Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Paper
  • Published:
Angiogenesis Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Chiang AC, Massague J (2008) Molecular basis of metastasis. N Engl J Med 359(26):2814–2823

    Article  PubMed  CAS  Google Scholar 

  2. Achen MG, Stacker SA (2008) Molecular control of lymphatic metastasis. Ann N Y Acad Sci 1131:225–234

    Article  PubMed  CAS  Google Scholar 

  3. Alitalo K, Tammela T, Petrova TV (2005) Lymphangiogenesis in development and human disease. Nature 438(7070):946–953

    Article  PubMed  CAS  Google Scholar 

  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):331–342

    Article  PubMed  CAS  Google Scholar 

  5. Mumprecht V, Detmar M (2009) Lymphangiogenesis and cancer metastasis. J Cell Mol Med 13(8A):1405–1416

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. 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):523–528

    PubMed  CAS  Google Scholar 

  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):4653–4665

    PubMed Central  PubMed  CAS  Google Scholar 

  9. Hong DS, Angelo LS, Kurzrock R (2007) Interleukin-6 and its receptor in cancer: implications for translational therapeutics. Cancer 110(9):1911–1928

    Article  PubMed  CAS  Google Scholar 

  10. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454(7203):436–444

    Article  PubMed  CAS  Google Scholar 

  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):329–337

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):750–757

    Article  PubMed  Google Scholar 

  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–F1046

    Article  PubMed  CAS  Google Scholar 

  14. Smith PC, Hobisch A, Lin DL, Culig Z, Keller ET (2001) Interleukin-6 and prostate cancer progression. Cytokine Growth Factor Rev 12(1):33–40

    Article  PubMed  CAS  Google Scholar 

  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):1149–1157

    Article  PubMed  CAS  Google Scholar 

  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):43–58

    Article  PubMed  CAS  Google Scholar 

  17. Hirano T, Nakajima K, Hibi M (1997) Signaling mechanisms through gp130: a model of the cytokine system. Cytokine Growth Factor Rev 8(4):241–252

    Article  PubMed  CAS  Google Scholar 

  18. Makinen T, Norrmen C, Petrova TV (2007) Molecular mechanisms of lymphatic vascular development. Cell Mol Life Sci 64(15):1915–1929

    Article  PubMed  CAS  Google Scholar 

  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):4762–4773

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):1223–1231

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):1786–1790

    PubMed  CAS  Google Scholar 

  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):192–198

    Article  PubMed  CAS  Google Scholar 

  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):186–191

    Article  PubMed  CAS  Google Scholar 

  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):5650–5659

    Article  PubMed  CAS  Google Scholar 

  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):10181–10189

    Article  PubMed  CAS  Google Scholar 

  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):11528–11535

    Article  PubMed  CAS  Google Scholar 

  27. Kishimoto T (2005) Interleukin-6: from basic science to medicine—40 years in immunology. Annu Rev Immunol 23:1–21

    Article  PubMed  CAS  Google Scholar 

  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):142–150

    Article  PubMed  CAS  Google Scholar 

  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):199–205

    Article  PubMed  CAS  Google Scholar 

  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):11–24

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):105–115

    Article  PubMed  CAS  Google Scholar 

  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):2098–2107

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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 2:104–115

    Google Scholar 

  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):525–533

    Article  PubMed  CAS  Google Scholar 

  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):344–354

    Article  PubMed  CAS  Google Scholar 

  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):e41623

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):1553–1563

    Article  PubMed  CAS  Google Scholar 

  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):554–564

    Article  PubMed  CAS  Google Scholar 

  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):1154–1163

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):2545–2552

    PubMed Central  PubMed  CAS  Google Scholar 

  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):954–963

    PubMed Central  PubMed  CAS  Google Scholar 

  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):362–367

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):375–384

    Article  PubMed  CAS  Google Scholar 

  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):553–559

    Article  PubMed  CAS  Google Scholar 

  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):255–264

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):3585–3592

    Google Scholar 

  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):1730–1741

    Article  PubMed  CAS  Google Scholar 

  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):717–725

    Article  PubMed  CAS  Google Scholar 

  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):320–328

    Article  PubMed  Google Scholar 

  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):8065–8075

    Article  PubMed  CAS  Google Scholar 

  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):387–395

    Article  PubMed  CAS  Google Scholar 

  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):143–159

    Article  PubMed  CAS  Google Scholar 

  53. Johnson GL, Lapadat R (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298(5600):1911–1912

    Article  PubMed  CAS  Google Scholar 

  54. Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9(11):798–809

    Article  PubMed  CAS  Google Scholar 

  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):17209–17218

    Article  PubMed  CAS  Google Scholar 

  56. Silva CM (2004) Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis. Oncogene 23(48):8017–8023

    Article  PubMed  CAS  Google Scholar 

  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–E88

    Article  PubMed  Google Scholar 

  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):2830–2840

    Article  PubMed  CAS  Google Scholar 

  59. DeBusk LM, Massion PP, Lin PC (2008) IkappaB kinase-alpha regulates endothelial cell motility and tumor angiogenesis. Cancer Res 68(24):10223–10228

    Article  PubMed  CAS  Google Scholar 

  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):2248–2258

    Article  PubMed  CAS  Google Scholar 

  61. Karin M (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441(7092):431–436

    Article  PubMed  CAS  Google Scholar 

  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):343–350

    Article  PubMed  CAS  Google Scholar 

  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):149–157

    Article  PubMed  CAS  Google Scholar 

  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):3829–3838

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):1473–1476

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):8145–8149

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):148–157

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  68. Duong T, Koopman P, Francois M (2012) Tumor lymphangiogenesis as a potential therapeutic target. J Oncol 2012:204946

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):6901–6909

    Article  PubMed  CAS  Google Scholar 

  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):2650–2657

    Article  PubMed  CAS  Google Scholar 

  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):209–223

    Article  PubMed  CAS  Google Scholar 

  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):546–553

    Article  PubMed  CAS  Google Scholar 

  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):167–182

    Article  PubMed  CAS  Google Scholar 

  74. Mima T, Nishimoto N (2009) Clinical value of blocking IL-6 receptor. Curr Opin Rheumatol 21(3):224–230

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

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

None.

Author information

Authors and Affiliations

  1. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Yu-Han Huang, Pei-Ting Chiu & Ming-Jen Hsu

  2. Division of Cardiology, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan

    Hung-Yu Yang

  3. Division of General Surgery, Department of Surgery, Landseed Hospital, Taoyuan, Taiwan

    Ya-Fen Hsu

  4. Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu-hsing St., Taipei, 11031, Taiwan

    George Ou & Ming-Jen Hsu

Authors
  1. Yu-Han Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hung-Yu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ya-Fen Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pei-Ting Chiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. George Ou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ming-Jen Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ming-Jen Hsu.

Additional information

Yu-Han Huang and Hung-Yu Yang have contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, YH., Yang, HY., Hsu, YF. et al. Src contributes to IL6-induced vascular endothelial growth factor-C expression in lymphatic endothelial cells. Angiogenesis 17, 407–418 (2014). https://doi.org/10.1007/s10456-013-9386-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10456-013-9386-1

Keywords

Search

Navigation