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Lymphangiogenesis and Inflammation—Looking for the “Missing Pieces” of the Puzzle

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Archivum Immunologiae et Therapiae Experimentalis Aims and scope

Abstract

Several papers about lymphangiogenesis and inflammation focused on the detailed and complicated descriptions of the molecular pathways accompanying both non-tumor and tumor inflammatory-induced lymphatic vessel development. Many authors are tempted to present inflammatory-induced lymphangiogenesis in pathologic conditions neglecting the role of inflammatory cells during embryonic lymphatic vessel development. Some of the inflammatory cells are largely characterized in inflammatory-induced lymphangiogenesis, while others as mast cells, eosinophils, or plasma cells are less studied. No phenotypic characterization of inflammation-activated lymphatic endothelial cell is available in this moment. Another paradox is related to the existence of few papers regarding lymphangiogenesis inside lymphoid organs and for their related pathology. There are still several “missing pieces of such a big puzzle” of lymphangiogenesis and inflammation, with a direct impact on the ineffectiveness of the anti-inflammatory therapy as lymphangiogenesis inhibitors. The present paper will focus on the controversial issues of lymphangiogenesis and inflammation.

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References

  • Abtahian F, Guerriero A, Sebzda E et al (2003) Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science 299:247–251

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Aebischer D, Willrodt AH, Halin C (2014) Oxazolone-induced contact hypersensitivity reduces lymphatic drainage but enhances the induction of adaptive immunity. PLoS ONE 9:e99297

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Akishima Y, Ito K, Zhang L et al (2004) Immunohistochemical detection of human small lymphatic vessels under normal and pathological conditions using the LYVE-1 antibody. Virchows Arch 444:153–157

    Article  CAS  PubMed  Google Scholar 

  • Algaba A, Linares PM, Fernández-Contreras ME et al (2013) Relationship between levels of angiogenic and lymphangiogenic factors and the endoscopic, histological and clinical activity, and acute-phase reactants in patients with inflammatory bowel disease. J Crohns Colitis 7:e569–e579

    Article  PubMed  Google Scholar 

  • Al-Rawi MA, Mansel RE, Jiang WG (2005) Molecular and cellular mechanisms of lymphangiogenesis. Eur J Surg Oncol 31:117–121

    Article  CAS  PubMed  Google Scholar 

  • Angeli V, Ginhoux F, Llodrà J et al (2006) B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity 24:203–215

    Article  CAS  PubMed  Google Scholar 

  • Bao H, Jiang M, Zhu M et al (2009) Overexpression of Annexin II affects the proliferation, apoptosis, invasion and production of proangiogenic factors in multiple myeloma. Int J Hematol 90:177–185

    Article  CAS  PubMed  Google Scholar 

  • Bekiaris V, Gaspal F, Kim MY et al (2009) CD30 is required for CCL21 expression and CD4 T cell recruitment in the absence of lymphotoxin signals. J Immunol 182:4771–4775

    Article  CAS  PubMed  Google Scholar 

  • Bernaudin JF, Kambouchner M, Lacave R (2013) Lymphatic vascular system, development and lymph formation (in French). Rev Pneumol Clin 69:93–101

    Article  PubMed  Google Scholar 

  • Berrih-Aknin S, Ruhlmann N, Bismuth J et al (2009) CCL21 overexpressed on lymphatic vessels drives thymic hyperplasia in myasthenia. Ann Neurol 66:521–531

    Article  CAS  PubMed  Google Scholar 

  • Berro AI, Perry GA, Agrawal DK (2004) Increased expression and activation of CD30 induce apoptosis in human blood eosinophils. J Immunol 173:2174–2183

    Article  CAS  PubMed  Google Scholar 

  • Best CL, Pudney J, Welch WR et al (1996) Localization and characterization of white blood cell populations within the human ovary throughout the menstrual cycle and menopause. Hum Reprod 11:790–797

    Article  CAS  PubMed  Google Scholar 

  • Bischoff SC, Sellge G, Manns MP et al (2001) Interleukin-4 induces a switch of human intestinal mast cells from proinflammatory cells to Th2-type cells. Int Arch Allergy Immunol 124:151–154

    Article  CAS  PubMed  Google Scholar 

  • Bogos K, Renyi-Vamos F, Dobos J et al (2009) High VEGFR-3-positive circulating lymphatic/vascular endothelial progenitor cell level is associated with poor prognosis in human small cell lung cancer. Clin Cancer Res 15:1741–1746

    Article  CAS  PubMed  Google Scholar 

  • Böhmer R, Neuhaus B, Bühren S et al (2010) Regulation of developmental lymphangiogenesis by Syk(+) leukocytes. Dev Cell 18:437–449

    Article  PubMed  CAS  Google Scholar 

  • Bouta EM, Wood RW, Brown EB et al (2014) In vivo quantification of lymph viscosity and pressure in lymphatic vessels and draining lymph nodes of arthritic joints in mice. J Physiol 592(Pt 6):1213–1223

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Brideau G, Mäkinen MJ, Elamaa H et al (2007) Endostatin overexpression inhibits lymphangiogenesis and lymph node metastasis in mice. Cancer Res 67:11528–11535

    Article  CAS  PubMed  Google Scholar 

  • Brown HM, Russell DL (2014) Blood and lymphatic vasculature in the ovary: development, function and disease. Hum Reprod Update 20:29–39

    Article  CAS  PubMed  Google Scholar 

  • Cao Y, Linden P, Farnebo J et al (1998) Vascular endothelial growth factor C induces angiogenesis in vivo. Proc Natl Acad Sci USA 95:14389–14394

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cimpean AM, Mazuru V, Cernii A et al (2011) Detection of early lymphangiogenesis by lymphatic microvascular density and endothelial proliferation status in preneoplastic and neoplastic lesions of the uterine cervix. Pathol Int 61:395–400

    Article  PubMed  Google Scholar 

  • Cimpean AM, Mazuru V, Saptefrati L et al (2012) Prox 1, VEGF-C and VEGFR3 expression during cervical neoplasia progression as evidence of an early lymphangiogenic switch. Histol Histopathol 27:1543–1550

    CAS  PubMed  Google Scholar 

  • Crivellato E, Nico B, Ribatti D (2008) Mast cells and tumour angiogenesis: new insight from experimental carcinogenesis. Cancer Lett 269:1–6

    Article  CAS  PubMed  Google Scholar 

  • Cueni LN, Detmar M (2008) The lymphatic system in health and disease. Lymphat Res Biol 6:109–122

    Article  PubMed Central  PubMed  Google Scholar 

  • Dellinger MT, Meadows SM, Wynne K et al (2013) Vascular endothelial growth factor receptor-2 promotes the development of the lymphatic vasculature. PLoS ONE 8:e74686

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Detoraki A, Staiano RI, Granata F et al (2009) Vascular endothelial growth factors synthesized by human lung mast cells exert angiogenic effects. J Allergy Clin Immunol 123:1142–1149

    Article  CAS  PubMed  Google Scholar 

  • Detry B, Blacher S, Erpicum C et al (2013) Sunitinib inhibits inflammatory corneal lymphangiogenesis. Invest Ophthalmol Vis Sci 54:3082–3093

    Article  CAS  PubMed  Google Scholar 

  • Duong T, Proulx ST, Luciani P et al (2012) Genetic ablation of SOX18 function suppresses tumor lymphangiogenesis and metastasis of melanoma in mice. Cancer Res 72:3105–3114

    Article  CAS  PubMed  Google Scholar 

  • El Filali E, Duijst S, Hiralall JK et al (2014) Human fetal liver cells for regulated ex vivo erythropoietin gene therapy. Mol Ther Methods Clin Dev 1:1–5

    Article  CAS  Google Scholar 

  • Farnsworth RH, Achen MG, Stacker SA (2006) Lymphatic endothelium: an important interactive surface for malignant cells. Pulm Pharmacol Ther 19:51–60

    Article  CAS  PubMed  Google Scholar 

  • Fiedler U, Christian S, Koidl S et al (2006) The sialomucin CD34 is a marker of lymphatic endothelial cells in human tumors. Am J Pathol 168:1045–1053

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Flister MJ, Wilber A, Hall KL et al (2010) Inflammation induces lymphangiogenesis through upregulation of VEGFR-3 mediated by NF-kappaB and Prox1. Blood 115:418–429

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Fridlender ZG, Albelda SM (2013) Modifying tumor associated macrophages: an important adjunct to immunotherapy. Oncoimmunology 2:e26620

    Article  PubMed Central  PubMed  Google Scholar 

  • Fukuhara J, Kase S, Ohashi T (2013) Expression of vascular endothelial growth factor C in human pterygium. Histochem Cell Biol 139:381–389

    Article  CAS  PubMed  Google Scholar 

  • Furtado GC, Marinkovic T, Martin AP et al (2007) Lymphotoxin beta receptor signaling is required for inflammatory lymphangiogenesis in the thyroid. Proc Natl Acad Sci USA 104:5026–5031

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gabillot-Carré M, Lepelletier Y, Humbert M et al (2006) Rapamycin inhibits growth and survival of D816V-mutated c-kit mast cells. Blood 108:1065–1072

    Article  PubMed  CAS  Google Scholar 

  • Galli SJ, Grimbaldeston M, Tsai M (2008) Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nat Rev Immunol 8:478–486

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gan HK, Seruga B, Knox JJ (2009) Sunitinib in solid tumors. Expert Opin Investig Drugs 18:821–834

    Article  CAS  PubMed  Google Scholar 

  • Genovese A, Detoraki A, Granata F et al (2012) Angiogenesis, lymphangiogenesis and atopic dermatitis. Chem Immunol Allergy 96:50–60

    Article  CAS  PubMed  Google Scholar 

  • Golenkov AK, Buravtsova IV, Dudina GA et al (2013) Gene expression of vascular endothelial growth factors and their receptors in different variants of the course of multiple myeloma (in Russian). Ter Arkh 85:98–102

    CAS  PubMed  Google Scholar 

  • Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964

    Article  CAS  PubMed  Google Scholar 

  • Gordon EJ, Rao S, Pollard JW et al (2010) Macrophages define dermal lymphatic vessel calibre during development by regulating lymphatic endothelial cell proliferation. Development 137:3899–3910

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gordon K, Schulte D, Brice G et al (2013a) Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant milroy-like primary lymphedema. Circ Res 112:956–960

    Article  CAS  PubMed  Google Scholar 

  • Gordon K, Spiden SL, Connell FC et al (2013b) FLT4/VEGFR3 and Milroy disease: novel mutations, a review of published variants and database update. Hum Mutat 34:23–31

    Article  CAS  PubMed  Google Scholar 

  • Grimbaldeston MA, Chen CC, Piliponsky AM et al (2005) Mast cell-deficient W-sash c-kit mutant Kit W-sh/W-sh mice as a model for investigating mast cell biology in vivo. Am J Pathol 167:835–848

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hall MA, Robinson H, Chan W et al (2013) Detection of lymphangiogenesis by near-infrared fluorescence imaging and responses to VEGF-C during healing in a mouse full-dermis thickness wound model. Wound Repair Regen 21:604–615

    Article  PubMed  Google Scholar 

  • Hameed A, Fox WM, Kurman RJ et al (1995) Perforin expression in human cell-mediated luteolysis. Int J Gynecol Pathol 14:151–157

    Article  CAS  PubMed  Google Scholar 

  • Harvey NL, Gordon EJ (2012) Deciphering the roles of macrophages in developmental and inflammation stimulated lymphangiogenesis. Vasc Cell 4:15

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hos D, Saban DR, Bock F et al (2011) Suppression of inflammatory corneal lymphangiogenesis by application of topical corticosteroids. Arch Ophthalmol 129:445–452

    Article  CAS  PubMed  Google Scholar 

  • Huggenberger R, Ullmann S, Proulx ST et al (2010) Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation. J Exp Med 207:2255–2269

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Huggenberger R, Siddiqui SS, Brander D et al (2011) An important role of lymphatic vessel activation in limiting acute inflammation. Blood 117:4667–4678

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ji RC (2012) Macrophages are important mediators of either tumor- or inflammation-induced lymphangiogenesis. Cell Mol Life Sci 69:897–914

    Article  CAS  PubMed  Google Scholar 

  • Ji RC, Eshita Y (2014) Rapamycin inhibition of CFA-induced lymphangiogenesis in PLN is independent of mast cells. Mol Biol Rep 41:2217–2228

    Article  CAS  PubMed  Google Scholar 

  • Johnson LA, Jackson DG (2013) Control of dendritic cell trafficking in lymphatics by chemokines. Angiogenesis 17:335–345

    Article  CAS  Google Scholar 

  • Kajiya K, Sawane M, Huggenberger R et al (2009) Activation of the VEGFR-3 pathway by VEGF-C attenuates UVB-induced edema formation and skin inflammation by promoting lymphangiogenesis. J Invest Dermatol 129:1292–1298

    Article  CAS  PubMed  Google Scholar 

  • Kalitin NN, Kostyukova MN, Kakpakova ES et al (2012) Expression of vascular endothelial growth factor receptors VEGFR1 in cultured multiple myeloma cells: correlation with immunophenotype and drug resistance. Bull Exp Biol Med 153:882–885

    Article  CAS  PubMed  Google Scholar 

  • Kanner WA, Galgano MT, Atkins KA (2010) Podoplanin expression in basal and myoepithelial cells: utility and potential pitfalls. Appl Immunohistochem Mol Morphol 18:226–230

    Article  CAS  PubMed  Google Scholar 

  • Kataru RP, Kim H, Jang C et al (2011) T lymphocytes negatively regulate lymph node lymphatic vessel formation. Immunity 34:96–107

    Article  CAS  PubMed  Google Scholar 

  • Kato S, Shimoda H, Ji RC et al (2006) Lymphangiogenesis and expression of specific molecules as lymphatic endothelial cell markers. Anat Sci Int 81:71–83

    Article  PubMed  Google Scholar 

  • Kelley PM, Connor AL, Tempero RM (2013) Lymphatic vessel memory stimulated by recurrent inflammation. Am J Pathol 182:2418–2428

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kerjaschki D, Regele HM, Moosberger I et al (2004) Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. J Am Soc Nephrol 15:603–612

    Article  CAS  PubMed  Google Scholar 

  • Kim H, Cruz M, Bourdeau A et al (2013) Cell-cell interactions influence vascular reprogramming by Prox1 during embryonic development. PLoS ONE 8:e52197

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Klueh U, Antar O, Qiao Y et al (2014) Role of vascular networks in extending glucose sensor function: impact of angiogenesis and lymphangiogenesis on continuous glucose monitoring in vivo. J Biomed Mater Res A 102:3512–3522

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Kume T (2010) Specification of arterial, venous, and lymphatic endothelial cells during embryonic development. Histol Histopathol 25:637–646

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kunder CA, St John AL, Li G et al (2009) Mast cell-derived particles deliver peripheral signals to remote lymph nodes. J Exp Med 206:2455–2467

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kunder CA, St John AL, Abraham SN (2011) Mast cell modulation of the vascular and lymphatic endothelium. Blood 118:5383–5393

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lachance PA, Hazen A, Sevick-Muraca EM (2013) Lymphatic vascular response to acute inflammation. PLoS ONE 8:e76078

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lahdenranta J, Hagendoorn J, Padera TP et al (2009) Endothelial nitric oxide synthase mediates lymphangiogenesis and lymphatic metastasis. Cancer Res 69:2801–2808

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Leak LV, Cadet JL, Griffin CP et al (1995) Nitric oxide production by lymphatic endothelial cells in vitro. Biochem Biophys Res Commun 217:96–105

    Article  CAS  PubMed  Google Scholar 

  • Lee JY, Park C, Cho YP et al (2010) Podoplanin-expressing cells derived from bone marrow play a crucial role in postnatal lymphatic neovascularization. Circulation 122:1413–1425

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lee BS, Lee BC, Park JE et al (2014) Primo vascular system in human umbilical cord and placenta. J Acupunct Meridian Stud 7:291–297

    Article  PubMed  Google Scholar 

  • Ling S, Liang L, Lin H et al (2012) Increasing lymphatic microvessel density in primary pterygia. Arch Ophthalmol 130:735–742

    Article  PubMed  Google Scholar 

  • Liu L, Ling SQ, Li QL et al (2012) Relations between lymphangiogenesis and the size of pterygium. Int J Ophthalmol 5:312–316

    PubMed Central  PubMed  Google Scholar 

  • Loffredo S, Staiano RI, Granata F et al (2014) Immune cells as a source and target of angiogenic and lymphangiogenic factors. Chem Immunol Allergy 99:15–36

    Article  CAS  PubMed  Google Scholar 

  • Long KB, Beatty GL (2013) Harnessing the antitumor potential of macrophages for cancer immunotherapy. Oncoimmunology 2:e26860

    Article  PubMed Central  PubMed  Google Scholar 

  • Mantovani A, Sica A, Sozzani S et al (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686

    Article  CAS  PubMed  Google Scholar 

  • Mareel M, Oliveira MJ, Madani I (2009) Cancer invasion and metastasis: interacting ecosystems. Virchows Arch 454:599–622

    Article  CAS  PubMed  Google Scholar 

  • Maruyama K, Ii M, Cursiefen C et al (2005) Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages. J Clin Invest 115:2363–2372

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Masuzawa M, Masuzawa M, Hamada Y et al (2012) Establishment and characterization of a novel lymphangiosarcoma cell line (MO-LAS) compared with the hemangiosarcoma cell line (ISO-HAS). Cancer Med 1:39–46

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Matsumoto M, Roufail S, Inder R et al (2013) Signaling for lymphangiogenesis via VEGFR-3 is required for the early events of metastasis. Clin Exp Metastasis 30:819–832

    Article  CAS  PubMed  Google Scholar 

  • Miteva M, Galimberti ML, Ricotti C et al (2009) D2-40 highlights lymphatic vessel proliferation of angiolymphoid hyperplasia with eosinophilia. J Cutan Pathol 36:1316–1322

    Article  CAS  PubMed  Google Scholar 

  • Mounzer RH, Svendsen OS, Baluk P et al (2010) Lymphotoxin-alpha contributes to lymphangiogenesis. Blood 116:2173–2182

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mouta Carreira C, Nasser SM, di Tomaso E et al (2001) LYVE-1 is not restricted to the lymph vessels: expression in normal liver blood sinusoid and down-regulation in human liver cancer and cirrhosis. Cancer Res 61:8079–8084

    CAS  PubMed  Google Scholar 

  • Nagy JA, Vasile E, Feng D et al (2002) Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med 196:1497–1506

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Neri S, Ishii G, Hashimoto H et al (2015) Podoplanin-expressing cancer-associated fibroblasts lead and enhance the local invasion of cancer cells in lung adenocarcinoma. Int J Cancer. doi:10.1002/ijc.29464

    PubMed  Google Scholar 

  • Nilsson I, Bahram F, Li X et al (2010) VEGF receptor 2/-3 heterodimers detected in situ by proximity ligation on angiogenic sprouts. EMBO J 29:1377–1388

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nitta A, Shirasuna K, Haneda S et al (2011) Possible involvement of IFNT in lymphangiogenesis in the corpus luteum during the maternal recognition period in the cow. Reproduction 142:879–892

    Article  CAS  PubMed  Google Scholar 

  • Oka M, Iwata C, Suzuki HI et al (2008) Inhibition of endogenous TGF-beta signaling enhances lymphangiogenesis. Blood 111:4571–4579

    Article  CAS  PubMed  Google Scholar 

  • Palomba A, Gallo O, Brahimi A et al (2010) Evaluation of lymphangiogenesis in premalignant conditions of the head and neck mucosa. Head Neck 32:1681–1685

    Article  PubMed  Google Scholar 

  • Patel SP, Dana R (2009) Corneal lymphangiogenesis: implications in immunity. Semin Ophthalmol 24:135–138

    Article  PubMed  Google Scholar 

  • Pearse G (2006) Normal structure, function and histology of the thymus. Toxicol Pathol 34:504–514

    Article  PubMed  Google Scholar 

  • Peranzoni E, Zilio S, Marigo I et al (2010) Myeloid-derived suppressor cell heterogeneity and subset definition. Curr Opin Immunol 22:238–244

    Article  CAS  PubMed  Google Scholar 

  • Proulx ST, Luciani P, Dieterich LC et al (2013) Expansion of the lymphatic vasculature in cancer and inflammation: new opportunities for in vivo imaging and drug delivery. J Control Release 172:550–557

    Article  CAS  PubMed  Google Scholar 

  • Qiu H, Cao L, Wang D et al (2013) High levels of circulating CD34+/VEGFR3+ lymphatic/vascular endothelial progenitor cells is correlated with lymph node metastasis in patients with epithelial ovarian cancer. J Obstet Gynaecol Res 39:1268–1275

    Article  PubMed  Google Scholar 

  • Quek R, George S (2010) Update on the treatment of gastrointestinal stromal tumors (GISTs): role of imatinib. Biologics 4:19–31

    PubMed Central  CAS  PubMed  Google Scholar 

  • Raica M, Cimpean AM, Ribatti D (2008) The role of podoplanin in tumor progression and metastasis. Anticancer Res 28:2997–3006

    PubMed  Google Scholar 

  • Raica M, Kondylis A, Mogoantă L et al (2010) Diagnostic and clinical significance of D2-40 expression in the normal human thymus and thymoma. Rom J Morphol Embryol 51:229–234

    CAS  PubMed  Google Scholar 

  • Raica M, Cimpean AM, Ceausu R et al (2013) Interplay between mast cells and lymphatic vessels in different molecular types of breast cancer. Anticancer Res 33:957–963

    PubMed  Google Scholar 

  • Ramani P, Norton A, Somerville MS et al (2012) PROX1 lymphatic density correlates with adverse clinicopathological factors, lymph node metastases and survival in neuroblastomas. J Neurooncol 108:375–383

    Article  CAS  PubMed  Google Scholar 

  • Russo E, Nitschké M, Halin C (2013) Dendritic cell interactions with lymphatic endothelium. Lymphat Res Biol 11:172–182

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Salmi M, Karikoski M, Elima K et al (2013) CD44 binds to macrophage mannose receptor on lymphatic endothelium and supports lymphocyte migration via afferent lymphatics. Circ Res 112:1577–1582

    Article  CAS  PubMed  Google Scholar 

  • Salven P, Mustjoki S, Alitalo R et al (2003) VEGFR-3 and CD133 identify a population of CD34+ lymphatic/vascular endothelial precursor cells. Blood 101:168–172

    Article  CAS  PubMed  Google Scholar 

  • Schlereth SL, Neuser B, Caramoy A et al (2014) Enrichment of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1)-positive macrophages around blood vessels in the normal human sclera. Invest Ophthalmol Vis Sci 55:865–872

    Article  PubMed  Google Scholar 

  • Schmid MC, Varner JA (2012) Myeloid cells in tumor inflammation. Vasc Cell 4:14

    Article  PubMed Central  PubMed  Google Scholar 

  • Schoppmann SF, Jesch B, Zacherl J et al (2013) Lymphangiogenesis and lymphovascular invasion diminishes prognosis in esophageal cancer. Surgery 153:526–534

    Article  PubMed  Google Scholar 

  • Schuijs MJ, Willart MA, Hammad H et al (2013) Cytokine targets in airway inflammation. Curr Opin Pharmacol 13:351–361

    Article  CAS  PubMed  Google Scholar 

  • Schwarz EM, Proulx ST, Ritchlin CT et al (2010) The role of bone marrow edema and lymphangiogenesis in inflammatory-erosive arthritis. Adv Exp Med Biol 658:1–10

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Secker GA, Harvey NL (2015) VEGFR signaling during lymphatic vascular development: from progenitor cells to functional vessels. Dev Dyn 244:323–331

    Article  CAS  PubMed  Google Scholar 

  • Shapira I, Sultan KS, Taioli E et al (2011) Role of myeloid derived hematopoietic cells in inflammation and immune tolerance to cancer. OncoReviews 1:1–12

    Google Scholar 

  • Shimamura K, Nakatani T, Ueda A et al (2009) Relationship between lymphangiogenesis and exudates during the wound-healing process of mouse skin full-thickness wound. Wound Repair Regen 17:598–605

    Article  PubMed  Google Scholar 

  • Shimoda H, Kato S (2006) A model for lymphatic regeneration in tissue repair of the intestinal muscle coat. Int Rev Cytol 250:73–108

    Article  CAS  PubMed  Google Scholar 

  • Shirasuna K, Nitta A, Sineenard J et al (2012) Vascular and immune regulation of corpus luteum development, maintenance, and regression in the cow. Domest Anim Endocrinol 43:198–211

    Article  CAS  PubMed  Google Scholar 

  • Shoyinka SV, Emehelu CO, Ezeibe MC (2005) Malignant mastocytoma in a Nigerian local dog. Nigerian Vet J 26:45–50

    Google Scholar 

  • Shukla S, Shukla H, Kumar S et al (2013) Allergy and inflammation: an immunological and therapeutic approach. Recent Pat Inflamm Allergy Drug Discov 7:135–150

    Article  CAS  PubMed  Google Scholar 

  • Soucek L, Lawlor ER, Soto D et al (2007) Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat Med 13:1211–1218

    Article  CAS  PubMed  Google Scholar 

  • Takaya R, Fukaya T, Sasano H et al (1997) Macrophages in normal cycling human ovaries: immunohistochemical localization and characterization. Hum Reprod 127:1508–1512

    Article  Google Scholar 

  • Tammela T, Zarkada G, Wallgard E et al (2008) Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454:656–660

    Article  CAS  PubMed  Google Scholar 

  • Tammela T, Zarkada G, Nurmi H et al (2011) VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nat Cell Biol 13:1202–1213

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tan KW, Chong SZ, Wong FH et al (2013) Neutrophils contribute to inflammatory lymphangiogenesis by increasing VEGF-A bioavailability and secreting VEGF-D. Blood 122:3666–3677

    Article  CAS  PubMed  Google Scholar 

  • Tan YZ, Wang HJ, Zhang MH et al (2014) CD34+VEGFR-3+ progenitor cells have a potential to differentiate towards lymphatic endothelial cells. J Cell Mol Med 18:422–433

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Teijeira Á, Palazón A, Garasa S et al (2012) CD137 on inflamed lymphatic endothelial cells enhances CCL21-guided migration of dendritic cells. FASEB J 26:3380–3392

    Article  CAS  PubMed  Google Scholar 

  • Theoharides TC, Alysandratos KD, Angelidou A et al (2012) Mast cells and inflammation. Biochim Biophys Acta 1822:21–33

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Vacca A, Ria R, Ribatti D et al (2003) A paracrine loop in the vascular endothelial growth factor pathway triggers tumor angiogenesis and growth in multiple myeloma. Haematologica 88:176–185

    CAS  PubMed  Google Scholar 

  • Van’t Hull EF, Bron S, Henry L et al (2014) Bone marrow-derived cells are implicated as a source of lymphatic endothelial progenitors in human breast cancer. Oncoimmunology 3:e29080

    Article  PubMed Central  PubMed  Google Scholar 

  • Vigl B, Aebischer D, Nitschké M et al (2011) Tissue inflammation modulates gene expression of lymphatic endothelial cells and dendritic cell migration in a stimulus-dependent manner. Blood 118:205–215

    Article  CAS  PubMed  Google Scholar 

  • Xu F, Stouffer RL (2009) Existence of the lymphatic system in the primate corpus luteum. Lymphat Res Biol 7:159–168

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yiannakopoulou E (2012) Modulation of lymphangiogenesis: a new target for aspirin and other nonsteroidal anti-inflammatory agents? A systematic review. J Clin Pharmacol 52:1749–1754

    Article  CAS  PubMed  Google Scholar 

  • Yin N, Zhang N, Xu J et al (2011) Targeting lymphangiogenesis after islet transplantation prolongs islet allograft survival. Transplantation 92:25–30

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zarkada G, Heinolainen K, Makinen T et al (2015) VEGFR3 does not sustain retinal angiogenesis without VEGFR2. Proc Natl Acad Sci USA 112:761–766

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhang L, Giraudo E, Hoffman JA et al (2006) Lymphatic zip codes in premalignant lesions and tumors. Cancer Res 66:5696–5706

    Article  CAS  PubMed  Google Scholar 

  • Zhang Q, Lu Y, Proulx ST et al (2007) Increased lymphangiogenesis in joints of mice with inflammatory arthritis. Arthritis Res Ther 9:R118

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Zimmer JK, Dahdal S, Mühlfeld C et al (2010) Lymphangiogenesis is upregulated in kidneys of patients with multiple myeloma. Anat Rec 293:1497–1505

    Article  Google Scholar 

  • Zumsteg A, Christofori G (2012) Myeloid cells and lymphangiogenesis. Cold Spring Harb Perspect Med 2:a006494

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Zumsteg A, Baeriswyl V, Imaizumi N et al (2009) Myeloid cells contribute to tumor lymphangiogenesis. PLoS ONE 4:e7067

    Article  PubMed Central  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by UEFSCDI grant IDEAS 345/2011 and “Victor Babes” University of Medicine and Pharmacy Timisoara, Romania—internal research grant—Innovative Basic Research Program PIII-C1-CFI-2014/2015-02.

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Authors and Affiliations

  1. Department of Microscopic Morphology/Histology, Angiogenesis Research Center, “Victor Babes” University of Medicine and Pharmacy, Piata Eftimie Murgu 2, 300041, Timisoara, Romania

    Anca Maria Cimpean & Marius Raica

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  1. Anca Maria Cimpean
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  2. Marius Raica
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Correspondence to Anca Maria Cimpean.

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Cimpean, A.M., Raica, M. Lymphangiogenesis and Inflammation—Looking for the “Missing Pieces” of the Puzzle. Arch. Immunol. Ther. Exp. 63, 415–426 (2015). https://doi.org/10.1007/s00005-015-0349-7

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  • DOI: https://doi.org/10.1007/s00005-015-0349-7

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