2,034
Views
25
CrossRef citations to date
0
Altmetric
Review

The dual role of tumor lymphatic vessels in dissemination of metastases and immune response development

, , , , &
Article: e1182278 | Received 02 Mar 2016, Accepted 18 Apr 2016, Published online: 30 Jun 2016

References

  • Stacker SA, Williams SP, Karnezis T, Shayan R, Fox SB, Achen MG. Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat Rev Cancer 2014; 14:159-72; PMID:24561443; http://dx.doi.org/10.1038/nrc3677
  • Francois M, Caprini A, Hosking B, Orsenigo F, Wilhelm D, Browne C, Paavonen K, Karnezis T, Shayan R, Downes M et al. Sox18 induces development of the lymphatic vasculature in mice. Nature 2008; 456:643-7; PMID:18931657; http://dx.doi.org/10.1038/nature07391
  • Lund AW, Duraes FV, Hirosue S, Raghavan VR, Nembrini C, Thomas SN, Issa A, Hugues S, Swartz MA. VEGF-C promotes immune tolerance in B16 melanomas and cross-presentation of tumor antigen by lymph node lymphatics. Cell Rep 2012; 1:191-9; PMID:22832193; http://dx.doi.org/10.1016/j.celrep.2012.01.005
  • Maby-El Hajjami H, Petrova TV. Developmental and pathological lymphangiogenesis: from models to human disease. Histochem Cell Biol 2008; 130:1063-78; PMID:18946678; http://dx.doi.org/10.1007/s00418-008-0525-5
  • Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS et al. Structural and functional features of central nervous system lymphatic vessels. Nature 2015; 523:337-41; PMID:26030524; http://dx.doi.org/10.1038/nature14432
  • Baluk P, Fuxe J, Hashizume H, Romano T, Lashnits E, Butz S, Vestweber D, Corada M, Molendini C, Dejana E et al. Functionally specialized junctions between endothelial cells of lymphatic vessels. J Exp Med 2007; 204:2349-62; PMID:17846148; http://dx.doi.org/10.1084/jem.20062596
  • Dieterich LC, Detmar M. Tumor lymphangiogenesis and new drug development. Adv Drug Deliv Rev 2016 Apr 1; 99(Pt B):148-60; PMID:26705849; http://dx.doi.org/10.1016/j.addr.2015.12.011
  • Hirosue S, Vokali E, Raghavan VR, Rincon-Restrepo M, Lund AW, Corthesy-Henrioud P, Capotosti F, Halin Winter C, Hugues S, Swartz MA. Steady-state antigen scavenging, cross-presentation, and CD8+ T cell priming: a new role for lymphatic endothelial cells. J Immunol 2014; 192:5002-11; PMID:24795456; http://dx.doi.org/10.4049/jimmunol.1302492
  • Lund AW, Swartz MA. Role of lymphatic vessels in tumor immunity: passive conduits or active participants? J Mammary Gland Biol Neoplasia 2010; 15:341-52; PMID:20835756; http://dx.doi.org/10.1007/s10911-010-9193-x
  • Fletcher AL, Malhotra D, Turley SJ. Lymph node stroma broaden the peripheral tolerance paradigm. Trends Immunol 2011; 32:12-8; PMID:21147035; http://dx.doi.org/10.1016/j.it.2010.11.002
  • Rovenska E, Rovensky J. Lymphatic vessels: structure and function. Isr Med Assoc J 2011; 13:762-8; PMID:22332449
  • Warren AG, Brorson H, Borud LJ, Slavin SA. Lymphedema: a comprehensive review. Ann Plast Surg 2007; 59:464-72; PMID:17901744; http://dx.doi.org/10.1097/01.sap.0000257149.42922.7e
  • Vigl B, Aebischer D, Nitschke M, Iolyeva M, Rothlin T, Antsiferova O, Halin C. Tissue inflammation modulates gene expression of lymphatic endothelial cells and dendritic cell migration in a stimulus-dependent manner. Blood 2011; 118:205-15; PMID:21596851; http://dx.doi.org/10.1182/blood-2010-12-326447
  • Duong T, Koopman P, Francois M. Tumor lymphangiogenesis as a potential therapeutic target. J Oncol 2012; 2012:204946; PMID:22481918; http://dx.doi.org/10.1155/2012/204946
  • Schoppmann SF, Birner P, Stockl J, Kalt R, Ullrich R, Caucig C, Kriehuber E, Nagy K, Alitalo K, Kerjaschki D. Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol 2002; 161:947-56; PMID:12213723; http://dx.doi.org/10.1016/S0002-9440(10)64255-1
  • Achen MG, McColl BK, Stacker SA. Focus on lymphangiogenesis in tumor metastasis. Cancer Cell 2005; 7:121-7; PMID:15710325; http://dx.doi.org/10.1016/j.ccr.2005.01.017
  • Min Y, Ghose S, Boelte K, Li J, Yang L, Lin PC. C/EBP-delta regulates VEGF-C autocrine signaling in lymphangiogenesis and metastasis of lung cancer through HIF-1alpha. Oncogene 2011; 30:4901-9; PMID:21666710; http://dx.doi.org/10.1038/onc.2011.187
  • Schito L, Rey S, Tafani M, Zhang H, Wong CC, Russo A, Russo MA, Semenza GL. Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells. Proc Natl Acad Sci USA 2012; 109:E2707-16; PMID:23012449; http://dx.doi.org/10.1073/pnas.1214019109
  • Bridges JP, Lin S, Ikegami M, Shannon JM. Conditional hypoxia inducible factor-1alpha induction in embryonic pulmonary epithelium impairs maturation and augments lymphangiogenesis. Dev Biol 2012; 362:24-41; PMID:22094019; http://dx.doi.org/10.1016/j.ydbio.2011.10.033
  • Morfoisse F, Kuchnio A, Frainay C, Gomez-Brouchet A, Delisle MB, Marzi S, Helfer AC, Hantelys F, Pujol F, Guillermet-Guibert J et al. Hypoxia induces VEGF-C expression in metastatic tumor cells via a HIF-1alpha-independent translation-mediated mechanism. Cell reports 2014; 6:155-67; PMID:24388748; http://dx.doi.org/10.1016/j.celrep.2013.12.011
  • Rofstad EK, Galappathi K, Mathiesen BS. Tumor interstitial fluid pressure – a link between tumor hypoxia, microvascular density, and lymph node metastasis. Neoplasia 2014; 16:586-94; PMID:25117980; http://dx.doi.org/10.1016/j.neo.2014.07.003
  • Van Trappen PO, Steele D, Lowe DG, Baithun S, Beasley N, Thiele W, Weich H, Krishnan J, Shepherd JH, Pepper MS et al. Expression of vascular endothelial growth factor (VEGF)-C and VEGF-D, and their receptor VEGFR-3, during different stages of cervical carcinogenesis. J Pathol 2003; 201:544-54; PMID:14648657; http://dx.doi.org/10.1002/path.1467
  • Ji H, Cao R, Yang Y, Zhang Y, Iwamoto H, Lim S, Nakamura M, Andersson P, Wang J, Sun Y et al. TNFR1 mediates TNF-alpha-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling. Nat Commun 2014; 5:4944; PMID:25229256; http://dx.doi.org/10.1038/ncomms5944
  • Maeng YS, Aguilar B, Choi SI, Kim EK. Inhibition of TGFBIp expression reduces lymphangiogenesis and tumor metastasis. Oncogene 2016; 35:196-205; PMID:25772247; http://dx.doi.org/10.1038/onc.2015.73
  • Maeng YS, Lee R, Lee B, Choi SI, Kim EK. Lithium inhibits tumor lymphangiogenesis and metastasis through the inhibition of TGFBIp expression in cancer cells. Scientific Rep 2016; 6:20739; PMID:26857144; http://dx.doi.org/10.1038/srep20739
  • Steeg PS. Cancer biology: emissaries set up new sites. Nature 2005; 438:750-1; PMID:16341000; http://dx.doi.org/10.1038/438750b
  • Lee E, Pandey NB, Popel AS. Pre-treatment of mice with tumor-conditioned media accelerates metastasis to lymph nodes and lungs: a new spontaneous breast cancer metastasis model. Clin Exp Metastasis 2014; 31:67-79; PMID:23963763; http://dx.doi.org/10.1007/s10585-013-9610-9
  • Xu J, Zhang C, He Y, Wu H, Wang Z, Song W, Li W, He W, Cai S, Zhan W. Lymphatic endothelial cell-secreted CXCL1 stimulates lymphangiogenesis and metastasis of gastric cancer. Int J Cancer J Int du Cancer 2012; 130:787-97; PMID:21387301; http://dx.doi.org/10.1002/ijc.26035
  • Lee E, Fertig EJ, Jin K, Sukumar S, Pandey NB, Popel AS. Breast cancer cells condition lymphatic endothelial cells within pre-metastatic niches to promote metastasis. Nat Commun 2014; 5:4715; PMID:25178650; http://dx.doi.org/10.1038/ncomms5715
  • Schafer ZT, Brugge JS. IL-6 involvement in epithelial cancers. J Clin Investig 2007; 117:3660-3; PMID:18060028; http://dx.doi.org/10.1172/JCI34237
  • Chang Q, Bournazou E, Sansone P, Berishaj M, Gao SP, Daly L, Wels J, Theilen T, Granitto S, Zhang X et al. The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis. Neoplasia 2013; 15:848-62; PMID:23814496; http://dx.doi.org/10.1593/neo.13706
  • Fertig EJ, Lee E, Pandey NB, Popel AS. Analysis of gene expression of secreted factors associated with breast cancer metastases in breast cancer subtypes. Scientific reports 2015; 5:12133; PMID:26173622; http://dx.doi.org/10.1038/srep12133
  • Oh K, Lee OY, Shon SY, Nam O, Ryu PM, Seo MW, Lee DS. A mutual activation loop between breast cancer cells and myeloid-derived suppressor cells facilitates spontaneous metastasis through IL-6 trans-signaling in a murine model. Breast Cancer Res 2013; 15:R79; PMID:24021059; http://dx.doi.org/10.1186/bcr3473
  • Amioka T, Kitadai Y, Tanaka S, Haruma K, Yoshihara M, Yasui W, Chayama K. Vascular endothelial growth factor-C expression predicts lymph node metastasis of human gastric carcinomas invading the submucosa. Eur J Cancer 2002; 38:1413-9; PMID:12091074; http://dx.doi.org/10.1016/S0959-8049(02)00106-5
  • Shields JD, Emmett MS, Dunn DB, Joory KD, Sage LM, Rigby H, Mortimer PS, Orlando A, Levick JR, Bates DO. Chemokine-mediated migration of melanoma cells towards lymphatics–a mechanism contributing to metastasis. Oncogene 2007; 26:2997-3005; PMID:17130836; http://dx.doi.org/10.1038/sj.onc.1210114
  • Pan MR, Hou MF, Chang HC, Hung WC. Cyclooxygenase-2 up-regulates CCR7 via EP2/EP4 receptor signaling pathways to enhance lymphatic invasion of breast cancer cells. J Biol Chem 2008; 283:11155-63; PMID:18319253; http://dx.doi.org/10.1074/jbc.M710038200
  • Denkert C, Winzer KJ, Muller BM, Weichert W, Pest S, Kobel M, Kristiansen G, Reles A, Siegert A, Guski H et al. Elevated expression of cyclooxygenase-2 is a negative prognostic factor for disease free survival and overall survival in patients with breast carcinoma. Cancer 2003; 97:2978-87; PMID:12784332; http://dx.doi.org/10.1002/cncr.11437
  • Tutunea-Fatan E, Majumder M, Xin X, Lala PK. The role of CCL21/CCR7 chemokine axis in breast cancer-induced lymphangiogenesis. Mol Cancer 2015; 14:35; PMID:25744065; http://dx.doi.org/10.1186/s12943-015-0306-4
  • Shields JD, Fleury ME, Yong C, Tomei AA, Randolph GJ, Swartz MA. Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Cancer Cell 2007; 11:526-38; PMID:17560334; http://dx.doi.org/10.1016/j.ccr.2007.04.020
  • McKimmie CS, Singh MD, Hewit K, Lopez-Franco O, Le Brocq M, Rose-John S, Lee KM, Baker AH, Wheat R, Blackbourn DJ et al. An analysis of the function and expression of D6 on lymphatic endothelial cells. Blood 2013; 121:3768-77; PMID:23479571; http://dx.doi.org/10.1182/blood-2012-04-425314
  • Wu FY, Ou ZL, Feng LY, Luo JM, Wang LP, Shen ZZ, Shao ZM. Chemokine decoy receptor d6 plays a negative role in human breast cancer. Mol Cancer Res 2008; 6:1276-88; PMID:18708360; http://dx.doi.org/10.1158/1541-7786.MCR-07-2108
  • Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001; 410:50-6; PMID:11242036; http://dx.doi.org/10.1038/35065016
  • Johnson LA, Clasper S, Holt AP, Lalor PF, Baban D, Jackson DG. An inflammation-induced mechanism for leukocyte transmigration across lymphatic vessel endothelium. J Exp Med 2006; 203:2763-77; PMID:17116732; http://dx.doi.org/10.1084/jem.20051759
  • Yan J, Jiang Y, Ye M, Liu W, Feng L. The clinical value of lymphatic vessel density, intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 expression in patients with oral tongue squamous cell carcinoma. J Cancer Res Therapeutics 2014; 10 Suppl:C125-30; PMID:25450269; http://dx.doi.org/10.4103/0973-1482.145827
  • Winger RC, Harp CT, Chiang MY, Sullivan DP, Watson RL, Weber EW, Podojil JR, Miller SD, Muller WA. Cutting edge: CD99 is a novel therapeutic target for control of T cell-mediated central nervous system autoimmune disease. J Immunol 2016; 196:1443-8; PMID:26773145; http://dx.doi.org/10.4049/jimmunol.1501634
  • Lou O, Alcaide P, Luscinskas FW, Muller WA. CD99 is a key mediator of the transendothelial migration of neutrophils. J Immunol 2007; 178:1136-43; PMID:17202377; http://dx.doi.org/10.4049/jimmunol.178.2.1136
  • Scotlandi K, Zuntini M, Manara MC, Sciandra M, Rocchi A, Benini S, Nicoletti G, Bernard G, Nanni P, Lollini PL et al. CD99 isoforms dictate opposite functions in tumour malignancy and metastases by activating or repressing c-Src kinase activity. Oncogene 2007; 26:6604-18; PMID:17471235; http://dx.doi.org/10.1038/sj.onc.1210481
  • Hajrasouliha AR, Funaki T, Sadrai Z, Hattori T, Chauhan SK, Dana R. Vascular endothelial growth factor-C promotes alloimmunity by amplifying antigen-presenting cell maturation and lymphangiogenesis. Investig Ophthalmol Visual Sci 2012; 53:1244-50; PMID:22281820; http://dx.doi.org/10.1167/iovs.11-8668
  • Mita AC, Takimoto CH, Mita M, Tolcher A, Sankhala K, Sarantopoulos J, Valdivieso M, Wood L, Rasmussen E, Sun YN et al. Phase 1 study of AMG 386, a selective angiopoietin 1/2-neutralizing peptibody, in combination with chemotherapy in adults with advanced solid tumors. Clin Cancer Res 2010; 16:3044-56; PMID:20501621; http://dx.doi.org/10.1158/1078-0432.CCR-09-3368
  • Dieras V, Wildiers H, Jassem J, Dirix LY, Guastalla JP, Bono P, Hurvitz SA, Gonçalves A, Romieu G, Limentani SA et al. Trebananib (AMG 386) plus weekly paclitaxel with or without bevacizumab as first-line therapy for HER2-negative locally recurrent or metastatic breast cancer: a phase 2 randomized study. Breast 2015; 24:182-90; PMID:25747197; http://dx.doi.org/10.1016/j.breast.2014.11.003
  • Spratlin JL, Cohen RB, Eadens M, Gore L, Camidge DR, Diab S, Leong S, O'Bryant C, Chow LQ, Serkova NJ et al. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol 2010; 28:780-7; PMID:20048182; http://dx.doi.org/10.1200/JCO.2009.23.7537
  • Song K, Herzog BH, Sheng M, Fu J, McDaniel JM, Chen H, Ruan J, Xia L. Lenalidomide inhibits lymphangiogenesis in preclinical models of mantle cell lymphoma. Cancer Res 2013; 73:7254-64; PMID:24158094; http://dx.doi.org/10.1158/0008-5472.CAN-13-0750
  • Lee E, Lee SJ, Koskimaki JE, Han Z, Pandey NB, Popel AS. Inhibition of breast cancer growth and metastasis by a biomimetic peptide. Scientific Rep 2014; 4:7139; PMID:25409905; http://dx.doi.org/10.1038/srep07139
  • Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther 2008; 7:3129-40; PMID:18852116; http://dx.doi.org/10.1158/1535-7163.MCT-08-0013
  • Mihaly Z, Sztupinszki Z, Surowiak P, Gyorffy B. A comprehensive overview of targeted therapy in metastatic renal cell carcinoma. Current cancer drug targets 2012; 12:857-72; PMID:22515521; http://dx.doi.org/10.2174/156800912802429265
  • Wachowska M, Muchowicz A, Golab J. Targeting epigenetic processes in photodynamic therapy-induced anticancer immunity. Front Oncol 2015; 5:176; PMID:26284197; http://dx.doi.org/10.3389/fonc.2015.00176
  • Agostinis P, Berg K, Cengel KA, Foster TH, Girotti AW, Gollnick SO, Hahn SM, Hamblin MR, Juzeniene A, Kessel D et al. Photodynamic therapy of cancer: an update. CA Cancer J Clin 2011; 61:250-81; PMID:21617154; http://dx.doi.org/10.1017/S0009840X10002799
  • Norrmen C, Tammela T, Petrova TV, Alitalo K. Biological basis of therapeutic lymphangiogenesis. Circulation 2011; 123:1335-51; PMID:21444892; http://dx.doi.org/10.1161/CIRCULATIONAHA.107.704098
  • Kilarski WW, Muchowicz A, Wachowska M, Mezyk-Kopec R, Golab J, Swartz MA, Nowak-Sliwinska P. Optimization and regeneration kinetics of lymphatic-specific photodynamic therapy in the mouse dermis. Angiogenesis 2014; 17:347-57; PMID:23892627; http://dx.doi.org/10.1007/s10456-013-9365-6
  • Wachowska M, Osiak A, Muchowicz A, Gabrysiak M, Domagala A, Kilarski WW, Golab J. Investigation of cell death mechanisms in human lymphatic endothelial cells undergoing photodynamic therapy. Photodiagnosis and photodynamic therapy 2016; Jun;14:57-65; PMID:26868051; http://dx.doi.org/10.1016/j.pdpdt.2016.02.004.
  • Van der Jeught K, Bialkowski L, Daszkiewicz L, Broos K, Goyvaerts C, Renmans D, Van Lint S, Heirman C, Thielemans K, Breckpot K. Targeting the tumor microenvironment to enhance antitumor immune responses. Oncotarget 2015; 6:1359-81; PMID:25682197; http://dx.doi.org/10.18632/oncotarget.3204
  • Forster R, Schubel A, Breitfeld D, Kremmer E, Renner-Muller I, Wolf ELipp M. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 1999; 99:23-33; PMID:10520991; http://dx.doi.org/10.1016/S0092-8674(00)80059-8
  • Raman D, Baugher PJ, Thu YM, Richmond A. Role of chemokines in tumor growth. Cancer Lett 2007; 256:137-65; PMID:17629396; http://dx.doi.org/10.1016/j.canlet.2007.05.013
  • Li JY, Ou ZL, Yu SJ, Gu XL, Yang C, Chen AX, Di GH, Shen ZZ, Shao ZM. The chemokine receptor CCR4 promotes tumor growth and lung metastasis in breast cancer. Breast Cancer Res Treat 2012; 131:837-48; PMID:21479551; http://dx.doi.org/10.1007/s10549-011-1502-6
  • Johnson JP. Cell adhesion molecules of the immunoglobulin supergene family and their role in malignant transformation and progression to metastatic disease. Cancer Metastasis Rev 1991; 10:11-22; PMID:1680575; http://dx.doi.org/10.1007/BF00046840
  • Rosette C, Roth RB, Oeth P, Braun A, Kammerer S, Ekblom J, Denissenko MF. Role of ICAM1 in invasion of human breast cancer cells. Carcinogenesis 2005; 26:943-50; PMID:15774488; http://dx.doi.org/10.1093/carcin/bgi070
  • Diaz-Munoz MD, Osma-Garcia IC, Iniguez MA, Fresno M. Cyclooxygenase-2 deficiency in macrophages leads to defective p110gamma PI3K signaling and impairs cell adhesion and migration. J Immunol 2013; 191:395-406; PMID:23733875; http://dx.doi.org/10.4049/jimmunol.1202002
  • Godbey WT, Atala A. Directed apoptosis in Cox-2-overexpressing cancer cells through expression-targeted gene delivery. Gene Ther 2003; 10:1519-27; PMID:12900768; http://dx.doi.org/10.1038/sj.gt.3302012
  • Kanamori M, Suzuki K, Yasuda T, Hori T. CD99-positive soft tissue sarcoma with chromosomal translocation between 1 and 16 and inversion of chromosome 5. Oncology Lett 2012; 3:1213-5; PMID:22783420; http://dx.doi.org/10.3892/ol.2012.641
  • Takahashi K, Mizukami H, Saga Y, Takei Y, Urabe M, Kume A, Machida S, Fujiwara H, Suzuki M, Ozawa K. Suppression of lymph node and lung metastases of endometrial cancer by muscle-mediated expression of soluble vascular endothelial growth factor receptor-3. Cancer Sci 2013; 104:1107-11; PMID:23614535; http://dx.doi.org/10.1111/cas.12184
  • Hwang-Bo J, Yoo KH, Park JH, Jeong HS, Chung IS. Recombinant canstatin inhibits angiopoietin-1-induced angiogenesis and lymphangiogenesis. Int J Cancer J Int du Cancer 2012; 131:298-309; PMID:21823121; http://dx.doi.org/10.1002/ijc.26353
  • Han KY, Azar DT, Sabri A, Lee H, Jain S, Lee BSChang JH. Characterization of the interaction between endostatin short peptide and VEGF receptor 3. Protein and peptide letters 2012; 19:969-74; PMID:22512651; http://dx.doi.org/10.2174/092986612802084465
  • Kinet V, Castermans K, Herkenne S, Maillard C, Blacher S, Lion M, Noël A, Martial JA, Struman I. The angiostatic protein 16K human prolactin significantly prevents tumor-induced lymphangiogenesis by affecting lymphatic endothelial cells. Endocrinology 2011; 152:4062-71; PMID:21862622; http://dx.doi.org/10.1210/en.2011-1081
  • Espagnolle N, Barron P, Mandron M, Blanc I, Bonnin J, Agnel M, Kerbelec E, Herault JP, Savi P, Bono F et al. Specific inhibition of the VEGFR-3 tyrosine kinase by SAR131675 reduces peripheral and tumor associated immunosuppressive myeloid cells. Cancers 2014; 6:472-90; PMID:24589997; http://dx.doi.org/10.3390/cancers6010472
  • Kashima K, Watanabe M, Satoh Y, Hata J, Ishii N, Aoki Y. Inhibition of lymphatic metastasis in neuroblastoma by a novel neutralizing antibody to vascular endothelial growth factor-D. Cancer Sci 2012; 103:2144-52; PMID:22937829; http://dx.doi.org/10.1111/cas.12010
  • Mumblat Y, Kessler O, Ilan N, Neufeld G. Full-length Semaphorin-3C is an inhibitor of tumor lymphangiogenesis and metastasis. Cancer Res 2015; 75:2177-86; PMID:25808871; http://dx.doi.org/10.1158/0008-5472.CAN-14-2464
  • Patel V, Marsh CA, Dorsam RT, Mikelis CM, Masedunskas A, Amornphimoltham P, Nathan CA, Singh B, Weigert R, Molinolo AA et al. Decreased lymphangiogenesis and lymph node metastasis by mTOR inhibition in head and neck cancer. Cancer Res 2011; 71:7103-12; PMID:21975930; http://dx.doi.org/10.1158/0008-5472.CAN-10-3192
  • Li XP, Jing W, Sun JJ, Liu ZY, Zhang JT, Sun W, Zhu W, Fan YZ. A potential small-molecule synthetic antilymphangiogenic agent norcantharidin inhibits tumor growth and lymphangiogenesis of human colonic adenocarcinomas through blocking VEGF-A,-C,-D/VEGFR-2,-3 “multi-points priming” mechanisms in vitro and in vivo. BMC Cancer 2015; 15:527; PMID:26187792; http://dx.doi.org/10.1186/s12885-015-1521-5
  • Kodera Y, Katanasaka Y, Kitamura Y, Tsuda H, Nishio K, Tamura T, Koizumi F. Sunitinib inhibits lymphatic endothelial cell functions and lymph node metastasis in a breast cancer model through inhibition of vascular endothelial growth factor receptor 3. Breast Cancer Res 2011; 13:R66; PMID:21693010; http://dx.doi.org/10.1186/bcr2903
  • Schmieder R, Hoffmann J, Becker M, Bhargava A, Muller T, Kahmann N, Ellinghaus P, Adams R, Rosenthal A, Thierauch KH et al. Regorafenib (BAY 73-4506): antitumor and antimetastatic activities in preclinical models of colorectal cancer. Int J Cancer J Int du Cancer 2014; 135:1487-96; PMID:24347491; http://dx.doi.org/10.1002/ijc.28669