Skip to main content
SpringerLink
Log in

Lymphangiogenesis in Cancer: Current Perspectives

  • Chapter
  • First Online:
Angiogenesis Inhibition

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 180))

Abstract

Although the lymphatic system has been initially described in the sixteenth century, basic research has been limited. Despite its importance for the maintenance of tissue fluid homeostasis and for the afferent immune response, research of the molecular mechanisms of lymphatic vessel formation and function has for a long time been hampered. One reason could be because of the difficulties of visibility due to the lack of lymphatic markers. But since the discovery of several molecules specifically expressed in lymphatic endothelial cells, a rediscovery of the lymphatic vasculature has taken place. New scientific insights has facilitated detailed analysis of the nature and organization of the lymphatic system in physiological and pathophysiological conditions, such as in chronic inflammation and metastatic cancer spread. Knowledge about the molecules that control lymphangiogenesis and tumor-associated lymphangiogenesis is now expanding, allowing better opportunities for the development of drugs interfering with the relevant signaling pathways. Advances in our understanding of the mechanisms have translated into a number of novel therapeutic studies.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abtahian F, Guerriero A, Sebzda E, Lu MM, Zhou R, Mocsai A, Myers EE, Huang B, Jackson DG, Ferrari VA, Tybulewicz V, Lowell CA, Lepore JJ, Koretzky GA, Kahn ML (2003) Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science 299:247–251

    Article  PubMed  CAS  Google Scholar 

  • Achen MG, Jeltsch M, Kukk E, Makinen T, Vitali A, Wilks AF, Alitalo K, Stacker SA (1998) 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 95:548–553

    Article  PubMed  CAS  Google Scholar 

  • Achen MG, McColl BK, Stacker SA (2005) Focus on lymphangiogenesis in tumor metastasis. Cancer Cell 7:121–127

    Article  PubMed  CAS  Google Scholar 

  • Alitalo K, Carmeliet P (2002) Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 1:219–227

    Article  PubMed  CAS  Google Scholar 

  • Alitalo K, Mohla S, Ruoslahti E (2004) Lymphangiogenesis and cancer: meeting report. Cancer Res 64:9225–9229

    Article  PubMed  CAS  Google Scholar 

  • Backhed F, Crawford PA, O’Donnell D, Gordon JI (2007) Postnatal lymphatic partitioning from the blood vasculature in the small intestine requires fasting-induced adipose factor. Proc Natl Acad Sci U S A 104:606–611

    Article  PubMed  Google Scholar 

  • Baldwin ME, Halford MM, Roufail S, Williams RA, Hibbs ML, Grail D, Kubo H, Stacker SA, Achen MG (2005) Vascular endothelial growth factor D is dispensable for development of the lymphatic system. Mol Cell Biol 25:2441–2449

    Article  PubMed  CAS  Google Scholar 

  • Banerji S, Ni J, Wang SX, Clasper S, Su J, Tammi R, Jones M, Jackson DG (1999) LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol 144:789–801

    Article  PubMed  CAS  Google Scholar 

  • Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marme D (1996) Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87:3336–3343

    PubMed  CAS  Google Scholar 

  • Barsky SH, Baker A, Siegal GP, Togo S, Liotta LA (1983) Use of anti-basement membrane antibodies to distinguish blood vessel capillaries from lymphatic capillaries. Am J Surg Pathol 7: 667–677

    Article  PubMed  CAS  Google Scholar 

  • Bjorndahl M, Cao R, Nissen LJ, Clasper S, Johnson LA, Xue Y, Zhou Z, Jackson D, Hansen AJ, Cao Y (2005) Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo. Proc Natl Acad Sci U S A 102:15593–15598

    Article  PubMed  CAS  Google Scholar 

  • Bollinger A, Isenring G, Franzeck UK, Brunner U (1983) Aplasia of superficial lymphatic capillaries in hereditary and connatal lymphedema (Milroy’s disease). Lymphology 16:27–30

    PubMed  CAS  Google Scholar 

  • Breiteneder-Geleff S, Soleiman A, Horvat R, Amann G, Kowalski H, Kerjaschki D (1999) Podoplanin–a specific marker for lymphatic endothelium expressed in angiosarcoma. Verh Dtsch Ges Pathol 83:270–275

    PubMed  CAS  Google Scholar 

  • Cahill RN, Frost H, Trnka Z (1976) The effects of antigen on the migration of recirculating lymphocytes through single lymph nodes. J Exp Med 143:870–888

    Article  PubMed  CAS  Google Scholar 

  • Cao Y, Linden P, Farnebo J, Cao R, Eriksson A, Kumar V, Qi JH, Claesson-Welsh L, Alitalo K (1998) Vascular endothelial growth factor C induces angiogenesis in vivo. Proc Natl Acad Sci U S A 95:14389–14394

    Article  PubMed  CAS  Google Scholar 

  • Cao R, Bjorndahl MA, Religa P, Clasper S, Garvin S, Galter D, Meister B, Ikomi F, Tritsaris K, Dissing S, Ohhashi T, Jackson DG, Cao Y (2004) PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell 6:333–345

    Article  PubMed  CAS  Google Scholar 

  • Cermenati S, Moleri S, Cimbro S, Corti P, Del Giacco L, Amodeo R, Dejana E, Koopman P, Cotelli F, Beltrame M (2008) Sox18 and Sox7 play redundant roles in vascular development. Blood 111:2657–2666

    Article  PubMed  CAS  Google Scholar 

  • Chang LK, Garcia-Cardena G, Farnebo F, Fannon M, Chen EJ, Butterfield C, Moses MA, Mulligan RC, Folkman J, Kaipainen A (2004) Dose-dependent response of FGF-2 for lymphangiogenesis. Proc Natl Acad Sci U S A 101:11658–11663

    Article  PubMed  CAS  Google Scholar 

  • Cursiefen C, Chen L, Dana MR, Streilein JW (2003) Corneal lymphangiogenesis: evidence, mechanisms, and implications for corneal transplant immunology. Cornea 22:273–281

    Article  PubMed  Google Scholar 

  • Cursiefen C, Cao J, Chen L, Liu Y, Maruyama K, Jackson D, Kruse FE, Wiegand SJ, Dana MR, Streilein JW (2004a) Inhibition of hemangiogenesis and lymphangiogenesis after normal-risk corneal transplantation by neutralizing VEGF promotes graft survival. Invest Ophthalmol Vis Sci 45:2666–2673

    Article  PubMed  Google Scholar 

  • Cursiefen C, Chen L, Borges LP, Jackson D, Cao J, Radziejewski C, D’Amore PA, Dana MR, Wiegand SJ, Streilein JW (2004b) VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest 113:1040–1050

    PubMed  CAS  Google Scholar 

  • Dadras SS, Paul T, Bertoncini J, Brown LF, Muzikansky A, Jackson DG, Ellwanger U, Garbe C, Mihm MC, Detmar M (2003) Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival. Am J Pathol 162:1951–1960

    PubMed  Google Scholar 

  • Dagenais SL, Hartsough RL, Erickson RP, Witte MH, Butler MG, Glover TW (2004) Foxc2 is expressed in developing lymphatic vessels and other tissues associated with lymphedema-distichiasis syndrome. Gene Expr Patterns 4:611–619

    Article  PubMed  CAS  Google Scholar 

  • Danilkovitch-Miagkova A, Zbar B (2002) Dysregulation of Met receptor tyrosine kinase activity in invasive tumors. J Clin Invest 109:863–867

    PubMed  CAS  Google Scholar 

  • Daroczy J (1995) Pathology of lymphedema. Clin Dermatol 13:433–444

    Article  PubMed  CAS  Google Scholar 

  • Dumont DJ, Jussila L, Taipale J, Lymboussaki A, Mustonen T, Pajusola K, Breitman M, Alitalo K (1998) Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282:946–949

    Article  PubMed  CAS  Google Scholar 

  • Fang J, Dagenais SL, Erickson RP, Arlt MF, Glynn MW, Gorski JL, Seaver LH, Glover TW (2000) Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. Am J Hum Genet 67:1382–1388

    Article  PubMed  CAS  Google Scholar 

  • Ferrara N, Hillan KJ, Gerber HP, Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3:391–400

    Article  PubMed  CAS  Google Scholar 

  • Fisher B, Fisher ER (1966) The interrelationship of hematogenous and lymphatic tumor cell dissemination. Surg Gynecol Obstet 122:791–798

    PubMed  CAS  Google Scholar 

  • Gale NW, Thurston G, Hackett SF, Renard R, Wang Q, McClain J, Martin C, Witte C, Witte MH, Jackson D, Suri C, Campochiaro PA, Wiegand SJ, Yancopoulos GD (2002) Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. Dev Cell 3:411–423

    Article  PubMed  CAS  Google Scholar 

  • Gale NW, Prevo R, Espinosa J, Ferguson DJ, Dominguez MG, Yancopoulos GD, Thurston G, Jackson DG (2007) Normal lymphatic development and function in mice deficient for the lymphatic hyaluronan receptor LYVE-1. Mol Cell Biol 27:595–604

    Article  PubMed  CAS  Google Scholar 

  • Garmy-Susini B, Makale M, Fuster M, Varner JA (2007) Methods to study lymphatic vessel integrins. Methods Enzymol 426:415–438

    Article  PubMed  CAS  Google Scholar 

  • Gerber LH (1998) A review of measures of lymphedema. Cancer 83:2803–2804

    Article  PubMed  CAS  Google Scholar 

  • Gerli R, Solito R, Weber E, Agliano M (2000) Specific adhesion molecules bind anchoring filaments and endothelial cells in human skin initial lymphatics. Lymphology 33:148–157

    PubMed  CAS  Google Scholar 

  • Gunn MD, Tangemann K, Tam C, Cyster JG, Rosen SD, Williams LT (1998) A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes. Proc Natl Acad Sci U S A 95:258–263

    Article  PubMed  CAS  Google Scholar 

  • Gunn MD, Kyuwa S, Tam C, Kakiuchi T, Matsuzawa A, Williams LT, Nakano H (1999) Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J Exp Med 189:451–460

    Article  PubMed  CAS  Google Scholar 

  • Hall JG, Morris B (1965) The immediate effect of antigens on the cell output of a lymph node. Br J Exp Pathol 46:450–454

    PubMed  CAS  Google Scholar 

  • Hamrah P, Chen L, Zhang Q, Dana MR (2003) Novel expression of vascular endothelial growth factor receptor (VEGFR)-3 and VEGF-C on corneal dendritic cells. Am J Pathol 163:57–68

    PubMed  CAS  Google Scholar 

  • Harrell MI, Iritani BM, Ruddell A (2007) Tumor-induced sentinel lymph node lymphangiogenesis and increased lymph flow precede melanoma metastasis. Am J Pathol 170:774–786

    Article  PubMed  Google Scholar 

  • Hay JB, Hobbs BB (1977) The flow of blood to lymph nodes and its relation to lymphocyte traffic and the immune response. J Exp Med 145:31–44

    Article  PubMed  CAS  Google Scholar 

  • He Y, Kozaki K, Karpanen T, Koshikawa K, Yla-Herttuala S, Takahashi T, Alitalo K (2002) Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J Natl Cancer Inst 94:819–825

    PubMed  CAS  Google Scholar 

  • He Y, Rajantie I, Pajusola K, Jeltsch M, Holopainen T, Yla-Herttuala S, Harding T, Jooss K, Takahashi T, Alitalo K (2005) Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. Cancer Res 65:4739–4746

    Article  PubMed  CAS  Google Scholar 

  • Heldin CH, Westermark B (1999) Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79:1283–1316

    PubMed  CAS  Google Scholar 

  • Hirakawa S, Hong YK, Harvey N, Schacht V, Matsuda K, Libermann T, Detmar M (2003) Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells. Am J Pathol 162:575–586

    PubMed  CAS  Google Scholar 

  • Hirakawa S, Kodama S, Kunstfeld R, Kajiya K, Brown LF, Detmar M (2005) VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med 201:1089–1099

    Article  PubMed  CAS  Google Scholar 

  • Hirakawa S, Brown LF, Kodama S, Paavonen K, Alitalo K, Detmar M (2007) VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. Blood 109: 1010–1017

    Article  PubMed  CAS  Google Scholar 

  • Hong SE, Shugart YY, Huang DT, Shahwan SA, Grant PE, Hourihane JO, Martin ND, Walsh CA (2000) Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet 26:93–96

    Article  PubMed  CAS  Google Scholar 

  • Hong YK, Lange-Asschenfeldt B, Velasco P, Hirakawa S, Kunstfeld R, Brown LF, Bohlen P, Senger DR, Detmar M (2004) VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1beta1 and alpha2beta1 integrins. FASEB J 18: 1111–1113

    PubMed  CAS  Google Scholar 

  • 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 66:8065–8075

    Article  PubMed  CAS  Google Scholar 

  • Huang XZ, Wu JF, Ferrando R, Lee JH, Wang YL, Farese RV Jr, Sheppard D (2000) Fatal bilateral chylothorax in mice lacking the integrin alpha9beta1. Mol Cell Biol 20:5208–5215

    Article  PubMed  CAS  Google Scholar 

  • Huntington G, McClure C (1910) The anatomy and development of the jugular lymph sac in the domestic cat (Felis domestica). Am J Anat 10:177–311

    Article  Google Scholar 

  • Irrthum A, Karkkainen MJ, Devriendt K, Alitalo K, Vikkula M (2000) Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase. Am J Hum Genet 67:295–301

    Article  PubMed  CAS  Google Scholar 

  • Irrthum A, Devriendt K, Chitayat D, Matthijs G, Glade C, Steijlen PM, Fryns JP, Van Steensel MA, Vikkula M (2003) Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. Am J Hum Genet 72:1470–1478

    Article  PubMed  CAS  Google Scholar 

  • Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, Swartz M, Fukumura D, Jain RK, Alitalo K (1997) Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276:1423–1425

    Article  PubMed  CAS  Google Scholar 

  • Jeltsch M, Tammela T, Alitalo K, Wilting J (2003) Genesis and pathogenesis of lymphatic vessels. Cell Tissue Res 314:69–84

    Article  PubMed  CAS  Google Scholar 

  • Johnson LA, Prevo R, Clasper S, Jackson DG (2007) Inflammation-induced uptake and degradation of the lymphatic endothelial hyaluronan receptor LYVE-1. J Biol Chem 282:33671–33680

    Article  PubMed  CAS  Google Scholar 

  • Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K (1996) A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J 15:1751

    PubMed  CAS  Google Scholar 

  • Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, Saksela O, Kalkkinen N, Alitalo K (1997) Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J 16:3898–3911

    Article  PubMed  CAS  Google Scholar 

  • Kaipainen A, Korhonen J, Mustonen T, van Hinsbergh VW, Fang GH, Dumont D, Breitman M, Alitalo K (1995) Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci U S A 92:3566–3570

    Article  PubMed  CAS  Google Scholar 

  • Kajiya K, Hirakawa S, Ma B, Drinnenberg I, Detmar M (2005) Hepatocyte growth factor promotes lymphatic vessel formation and function. EMBO J 24:2885–2895

    Article  PubMed  CAS  Google Scholar 

  • Karkkainen MJ, Ferrell RE, Lawrence EC, Kimak MA, Levinson KL, McTigue MA, Alitalo K, Finegold DN (2000) Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Nat Genet 25:153–159

    Article  PubMed  CAS  Google Scholar 

  • Karkkainen MJ, Saaristo A, Jussila L, Karila KA, Lawrence EC, Pajusola K, Bueler H, Eichmann A, Kauppinen R, Kettunen MI, Yla-Herttuala S, Finegold DN, Ferrell RE, Alitalo K (2001) A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci U S A 98:12677–12682

    Article  PubMed  CAS  Google Scholar 

  • Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV, Jeltsch M, Jackson DG, Talikka M, Rauvala H, Betsholtz C, Alitalo K (2004) Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol 5:74–80

    Article  PubMed  CAS  Google Scholar 

  • 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 61:1786–1790

    PubMed  CAS  Google Scholar 

  • Kato Y, Fujita N, Kunita A, Sato S, Kaneko M, Osawa M, Tsuruo T (2003) Molecular identification of Aggrus/T1alpha as a platelet aggregation-inducing factor expressed in colorectal tumors. J Biol Chem 278:51599–51605

    Article  PubMed  CAS  Google Scholar 

  • Kerjaschki D, Regele HM, Moosberger I, Nagy-Bojarski K, Watschinger B, Soleiman A, Birner P, Krieger S, Hovorka A, Silberhumer G, Laakkonen P, Petrova T, Langer B, Raab I (2004) Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. J Am Soc Nephrol 15:603–612

    Article  PubMed  CAS  Google Scholar 

  • Kerjaschki D, Huttary N, Raab I, Regele H, Bojarski-Nagy K, Bartel G, Krober SM, Greinix H, Rosenmaier A, Karlhofer F, Wick N, Mazal PR (2006) Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants. Nat Med 12: 230–234

    Article  PubMed  CAS  Google Scholar 

  • Kono T, Kubo H, Shimazu C, Ueda Y, Takahashi M, Yanagi K, Fujita N, Tsuruo T, Wada H, Yamashita JK (2006) Differentiation of lymphatic endothelial cells from embryonic stem cells on OP9 stromal cells. Arterioscler Thromb Vasc Biol 26:2070–2076

    Article  PubMed  CAS  Google Scholar 

  • Kreuger J, Nilsson I, Kerjaschki D, Petrova T, Alitalo K, Claesson-Welsh L (2006) Early lymph vessel development from embryonic stem cells. Arterioscler Thromb Vasc Biol 26:1073–1078

    Article  PubMed  CAS  Google Scholar 

  • Kubo H, Cao R, Brakenhielm E, Makinen T, Cao Y, Alitalo K (2002) Blockade of vascular endothelial growth factor receptor-3 signaling inhibits fibroblast growth factor-2-induced lymphangiogenesis in mouse cornea. Proc Natl Acad Sci U S A 99:8868–8873

    Article  PubMed  CAS  Google Scholar 

  • Kunstfeld R, Hirakawa S, Hong YK, Schacht V, Lange-Asschenfeldt B, Velasco P, Lin C, Fiebiger E, Wei X, Wu Y, Hicklin D, Bohlen P, Detmar M (2004) Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia. Blood 104:1048–1057

    Article  PubMed  CAS  Google Scholar 

  • Laakkonen P, Porkka K, Hoffman JA, Ruoslahti E (2002) A tumor-homing peptide with a targeting specificity related to lymphatic vessels. Nat Med 8:751–755

    PubMed  CAS  Google Scholar 

  • Laakkonen P, Waltari M, Holopainen T, Takahashi T, Pytowski B, Steiner P, Hicklin D, Persaud K, Tonra JR, Witte L, Alitalo K (2007) Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. Cancer Res 67:593–599

    Article  PubMed  CAS  Google Scholar 

  • Leak LV, Burke JF (1966) Fine structure of the lymphatic capillary and the adjoining connective tissue area. Am J Anat 118:785–809

    Article  PubMed  CAS  Google Scholar 

  • Leak LV, Burke JF (1968) Electron microscopic study of lymphatic capillaries in the removal of connective tissue fluids and particulate substances. Lymphology 1:39–52

    PubMed  CAS  Google Scholar 

  • Lee J, Gray A, Yuan J, Luoh SM, Avraham H, Wood WI (1996) Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4. Proc Natl Acad Sci U S A 93:1988–1992

    Article  PubMed  CAS  Google Scholar 

  • Lee AH, Pinder SE, Macmillan RD, Mitchell M, Ellis IO, Elston CW, Blamey RW (2006) Prognostic value of lymphovascular invasion in women with lymph node negative invasive breast carcinoma. Eur J Cancer 42:357–362

    Article  PubMed  CAS  Google Scholar 

  • Lee CC, Wu CW, Lo SS, Chen JH, Li AF, Hsieh MC, Shen KH, Lui WY (2007) Survival predictors in patients with node-negative gastric carcinoma. J Gastroenterol Hepatol 22:1014–1018

    Article  PubMed  Google Scholar 

  • Liersch R, Nay F, Lu L, Detmar M (2006) Induction of lymphatic endothelial cell differentiation in embryoid bodies. Blood 107:1214–1216

    Article  PubMed  CAS  Google Scholar 

  • Liotta LA, Stetler-Stevenson WG, Steeg PS (1991) Cancer invasion and metastasis: positive and negative regulatory elements. Cancer Invest 9:543–551

    Article  PubMed  CAS  Google Scholar 

  • Lotan Y, Gupta A, Shariat SF, Palapattu GS, Vazina A, Karakiewicz PI, Bastian PJ, Rogers CG, Amiel G, Perotte P, Schoenberg MP, Lerner SP, Sagalowsky AI (2005) Lymphovascular invasion is independently associated with overall survival, cause-specific survival, and local and distant recurrence in patients with negative lymph nodes at radical cystectomy. J Clin Oncol 23:6533–6539

    Article  PubMed  Google Scholar 

  • 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 (2001a) Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med 7:199–205

    Article  PubMed  CAS  Google Scholar 

  • 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 (2001b) Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J 20:4762–4773

    Article  PubMed  CAS  Google Scholar 

  • Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, Banerji S, Huarte J, Montesano R, Jackson DG, Orci L, Alitalo K, Christofori G, Pepper MS (2001) Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J 20:672–682

    Article  PubMed  CAS  Google Scholar 

  • Marconcini L, Marchio S, Morbidelli L, Cartocci E, Albini A, Ziche M, Bussolino F, Oliviero S (1999) c-fos-induced growth factor/vascular endothelial growth factor D induces angiogenesis in vivo and in vitro. Proc Natl Acad Sci U S A 96:9671–9676

    Article  PubMed  CAS  Google Scholar 

  • Mashino K, Sadanaga N, Yamaguchi H, Tanaka F, Ohta M, Shibuta K, Inoue H, Mori M (2002) Expression of chemokine receptor CCR7 is associated with lymph node metastasis of gastric carcinoma. Cancer Res 62:2937–2941

    PubMed  CAS  Google Scholar 

  • May M, Kaufmann O, Hammermann F, Loy V, Siegsmund M (2007) Prognostic impact of lymphovascular invasion in radical prostatectomy specimens. BJU Int 99:539–544

    Article  PubMed  Google Scholar 

  • Melder RJ, Koenig GC, Witwer BP, Safabakhsh N, Munn LL, Jain RK (1996) During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. Nat Med 2:992–997

    Article  PubMed  CAS  Google Scholar 

  • Mishima K, Watabe T, Saito A, Yoshimatsu Y, Imaizumi N, Masui S, Hirashima M, Morisada T, Oike Y, Araie M, Niwa H, Kubo H, Suda T, Miyazono K (2007) Prox1 induces lymphatic endothelial differentiation via integrin alpha9 and other signaling cascades. Mol Biol Cell 18:1421–1429

    Article  PubMed  CAS  Google Scholar 

  • Mortimer PS (1998) The pathophysiology of lymphedema. Cancer 83:2798–2802

    Article  PubMed  CAS  Google Scholar 

  • Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegui E, Zlotnik A (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410:50–56

    Article  PubMed  CAS  Google Scholar 

  • Nagy JA, Vasile E, Feng D, Sundberg C, Brown LF, Detmar MJ, Lawitts JA, Benjamin L, Tan X, Manseau EJ, Dvorak AM, Dvorak HF (2002) Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med 196:1497–1506

    Article  PubMed  CAS  Google Scholar 

  • Northup KA, Witte MH, Witte CL (2003) Syndromic classification of hereditary lymphedema. Lymphology 36:162–189

    PubMed  CAS  Google Scholar 

  • Ny A, Koch M, Schneider M, Neven E, Tong RT, Maity S, Fischer C, Plaisance S, Lambrechts D, Heligon C, Terclavers S, Ciesiolka M, Kalin R, Man WY, Senn I, Wyns S, Lupu F, Brandli A, Vleminckx K, Collen D, Dewerchin M, Conway EM, Moons L, Jain RK, Carmeliet P (2005) A genetic Xenopus laevis tadpole model to study lymphangiogenesis. Nat Med 11:998–1004

    PubMed  CAS  Google Scholar 

  • Oh SJ, Jeltsch MM, Birkenhager R, McCarthy JE, Weich HA, Christ B, Alitalo K, Wilting J (1997) VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane. Dev Biol 188:96–109

    Article  PubMed  CAS  Google Scholar 

  • Okada S, Albrecht RM, Aharinejad S, Schraufnagel DE (2002) Structural aspects of the lymphocyte traffic in rat submandibular lymph node. Microsc Microanal 8:116–133

    Article  PubMed  CAS  Google Scholar 

  • Ostman A, Heldin CH (2007) PDGF receptors as targets in tumor treatment. Adv Cancer Res 97:247–274

    Article  PubMed  CAS  Google Scholar 

  • Padera TP, Kadambi A, di Tomaso E, Carreira CM, Brown EB, Boucher Y, Choi NC, Mathisen D, Wain J, Mark EJ, Munn LL, Jain RK (2002) Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296:1883–1886

    Article  PubMed  CAS  Google Scholar 

  • Padera TP, Kuo AH, Hoshida T, Liao S, Lobo J, Kozak KR, Fukumura D, Jain RK (2008) Differential response of primary tumor versus lymphatic metastasis to VEGFR-2 and VEGFR-3 kinase inhibitors cediranib and vandetanib. Mol Cancer Ther 7:2272–2279

    Article  PubMed  CAS  Google Scholar 

  • Paget S. The distribution of secondary growths in cancer of the breast. Lancet. 1889;1:571–573.

    Google Scholar 

  • Partanen TA, Arola J, Saaristo A, Jussila L, Ora A, Miettinen M, Stacker SA, Achen MG, Alitalo K (2000) VEGF-C and VEGF-D expression in neuroendocrine cells and their receptor, VEGFR-3, in fenestrated blood vessels in human tissues. FASEB J 14:2087–2096

    Article  PubMed  CAS  Google Scholar 

  • Petrova TV, Makinen T, Makela TP, Saarela J, Virtanen I, Ferrell RE, Finegold DN, Kerjaschki D, Yla-Herttuala S, Alitalo K (2002) Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. EMBO J 21:4593–4599

    Article  PubMed  CAS  Google Scholar 

  • Petrova TV, Karpanen T, Norrmen C, Mellor R, Tamakoshi T, Finegold D, Ferrell R, Kerjaschki D, Mortimer P, Yla-Herttuala S, Miura N, Alitalo K (2004) Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nat Med 10:974–981

    Article  PubMed  CAS  Google Scholar 

  • Podgrabinska S, Braun P, Velasco P, Kloos B, Pepper MS, Skobe M (2002) Molecular characterization of lymphatic endothelial cells. Proc Natl Acad Sci U S A 99:16069–16074

    Article  PubMed  CAS  Google Scholar 

  • Pytowski B, Goldman J, Persaud K, Wu Y, Witte L, Hicklin DJ, Skobe M, Boardman KC, Swartz MA (2005) Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody. J Natl Cancer Inst 97:14–21

    Article  PubMed  CAS  Google Scholar 

  • Qian CN, Berghuis B, Tsarfaty G, Bruch M, Kort EJ, Ditlev J, Tsarfaty I, Hudson E, Jackson DG, Petillo D, Chen J, Resau JH, Teh BT (2006) Preparing the “soil”: the primary tumor induces vasculature reorganization in the sentinel lymph node before the arrival of metastatic cancer cells. Cancer Res 66:10365–10376

    Article  PubMed  CAS  Google Scholar 

  • Reinmuth N, Liersch R, Raedel M, Fehrmann F, Fehrmann N, Bayer M, Schwoeppe C, Kessler T, Berdel W, Thomas M, Mesters RM (2009) Combined anti-PDGFRalpha and PDGFRbeta targeting in non-small cell lung cancer. Int J Cancer 124(7):1535–1544

    Article  PubMed  CAS  Google Scholar 

  • Rissanen TT, Markkanen JE, Gruchala M, Heikura T, Puranen A, Kettunen MI, Kholova I, Kauppinen RA, Achen MG, Stacker SA, Alitalo K, Yla-Herttuala S (2003) VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Circ Res 92:1098–1106

    Article  PubMed  CAS  Google Scholar 

  • 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 66:2650–2657

    Article  PubMed  CAS  Google Scholar 

  • Rockson SG (2001) Lymphedema. Am J Med 110:288–295

    Article  PubMed  CAS  Google Scholar 

  • Rubbia-Brandt L, Terris B, Giostra E, Dousset B, Morel P, Pepper MS (2004) Lymphatic vessel density and vascular endothelial growth factor-C expression correlate with malignant behavior in human pancreatic endocrine tumors. Clin Cancer Res 10:6919–6928

    Article  PubMed  CAS  Google Scholar 

  • Ruddell A, Mezquita P, Brandvold KA, Farr A, Iritani BM (2003) B lymphocyte-specific c-Myc expression stimulates early and functional expansion of the vasculature and lymphatics during lymphomagenesis. Am J Pathol 163:2233–2245

    PubMed  CAS  Google Scholar 

  • Sabin F (1902) On the origin of the lymphatics system from the veins and the development of the lymph hearts and thorarcic duct in the pig. Am J Anat 1:367–391

    Article  Google Scholar 

  • Sabin F (1904) On the development of the superficial lymphatics in the skin of the pig. Am J Anat 3:183–195

    Article  Google Scholar 

  • Saeki H, Moore AM, Brown MJ, Hwang ST (1999) Cutting edge: secondary lymphoid-tissue chemokine (SLC) and CC chemokine receptor 7 (CCR7) participate in the emigration pathway of mature dendritic cells from the skin to regional lymph nodes. J Immunol 162:2472–2475

    PubMed  CAS  Google Scholar 

  • Sauter B, Foedinger D, Sterniczky B, Wolff K, Rappersberger K (1998) Immunoelectron microscopic characterization of human dermal lymphatic microvascular endothelial cells. Differential expression of CD31, CD34, and type IV collagen with lymphatic endothelial cells vs blood capillary endothelial cells in normal human skin, lymphangioma, and hemangioma in situ. J Histochem Cytochem 46: 165–176

    PubMed  CAS  Google Scholar 

  • Schacht V, Ramirez MI, Hong YK, Hirakawa S, Feng D, Harvey N, Williams M, Dvorak AM, Dvorak HF, Oliver G, Detmar M (2003) T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. EMBO J 22:3546–3556

    Article  PubMed  CAS  Google Scholar 

  • Schneider M, Othman-Hassan K, Christ B, Wilting J (1999) Lymphangioblasts in the avian wing bud. Dev Dyn 216:311–319

    Article  PubMed  CAS  Google Scholar 

  • Schoppmann SF, Birner P, Stockl J, Kalt R, Ullrich R, Caucig C, Kriehuber E, Nagy K, Alitalo K, Kerjaschki D (2002) Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol 161:947–956

    PubMed  CAS  Google Scholar 

  • Shields JD, Emmett MS, Dunn DB, Joory KD, Sage LM, Rigby H, Mortimer PS, Orlando A, Levick JR, Bates DO (2007) Chemokine-mediated migration of melanoma cells towards lymphatics–a mechanism contributing to metastasis. Oncogene 26:2997–3005

    Article  PubMed  CAS  Google Scholar 

  • Shirasawa Y, Ikomi F, Ohhashi T (2000) Physiological roles of endogenous nitric oxide in lymphatic pump activity of rat mesentery in vivo. Am J Physiol Gastrointest Liver Physiol 278:G551–G556

    Google Scholar 

  • 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 7:192–198

    Article  PubMed  CAS  Google Scholar 

  • Stacker SA, Stenvers K, Caesar C, Vitali A, Domagala T, Nice E, Roufail S, Simpson RJ, Moritz R, Karpanen T, Alitalo K, Achen MG (1999) Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers. J Biol Chem 274:32127–32136

    Article  PubMed  CAS  Google Scholar 

  • 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 7:186–191

    Article  PubMed  CAS  Google Scholar 

  • Stacker SA, Achen MG, Jussila L, Baldwin ME, Alitalo K (2002) Lymphangiogenesis and cancer metastasis. Nat Rev Cancer 2:573–583

    Article  PubMed  CAS  Google Scholar 

  • Suzuki-Inoue K, Kato Y, Inoue O, Kaneko MK, Mishima K, Yatomi Y, Yamazaki Y, Narimatsu H, Ozaki Y (2007) Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells. J Biol Chem 282:25993–26001

    Article  PubMed  CAS  Google Scholar 

  • Szuba A, Skobe M, Karkkainen MJ, Shin WS, Beynet DP, Rockson NB, Dakhil N, Spilman S, Goris ML, Strauss HW, Quertermous T, Alitalo K, Rockson SG (2002) Therapeutic lymphangiogenesis with human recombinant VEGF-C. FASEB J 16:1985–1987

    PubMed  CAS  Google Scholar 

  • Tait CR, Jones PF (2004) Angiopoietins in tumours: the angiogenic switch. J Pathol 204:1–10

    Article  PubMed  CAS  Google Scholar 

  • Takanami I (2003) Overexpression of CCR7 mRNA in nonsmall cell lung cancer: correlation with lymph node metastasis. Int J Cancer 105:186–189

    Article  PubMed  CAS  Google Scholar 

  • Takeuchi H, Fujimoto A, Tanaka M, Yamano T, Hsueh E, Hoon DS (2004) CCL21 chemokine regulates chemokine receptor CCR7 bearing malignant melanoma cells. Clin Cancer Res 10:2351–2358

    Article  PubMed  CAS  Google Scholar 

  • Tammela T, Saaristo A, Holopainen T, Lyytikka J, Kotronen A, Pitkonen M, Abo-Ramadan U, Yla-Herttuala S, Petrova TV, Alitalo K (2007) Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation. Nat Med 13:1458–1466

    Article  PubMed  CAS  Google Scholar 

  • Tammela T, Zarkada G, Wallgard E, Murtomaki A, Suchting S, Wirzenius M, Waltari M, Hellstrom M, Schomber T, Peltonen R, Freitas C, Duarte A, Isoniemi H, Laakkonen P, Christofori G, Yla-Herttuala S, Shibuya M, Pytowski B, Eichmann A, Betsholtz C, Alitalo K (2008) Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454:656–660

    Article  PubMed  CAS  Google Scholar 

  • Tang Y, Zhang D, Fallavollita L, Brodt P (2003) Vascular endothelial growth factor C expression and lymph node metastasis are regulated by the type I insulin-like growth factor receptor. Cancer Res 63:1166–1171

    PubMed  CAS  Google Scholar 

  • Taniguchi K, Kohno R, Ayada T, Kato R, Ichiyama K, Morisada T, Oike Y, Yonemitsu Y, Maehara Y, Yoshimura A (2007) Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor receptor 3 signaling. Mol Cell Biol 27:4541–4550

    Article  PubMed  CAS  Google Scholar 

  • Van den Eynden GG, Van der Auwera I, Van Laere SJ, Huygelen V, Colpaert CG, van Dam P, Dirix LY, Vermeulen PB, Van Marck EA (2006) Induction of lymphangiogenesis in and around axillary lymph node metastases of patients with breast cancer. Br J Cancer 95:1362–1366

    Article  PubMed  Google Scholar 

  • Van den Eynden GG, Vandenberghe MK, van Dam PJ, Colpaert CG, van Dam P, Dirix LY, Vermeulen PB, Van Marck EA (2007) Increased sentinel lymph node lymphangiogenesis is associated with nonsentinel axillary lymph node involvement in breast cancer patients with a positive sentinel node. Clin Cancer Res 13:5391–5397

    Article  PubMed  CAS  Google Scholar 

  • 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 20:1223–1231

    Article  PubMed  CAS  Google Scholar 

  • Veikkola T, Lohela M, Ikenberg K, Makinen T, Korff T, Saaristo A, Petrova T, Jeltsch M, Augustin HG, Alitalo K (2003) Intrinsic versus microenvironmental regulation of lymphatic endothelial cell phenotype and function. FASEB J 17:2006–2013

    Article  PubMed  CAS  Google Scholar 

  • von der Weid PY (2001) Lymphatic vessel pumping and inflammation–the role of spontaneous constrictions and underlying electrical pacemaker potentials. Aliment Pharmacol Ther 15:1115–1129

    Article  PubMed  Google Scholar 

  • Wang JF, Zhang XF, Groopman JE (2001) Stimulation of beta 1 integrin induces tyrosine phosphorylation of vascular endothelial growth factor receptor-3 and modulates cell migration. J Biol Chem 276:41950–41957

    Article  PubMed  CAS  Google Scholar 

  • Wang J, Xi L, Hunt JL, Gooding W, Whiteside TL, Chen Z, Godfrey TE, Ferris RL (2004) Expression pattern of chemokine receptor 6 (CCR6) and CCR7 in squamous cell carcinoma of the head and neck identifies a novel metastatic phenotype. Cancer Res 64:1861–1866

    Article  PubMed  CAS  Google Scholar 

  • Weiss L (1992) Biomechanical interactions of cancer cells with the microvasculature during hematogenous metastasis. Cancer Metastasis Rev 11:227–235

    Article  PubMed  CAS  Google Scholar 

  • Wetterwald A, Hoffstetter W, Cecchini MG, Lanske B, Wagner C, Fleisch H, Atkinson M (1996) Characterization and cloning of the E11 antigen, a marker expressed by rat osteoblasts and osteocytes. Bone 18:125–132

    Article  PubMed  CAS  Google Scholar 

  • Whitehurst B, Flister MJ, Bagaitkar J, Volk L, Bivens CM, Pickett B, Castro-Rivera E, Brekken RA, Gerard RD, Ran S (2007) Anti-VEGF-A therapy reduces lymphatic vessel density and expression of VEGFR-3 in an orthotopic breast tumor model. Int J Cancer 121:2181–2191

    Article  PubMed  CAS  Google Scholar 

  • Wick N, Saharinen P, Saharinen J, Gurnhofer E, Steiner CW, Raab I, Stokic D, Giovanoli P, Buchsbaum S, Burchard A, Thurner S, Alitalo K, Kerjaschki D (2007) Transcriptomal comparison of human dermal lymphatic endothelial cells ex vivo and in vitro. Physiol Genomics 28:179–192

    PubMed  CAS  Google Scholar 

  • Wicki A, Lehembre F, Wick N, Hantusch B, Kerjaschki D, Christofori G (2006) Tumor invasion in the absence of epithelial-mesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton. Cancer Cell 9:261–272

    Article  PubMed  CAS  Google Scholar 

  • Wigle JT, Oliver G (1999) Prox1 function is required for the development of the murine lymphatic system. Cell 98:769–778

    Article  PubMed  CAS  Google Scholar 

  • Wigle JT, Harvey N, Detmar M, Lagutina I, Grosveld G, Gunn MD, Jackson DG, Oliver G (2002) An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J 21:1505–1513

    Article  PubMed  CAS  Google Scholar 

  • Wiley HE, Gonzalez EB, Maki W, Wu MT, Hwang ST (2001) Expression of CC chemokine receptor-7 and regional lymph node metastasis of B16 murine melanoma. J Natl Cancer Inst 93:1638–1643

    Article  PubMed  CAS  Google Scholar 

  • Wilting J, Neeff H, Christ B (1999) Embryonic lymphangiogenesis. Cell Tissue Res 297:1–11

    Article  PubMed  CAS  Google Scholar 

  • Wirzenius M, Tammela T, Uutela M, He Y, Odorisio T, Zambruno G, Nagy JA, Dvorak HF, Yla-Herttuala S, Shibuya M, Alitalo K (2007) Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting. J Exp Med 204:1431–1440

    Article  PubMed  CAS  Google Scholar 

  • Wissmann C, Detmar M (2006) Pathways targeting tumor lymphangiogenesis. Clin Cancer Res 12:6865–6868

    Article  PubMed  CAS  Google Scholar 

  • Witte MH, Erickson R, Bernas M, Andrade M, Reiser F, Conlon W, Hoyme HE, Witte CL (1998) Phenotypic and genotypic heterogeneity in familial Milroy lymphedema. Lymphology 31:145–155

    PubMed  CAS  Google Scholar 

  • Witzenbichler B, Asahara T, Murohara T, Silver M, Spyridopoulos I, Magner M, Principe N, Kearney M, Hu JS, Isner JM (1998) Vascular endothelial growth factor-C (VEGF-C/VEGF-2) promotes angiogenesis in the setting of tissue ischemia. Am J Pathol 153:381–394

    PubMed  CAS  Google Scholar 

  • Yan C, Zhu ZG, Yu YY, Ji J, Zhang Y, Ji YB, Yan M, Chen J, Liu BY, Yin HR, Lin YZ (2004) Expression of vascular endothelial growth factor C and chemokine receptor CCR7 in gastric carcinoma and their values in predicting lymph node metastasis. World J Gastroenterol 10: 783–790

    PubMed  CAS  Google Scholar 

  • Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J (2000) Vascular-specific growth factors and blood vessel formation. Nature 407:242–248

    Article  PubMed  CAS  Google Scholar 

  • Yuan L, Moyon D, Pardanaud L, Breant C, Karkkainen MJ, Alitalo K, Eichmann A (2002) Abnormal lymphatic vessel development in Neuropilin-2 mutant mice. Development 129:4797–4806

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Hematology/Oncology, University Hospital Münster, Albert-Schweitzer-str. 33, 48129, Münster, Germany

    Rüediger Liersch

Authors
  1. Rüediger Liersch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christoph Biermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rolf M. Mesters
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wolfgang E. Berdel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rüediger Liersch .

Editor information

Editors and Affiliations

  1. Medizinische Klinik und Poliklinik A, Universitätsklinikum Münster, Albert-Schweitzer-Str. 33, Münster, 48149, Germany

    Rüdiger Liersch

  2. Medizinische Klinik und Poliklinik, Universitätsklinikum Münster, Albert-Schweitzer-Str. 33, Münster, 48149, Germany

    Wolfgang E. Berdel

  3. Medizinische Klinik und Poliklinik A, Universitätsklinikum Münster, Albert-Schweitzer-Str. 33, Münster, 48149, Germany

    Torsten Kessler

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Liersch, R., Biermann, C., Mesters, R.M., Berdel, W.E. (2010). Lymphangiogenesis in Cancer: Current Perspectives. In: Liersch, R., Berdel, W., Kessler, T. (eds) Angiogenesis Inhibition. Recent Results in Cancer Research, vol 180. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-78281-0_8

Download citation

  • DOI: https://doi.org/10.1007/978-3-540-78281-0_8

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-540-78280-3

  • Online ISBN: 978-3-540-78281-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation