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Lymphangiogenesis and expression of specific molecules as lymphatic endothelial cell markers

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Abstract

In recent years, several functional molecules specifically expressed and localized in lymphatic endothelial cells, such as 5’-nucleotidase, lymphatic vessel endothelial receptor-1, vascular endothelial growth factor receptor-3, podoplanin and Prox-1, have been identified. The discovery of the lymphatic endothelial cell markers facilitated detailed analysis of the nature and structural organization of the lymphatic vessels and their growth (lymphangiogenesis). As a result, over the past few years, advances have been made in understanding the cellular and molecular aspects of physiological lymphangiogenesis and tumor-induced lymphangiogenesis. The biology of lymphangiogenesis, particularly the mechanism of its regulation, is very important in understanding the formation of the lymphatic system as a biological regulation system transporting tissue fluid and wandering cells, including lymphocytes, and disease involving lymphangiogenesis. The understanding of the molecular mechanism of lymphangiogenesis and the elucidation of the development of normal and pathological tissues are expected to lead to the development of therapy for intractable diseases, such as malignant tumors and lymphedema.

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References

  • Abtahian F, Guerriero A, Kahn MLet al. (2003) Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk.Science 299, 247–51.

    Article  PubMed  CAS  Google Scholar 

  • Akagi K, Ikeda Y, Miyazaki Met al. (2000) Vascular endothelial growth factor-c (VEGF-C) expression in human colorectal cancer tissues.Br J Cancer 83, 887–91.

    Article  PubMed  CAS  Google Scholar 

  • Alitalo K (2002) Growth factors controlling angiogenesis and lymph angiogenesis.Ugeskr Laeger 164, 3170–2.

    PubMed  Google Scholar 

  • Al-Rawi MA, Watkins G, Mansel RE, Jiang WG (2005) Interleukin 7 upregulates vascular endothelial growth factor D in breast cancer cells and induces lymphangiogenesisin vivo.Br J Surg 92, 305–10.

    Article  PubMed  CAS  Google Scholar 

  • Arinaga M, Noguchi T, Takeno Set al. (2003) Clinical significance of vascular endothelial growth factor C and vascular endothelial growth factor receptor-3 in patients with nonsmall cell lung carcinoma.Cancer 97, 457–64.

    Article  PubMed  CAS  Google Scholar 

  • Auvinen MI, Sihvo EI, Ruohtula Tet al. (2002) Incipient angiogenesis in Barrett’s epithelium and lymphangiogenesis in Barrett’s adenocarcinoma.J Clin Oncol 20, 2971–9.

    Article  PubMed  Google Scholar 

  • Banerji S, Ni J, Wang S-Xet al. (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 

  • Beasley NJ, Prevo R, Banerji S {eaet al.} (2002) Intratumoral lymphangiogenesis and lymph node metastasis in ehad and neck cancer.Cancer Res 62, 1315–20.

    PubMed  CAS  Google Scholar 

  • Bilchik A, Giuliano A, Essner Ret al. (1998) Universal application of intraoperative lymphatic mapping and sentinel lymphadenectomy in solid neoplasms.Cancer J 4, 351–8.

    CAS  Google Scholar 

  • Boardman KC, Swartz MA (2003) Interstitial flow as a guide for lymphangiogenesis.Circ Res 92, 801–8.

    Article  PubMed  CAS  Google Scholar 

  • Breiteneder-Geleff S, Matsui K, Soleiman Aet al. (1997) Podoplanin, novel 43-kd membrane protein of glomerular epithelial cells, is down-regulated in puromycin nephrosis.Am J Pathol 151, 1141–52.

    PubMed  CAS  Google Scholar 

  • Breiteneder-Geleff S, Soleiman A, Kowalski Het al. (1999) Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: Podoplanin as a specific marker for lymphatic endothelium.Am J Pathol 154, 385–94.

    PubMed  CAS  Google Scholar 

  • Bunone G, Vigneri P, Mariani Let al. (1999) Expression of angiogenesis stimulators and inhibitors in human thyroid tumors and correlation with clinical pathological features.Am J Pathol 155, 1967–76.

    PubMed  CAS  Google Scholar 

  • Cann SA, vanNetten JP, Ashby TLet al. (1995) Role of lymphangenesis in neovascularisation.Lancet 346, 388–90.

    Article  Google Scholar 

  • Cao Y, Linden P, Farmebo Jet al. (1998) Vascular endothelial growth factor C induced angiogenesisin vivo.Proc Natl Acad Sci, USA 95, 14 389–94.

    Google Scholar 

  • Carreira CM, Nasser SM, diTomasoet al. (2000) LYVE-1 is not restricted to lymph vessels: Expression in normal liver sinusoids and down regulation in human liver cancer and cirrhosis.Cancer Res 61, 8079–84.

    Google Scholar 

  • Castenholz A, Hauck G, Rettberg U (1991) Light and electron microscopy of the structural organization of the tissue- lymphatic fluid drainage system in the mesentery: An experimental study.Lymphology 24, 82–92.

    PubMed  CAS  Google Scholar 

  • Cursiefen C, Chen L, Borges LPet al. (2004) VEGF-A stimulates lymphangiogenesis and hemoangiogenesis in inflammatory neovascularrization via macrophage recruitment.J Clin Invest 113, 1040–50.

    PubMed  CAS  Google Scholar 

  • Dadras SS, Paul T, Bertoncini Jet al. (2003) Tumor lymphangio- genesis. A novel prognostic indicator for cutaneous melanoma metastasis and survival.Am J Pathol 162, 1951–60.

    PubMed  Google Scholar 

  • Dagenais SL, Hartsough RL, Erickson RPet al. (2004) Foxc2 is expressed in developing lymphatic vessels and other tissues associated with lymphedema-distichiasis syndrome.Gene Expr Patterns 4, 611–19.

    Article  PubMed  CAS  Google Scholar 

  • Duff SE, Li C, Jeziorska Met al. (2003) Vascular endothelial growth factors C and D and lymphangiogenesis in gastrointestinal tract malignancy.Br J Cancer 89, 426–30.

    Article  PubMed  CAS  Google Scholar 

  • Dumont DJ, Fong G, Puri PCet al. (1995) Vascularization of the mouse embryo: A study of flk-1, tek, tie, and vascular endothelial growth factor expression during development.Dev Dyn 203, 80–92.

    PubMed  CAS  Google Scholar 

  • Dumont DJ, Jussila L, Taipale J (1998) Cardiovascular failure in mouse embryos deficient in VEGF receptor-3.Science 282, 946–9.

    Article  PubMed  CAS  Google Scholar 

  • Ezaki T, Kuwahara K (2002) Analysis of a specific marker for mouse lymphatics.Acta Anat Nipp 77 (Suppl.), 37 (Abstract).

    Google Scholar 

  • Ezaki T, Matsuno K, Fujii Het al. (1990) A new approach for identification of rat lymphatic capillaries using a monoclonal antibody.Arch Histol Cytol 53 (Suppl.), 77–86.

    Article  PubMed  Google Scholar 

  • Ezaki T, Kuwahara K, Morikawa Set al. (2004) Characterization of adjuvant-induced rat lymphangiomas as a model to study the lymph drainage from abdominal cavity.Jpn J Lymphol 27, 1–10.

    Google Scholar 

  • Ferrara N (2004) Vascular endothelial growth factor: Basic science and clinical progress.Endocr Rev 25, 581–611.

    Article  PubMed  CAS  Google Scholar 

  • Furudoi A, Tanaka S, Haruma Ket al. (2002) Clinical significance of vascular endothelial growth factor C expression and angiogenesis at the deepest invasive site of advanced colorectal carcinoma.Oncology 62, 157–66.

    Article  PubMed  CAS  Google Scholar 

  • Gale NW, Thurston G, Hackett SFet al. (2002) Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by angiopoietin-1.Dev Cell 3, 411–23.

    Article  PubMed  CAS  Google Scholar 

  • Gould EA, Winship T, Philbin PHet al. (1960) Observation on a ‘sentinel node’ in cancer of the parotid.Cancer 13, 77–8.

    Article  PubMed  CAS  Google Scholar 

  • Hall FT, Freeman JL, Asa SLet al. (2003) Intratumoral lymphatics and lymph node metastases in papillary thyroid carcinoma.Arch Otolaryngol Head Neck Surg 129, 716–19.

    Article  PubMed  Google Scholar 

  • Hashimoto I, Kodama J, Seki Net al. (2001) Vascular endothelial growth factor-C expression and its relationship to pelvic lymph node status in invasive cervical cancer.Br J Cancer 85, 93–7.

    Article  PubMed  CAS  Google Scholar 

  • He L, Papousti M, Hung Ret al. (2003) Three different fates of cells migrating from somites into the limb bud.Anat Embryol 207, 29–34.

    Article  PubMed  Google Scholar 

  • He Y, Kozaki K, Kapanen Tet al. (2002) Supression of tumor lymphangiogenesis and lymph node metastasis by bloking vascular endothelial growth factor receptor 3 signaling.J Natl Cancer Inst 94, 819–25.

    PubMed  CAS  Google Scholar 

  • He Y, Rajantie I, Ilmonen Met al. (2004a) Preexisting lymphatic endothelium but not endothelial progenitor cells are essential for tumor lymphangiogenesis and lymphatic metastasis.Cancer Res 64, 3737–40.

    Article  PubMed  CAS  Google Scholar 

  • He Y, Karpanen T, Alitalo K (2004b) Role of lymphangiogenenic factors in tumor metastasis.Biochem Biophys Acta 1654, 3–12.

    PubMed  CAS  Google Scholar 

  • Hirai M, Nakagawara A, Oosaki Tet al. (2001) Expression of vascular endothelial growth factor (VEGF-A/VEGF-1 and VEGF-C/VEGF-2) in post menopausal uterine endothelial carcinoma.Gynecol Oncol 80, 181–8.

    Article  PubMed  CAS  Google Scholar 

  • Hirakawa S, Kodama S, Kunstfeld Ret al. (2005) VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis.J Exp Med 201, 1089–99.

    Article  PubMed  CAS  Google Scholar 

  • Hong YK, Harvey N, Noh YHet al. (2002) Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate.Dev Dyn 225, 351–7.

    Article  PubMed  CAS  Google Scholar 

  • Hong YK, Lange-Asschenfeldt B, Velasco Pet al. (2004) VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the α1p1and α2β1 integrinsFASEB J 18, 1111–13.

    PubMed  CAS  Google Scholar 

  • Jackson DG, prevo R, Clasper S, Banerji S (2001) LYVE-1, the lymphatic system and tumor lymphangiogenesis.Trends Immunol 22, 317–21.

    Article  PubMed  CAS  Google Scholar 

  • Ji RC, Kato S (2001) Histochemical analysis of lymphatic endothelial cells in lymphostasis.Microsc Res Tech 55, 70–80

    Article  PubMed  CAS  Google Scholar 

  • Ji RC, Kato S (2003) Lymphatic network and lymphangiogenesis in the gastric wall.J Histochem Cytochem 51, 331–8

    PubMed  CAS  Google Scholar 

  • Ji RC, Miura M, Qu P, Kato S (2004) Expression of VEGFR-3 and 5’-Nase in regenerating lymphatic vessels of the cutaneous wound healing.Microsc Res Tech 64, 279–86

    Article  PubMed  CAS  Google Scholar 

  • Jodanov DA (1996) On senile changes in lymphatic capillaries and vessels.J Cardiovasc Surg 7, 108–16

    Google Scholar 

  • Joukov V, Pajusola K, Kaipainen A (1996) A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt-4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinasesEMBO J 15, 290–8

    PubMed  CAS  Google Scholar 

  • Jussila L, Alitalo K (2002) Vascular growth factors and lymphangiogenesis.Phsiol Rev 82, 673–700

    CAS  Google Scholar 

  • Kaipainen A, Korhonen J, Pajusola Ket al. (1993) The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells.J Exp Med 178, 2077–88

    Article  PubMed  CAS  Google Scholar 

  • Kaipainen A, Vlaykova T, Hatva Eet al. (1994) Enhanced expression of the receptor tyrosine kinase messenger RNA in the vascular endothelium of metastatic melanomasCancer Res 54, 6571–7

    PubMed  CAS  Google Scholar 

  • Kaipainen A, Korhonen J, Mustonen Tet al. (1995) Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development.Proc Natl Acad Sci USA 92, 3566–70

    Article  PubMed  CAS  Google Scholar 

  • Kajiya K, Hirokawa S, Ma Bet al. (2005) Hepatocyte growth factor promotes lymphatic vessel formation and functionEMBO J 24, 2885–95

    Article  PubMed  CAS  Google Scholar 

  • Karkkainen MJ, Jussila L, Ferrell REet al. (2001) Molecular regulation of lymphangiogenesis and targets for tissue edema.Trends Mol Med 7, 18–22

    Article  PubMed  CAS  Google Scholar 

  • Kato S (1990) Enzyme-histochemical identification of lymphatic vessels by light and backscattered image scanning electron microscopy.Stain Technol 65, 131–7.

    PubMed  CAS  Google Scholar 

  • Kato S (2000) Organ specificity of the structural organization and fine distribution of lymphatic capillary networks Histochemical study.Histol Histopathol 15, 185–97

    PubMed  CAS  Google Scholar 

  • Kato S (2003) Lymphatic endothelial cell markers and lymphangiogenesis.Jpn J Lymphol 26, 1–20 (in Japanese with an English abstract)

    CAS  Google Scholar 

  • Kato S, Gotoh M (1990) Application of backscattered elecron imaging to enzyme histochemistry of lymphatic capillariesJ Electron Microsc 39, 186–90

    CAS  Google Scholar 

  • Kato S, Miura M, Miyauchi R (1993) Structural organization of the initial lymphatics in the monkey mesentery and intestinal wall as revealed by an enzyme-histochemistry.Arch Histol Cytol 56, 149–60

    Article  PubMed  CAS  Google Scholar 

  • Kato S, Itonaga I, Ji RCet al. (1996) Enzyme triple staining for differentiation of lymphatics from venous and arterial capillaries.Lymphology 29, 15–19

    PubMed  CAS  Google Scholar 

  • Katsuta M, Miyashita M, Makino Het al. (2005) Correlation of hypoxia inducible factor-1α with lymphatic metastasis via vascular endothelial growth factor-C in human esophageal cancer.Exp Mol Pathol 78, 123–30.

    Article  PubMed  CAS  Google Scholar 

  • Kitagawa Y, Fujii H, Mukai Wet al. (2002) Radio-guided sentinel node detection for gastric cancer.Br J Surg 89, 604–8.

    Article  PubMed  CAS  Google Scholar 

  • Kotani M (1990) The lymphatics and lymphoreticular tissues in relation to the action of sex hormones.Arch Histol Cytol 53 (Suppl.), 1–76.

    Article  PubMed  Google Scholar 

  • Koukourakis MI, Giatromanolaki A, Sivridis Eet al. (2005) LYVE- 1 immunohistochemical assessment of lymphangiegenesis in endometrial and cancer.J Clin Pathol 58, 202–6.

    Article  PubMed  CAS  Google Scholar 

  • Kukk E, Lymboussaki A, Taira Set al. (1996) VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development.Development 122, 3829–37.

    PubMed  CAS  Google Scholar 

  • Kukk E, Wartiovaara U, Gunji Yet al. (1997) Analysis of Tie receptor tyrosine kinase in haemopoietic progenitor and leukaemia cells.Br J Haematol 98, 195–203.

    Article  PubMed  CAS  Google Scholar 

  • Kuwai T, Kitadai Y, Tanaka Set al. (2003) Expression of hypoxia- inducible factor 1 alpha is associated with tumor vascularization in human colorectal carcinoma.Int J Cancer 105, 176–81.

    Article  PubMed  CAS  Google Scholar 

  • Kyzas P, Geleff S, Batistatou Aet al. (2005) Evidence for lymphangiogenesis and its prognostic implications in head and neck squamous cell carcinoma.J Pathol 206, 170–7.

    Article  PubMed  Google Scholar 

  • Leak LV, Jones M (1994) Lymphangiogenesisin vitro: Formation of lymphatic capillary-like channels from confluent monolayers of lymphatic endothelial cells.In Vitro Cell Dev Biol Anim 30, 512–18.

    Article  Google Scholar 

  • Lee AK, DeLellis RA, Silverman MLet al. (1990) Prognostic significance of peritumoral lymphatic and blood vessel invasion in node-negative carcinoma of the breast.J Clin Oncol 8, 1457–65.

    PubMed  CAS  Google Scholar 

  • Leu AJ, Berk DA, Lymboussaki Aet al. (2000) Absence of functional lymphatics within a murine sarcoma: A molecular and functional evaluation.Cancer Res 61, 4324–7.

    Google Scholar 

  • Lymboussaki A, Partanen TA, Olofsson B (1998) Expression of vascular endothelial growth factor C receptor VEGFR-3 in lymphatic endothelium for the skin and in vascular tumors.Am J Pathol 153, 395–403.

    PubMed  CAS  Google Scholar 

  • Lymboussaki A, Olofsson B, Eriksson U, Alitalo K (1999) Vascular endothelial growth factor (VEGF) and VEGF-C show overlapping binding sites in embryonic endothelia and distinct sites in differentiated adult endothelia.Circ Res 85, 992–9.

    PubMed  CAS  Google Scholar 

  • Mäkinen T, Jussila L, Veikkola Tet al. (2001) Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3.Nat Med 7, 199–205.

    Article  PubMed  Google Scholar 

  • Mandriota S, Jussila L, Jeltsch Met al. (2001) Vascular endothelial growth factor-C medicated lymphangiogenesis promotes tumor metastasis.EMBO J 20, 672–82.

    Article  PubMed  CAS  Google Scholar 

  • Maula SM, Luukkaa M, Grenman Ret al. (2003) Intratumoral lymphatics are essential for the metastic spread and prognosis in squamous cell carcinomas of the head and neck region.Cancer Res 63, 1920–6.

    PubMed  CAS  Google Scholar 

  • Mizuno R, Yokoyama Y, Ono Net al. (2003) Establishment of rat lymphatic endothelial cell line.Microcirculation 10, 127–31.

    Article  PubMed  CAS  Google Scholar 

  • Morton DL, Wen DR, Wong JHet al. (1992) Technical details of intraoperative lymphatic mapping for early stage melanoma.Arch Surg 127, 392–9.

    PubMed  CAS  Google Scholar 

  • Niki T, Iba S, Tokunou Met al. (2000) Expression of vascular endothelial growth factors A, B, C and D and their relationships to lymph node status in lung adenocarcinoma.Clin Cancer Res 6, 2431–9.

    PubMed  CAS  Google Scholar 

  • Noguchi T, Takeno S, Shibata Tet al. (2002) VEGF-C expression correlates with histological differentiation and metastssis in squamous cell carcinoma of the esophagus.Oncol Rep 9, 995–9.

    PubMed  CAS  Google Scholar 

  • Oh SJ, Jeltsch MM, Birkengager R*et al. (1997) VEGF and VEGF-C: Specific induction of angiogenesis and lymphang- iogenesis in the differentiated avian chorioallantoic membrane.Dev Biol 188, 96–109.

    Article  PubMed  CAS  Google Scholar 

  • Ohta Y, Nozawa H, Tanaka Yet al. (2000) Increased vascular endothelial growth factor and vascular endothelial growth factor-C and increased um23 expression associated with microdissemination in the lymph nodes in stage non-small cell lung cancer.J Thorac Cardiovasc Surg 119, 804–13.

    Article  PubMed  CAS  Google Scholar 

  • Ohtani Y, Ohtani O (2001) Postnatal development of lymphatic vessels and their smooth muscle cells in the rat diaphragm: A confocal microscopic study.Arch Histol Cytol 64, 513–22.

    Article  PubMed  CAS  Google Scholar 

  • Oliver G, Detmar M (2002) The rediscovery of the lymphatic system: Old and new insights into the development and biological function of the lymphatic vasculature.Gene Dev 16, 772–83.

    Article  Google Scholar 

  • Paavonen K, Puolakkainen P, Jussila Let al. (2000) Vascular endothelial growth factor-3 in lymphangiogenesis in wound healing.Am J Pathol 156, 1499–504.

    PubMed  CAS  Google Scholar 

  • Padera TP, Kadambi A, di Tomaso Eet al. (2002) Lymphatic metastasis in the absence of functional intratumor lymphatics.Science 296, 1883–6.

    Article  PubMed  CAS  Google Scholar 

  • Papousti M, Tomarev SI, Eichmann Aet al. (2001) Endogeneous origin of the lymphatics in the avian chorioallantoic membrane.Dev Dyn 222, 238–51.

    Article  Google Scholar 

  • Pepper MS, Tille J-C, Nisato R, Skobe M (2003) Lymphangio- genesis and tumor metastasis.Cell Tissue Res 314, 167–77.

    Article  PubMed  CAS  Google Scholar 

  • Petrova TV, Makinen T, Makela TPet al. (2002) Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor.EMBO J 21, 4593–9.

    Article  PubMed  CAS  Google Scholar 

  • Petrova TV, Karpanen T, Norrmén Cet al. (2004) Defective valves and abdominal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis.Nat Med 10, 974–81.

    Article  PubMed  CAS  Google Scholar 

  • Pytowski B, Goldman J, Persaud Ket al. (2005) Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing angibody.J Natl Cancer Inst 97, 14–21.

    Article  PubMed  CAS  Google Scholar 

  • Saaristo A, Veikkola T, Tammela Tet al. (2002) Lymphangiogenic gene therapy with minimal blood vascular side effects.J Exp Med 196, 719–30.

    Article  PubMed  CAS  Google Scholar 

  • Saaristo A, Tammela T, Timonen Jet al. (2004) Vascular endothelial growth factor-C gene therapy restores lymphatic flow across incision wounds.FASEB J 18, 1707–9.

    PubMed  CAS  Google Scholar 

  • Salven P, Lymboussaki A, Heikkila Pet al. (1998) Vascular endothelial growth factors VEGF-B and VEGF-C are expressed in human tumors.Am J Pathol 153, 103–8.

    PubMed  CAS  Google Scholar 

  • Schacht V, Ramirez MI, Hong Y-Ket al. (2003) T1αpodoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema.EMBO J 22, 3546–56.

    Article  PubMed  CAS  Google Scholar 

  • Schneider M, Othman-Hassan K, Crist Bet al. (1999) Lymphangioblasts in the avian wing bud.Dev Dyn 216, 311–19.

    Article  PubMed  CAS  Google Scholar 

  • Sedivy R, Beck-Mannagetta J, Haverkampf Cet al. (2001) Expression of vascular endothelial growth factor-C correlates with the lymphatic microvessel density and the nodal status in oral squamous cell cancer.J Oral Pathol Med 32, 455–60.

    Article  Google Scholar 

  • Shao X-J, Ohtani O, Saitoh Met al. (1998) Development of diaphragmatic lymphatics: The process of their direct connection to the peritoneal cavity.Arch Histol Cytol 61, 137–49.

    Article  PubMed  CAS  Google Scholar 

  • Shields JD, Borsetti M, Rigby Het al. (2004) Lymphatic density and metastatic spread in human malignant melanoma.Br J Cancer 90, 693–70.

    Article  PubMed  CAS  Google Scholar 

  • Shimizu K, Kubo H, Ymaguchi Ket al. (2004) Supression of VEGFR-3 signaling inhibits lymph node metastasis in gastric cancer.Cancer Res 95, 328–33.

    CAS  Google Scholar 

  • Shimoda H, Takahashi Y, Kato S (2001) Development of the lymphatic network in the muscle coat of the rat jejunum as revealed by enzyme-histochemistry.Arch Histol Cytol 64, 523–33.

    Article  PubMed  CAS  Google Scholar 

  • Shimoda H, Takahashi Y, Kajihara T, Kato S (2003) Demonstration of the ratlymphatic vessels using immunohistochemistry andin situ hybridization for 5’-nucleotidase.Biomed Res 24, 51–7.

    CAS  Google Scholar 

  • Shimoda H, Takahashi Y, Kato S (2004) Regrowth of lymphatic vessels following transaction of the muscle coat in the rat small intestine.Cell Tissue Res 316, 325–38.

    Article  PubMed  Google Scholar 

  • Skobe M, Hawighorst T, Jackson DGet al. (2001) Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis.Nat Med 7, 192–8.

    Article  PubMed  CAS  Google Scholar 

  • Stacker S, Caesar C, Baldwin MEet al. (2001) VEGF-D promots the metastastic spread of tumor cells via the lymphatics.Nat Med 7, 186–91.

    Article  PubMed  CAS  Google Scholar 

  • Swartz M, Skobe M (2001) Lymphatic function, lymphangiogenesis and cancer metastasis.Microsc Res Tech 55, 92–9.

    Article  PubMed  CAS  Google Scholar 

  • Tan Y (1998) Basic fibroblast growth factor-midiated lymphang- iogenesis of lymphatic endothelial cells isolated from dog thoracic ducts: Effect of heparin.Jpn J Physiol 48, 133–41.

    Article  PubMed  CAS  Google Scholar 

  • Tanigawa N, Kanazawa T, Satomura Ket al. (1981) Experimental- study on lymphatic vascular changes in the development of cancer.Lymphology 14, 149–54.

    PubMed  CAS  Google Scholar 

  • Travella W, Dugan MC (1990) Endothelial interactions. In:Progress in Lymphology, VII. (Nishi M, Uchino S, Yabuki Set al., eds). Elsevier Science, Amsterdam, 269–70.

    Google Scholar 

  • Tsurusaki T, Kanda S, Sakai Het al. (1999) Vascular endothelial growth factor-C expression in human prostatic carcinoma andits relationship to lymph node metastasis.Br J Cancer 80, 309–13.

    Article  PubMed  CAS  Google Scholar 

  • Valtola R, Salven P, Heikkila Pet al. (1999) VEGF-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer.Am J Pathol 154, 1381–90.

    PubMed  CAS  Google Scholar 

  • Veikkola T, Jussila I, Makinen Tet al. (2001) Signaling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice.EMBO J 20, 123–1.

    Article  Google Scholar 

  • Weninger W, PartanenT, Breiteneder-Geleff Set al. (1999) Expression of vascular endothelial growth factor receptor-3 and podoplanin suggests a lymphatic endothelial cell origin of Kaposi’s sarcoma tumor cells.Lab Invest 78, 243–51.

    Google Scholar 

  • Wigle JT, Oliver G (1999) Prox-1 function is required for the development of the murine lymphatic system.Cell 98, 769–78.

    Article  PubMed  CAS  Google Scholar 

  • Wigle JT, Harvey N, Detmar Met al. (2002) An essential role forProx 1 in the induction of the lymphatic endothelial cell phenotype.EMBO J 21, 1505–13.

    Article  PubMed  CAS  Google Scholar 

  • Williams CSM, Leek RD, Robson AMet al. (2003) Absence of lymphangiogenesis and intratumoural lymph vessels in human metastatic breast cancer.J Pathol 200, 195–206.

    Article  PubMed  CAS  Google Scholar 

  • Wilting J, Christ B, Bokeloh Met al. (1991) A modified chorioal- lantoic membrane (CAM) assay for qualitative and quantitative study of growth factors. Studies on the effects of carriers, PBS, angiogenin, and bFGF.Anat Embryol 183, 259–71.

    Article  PubMed  CAS  Google Scholar 

  • Wilting J, Eichmann A, Christ Bet al. (1997) Expression of the avian VEGF receptor homologues Quek 1 and Quek 2 in blood-vascular and lymphatic endothelial and nonendothelial cells during quail embryonic development.Cell Tissue Res 288, 207–23.

    Article  PubMed  CAS  Google Scholar 

  • Wilting J, Kurz H, Oh STet al. (1998) Angiogenesis and lymphangiogenesis: Analogous mechanisms and homologous growth factors. In:Vascular Morphogenesis: In Vitro, In Vivo and In Mente (Little C, Mironov V, Sage H, eds). Birkhäusen, Bostone, 21–34.

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Wilting J, Tomarev SI, Christ B (2003) Lymphangioblasts in embryonic lymphangiogenesis.Lymphat Res Biol 1, 33–40.

    Article  PubMed  Google Scholar 

  • Witte CL, Witte MH (1985) Lymphatics in pathophysiology of edema. In:Experimental Biology of the Lymphatic Circulation (Johnston MG, ed.). Elsevier, Amsterdam, 165–179.

    Google Scholar 

  • Yamashita Y, Hooker SW, Jiang Het al. (1998) CD73 expression and fyn-dependent signaling on murine lymphocytes.Eur J Immunol 28, 2981–90.

    Article  PubMed  CAS  Google Scholar 

  • Yonemura Y, Endo Y, Fujita Het al. (1999) Role of vascular endothelial growth factor C in the development of lymph node metastasis in gastric cancer.Clin Cancer Res 5, 1823–9.

    PubMed  CAS  Google Scholar 

  • Yonemura Y, Fushida S, Bando Eet al. (2001) Lymphangiogenesis and the vascular endothelial growth factor receptor (VEGFR)-3 in gastric cancer.Eur J Cancer 37, 918–23.

    Article  PubMed  CAS  Google Scholar 

  • Yoon YS, Murayama T, Gravereaux Eet al. (2003) VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema.J Clin Invest 11, 717–25.

    Google Scholar 

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Kato, S., Shimoda, H., Ji, RC. et al. Lymphangiogenesis and expression of specific molecules as lymphatic endothelial cell markers. Anato Sci Int 81, 71–83 (2006). https://doi.org/10.1111/j.1447-073X.2006.00142.x

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