1992) A member of the C/EBP family, NF-IL6 beta, forms a heterodimer and transcriptionally synergizes with NF-IL6. Proc Natl Acad Sci USA 89(4):1473–1476PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    LeClair KP, Blanar MA, Sharp PA (1992) The p50 subunit of NF-kappa B associates with the NF-IL6 transcription factor. Proc Natl Acad Sci USA 89(17):8145–8149PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Goldhar AS, Duan R, Ginsburg E, Vonderhaar BK (2011) Progesterone induces expression of the prolactin receptor gene through cooperative action of Sp1 and C/EBP. Mol Cell Endocrinol 335(2):148–157PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Duong T, Koopman P, Francois M (2012) Tumor lymphangiogenesis as a potential therapeutic target. J Oncol 2012:204946PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    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(15):6901–6909PubMedCrossRefGoogle Scholar
  70. 70.
    Roberts N, Kloos B, Cassella M, Podgrabinska S, Persaud K, Wu Y, Pytowski B, Skobe M (2006) Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. Cancer Res 66(5):2650–2657PubMedCrossRefGoogle Scholar
  71. 71.
    Su JL, Yang PC, Shih JY, Yang CY, Wei LH, Hsieh CY, Chou CH, Jeng YM, Wang MY, Chang KJ, Hung MC, Kuo ML (2006) The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells. Cancer Cell 9(3):209–223PubMedCrossRefGoogle Scholar
  72. 72.
    Ischenko I, Seeliger H, Camaj P, Kleespies A, Guba M, Eichhorn ME, Jauch KW, Bruns CJ (2010) Src tyrosine kinase inhibition suppresses lymphangiogenesis in vitro and in vivo. Curr Cancer Drug Targets 10(5):546–553PubMedCrossRefGoogle Scholar
  73. 73.
    Ischenko I, Guba M, Yezhelyev M, Papyan A, Schmid G, Green T, Fennell M, Jauch KW, Bruns CJ (2007) Effect of Src kinase inhibition on metastasis and tumor angiogenesis in human pancreatic cancer. Angiogenesis 10(3):167–182PubMedCrossRefGoogle Scholar
  74. 74.
    Mima T, Nishimoto N (2009) Clinical value of blocking IL-6 receptor. Curr Opin Rheumatol 21(3):224–230PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Yu-Han Huang
    • 1
  • Hung-Yu Yang
    • 2
  • Ya-Fen Hsu
    • 3
  • Pei-Ting Chiu
    • 1
  • George Ou
    • 4
  • Ming-Jen Hsu
    • 1
    • 4
    Email author
  1. 1.Graduate Institute of Medical Sciences, College of MedicineTaipei Medical UniversityTaipeiTaiwan
  2. 2.Division of CardiologyTaipei Medical University-Wan Fang HospitalTaipeiTaiwan
  3. 3.Division of General Surgery, Department of SurgeryLandseed HospitalTaoyuanTaiwan
  4. 4.Department of Pharmacology, School of Medicine, College of MedicineTaipei Medical UniversityTaipeiTaiwan

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