Abstract
The cancer-promoting ligand vascular endothelial growth factor-C (VEGF-C) activates VEGF receptor-3 (VEGFR-3). The VEGF-C/VEGFR-3 axis is expressed by a range of human tumor cells in addition to lymphatic endothelial cells. Activating the VEGF-C/VEGFR-3 signaling enhances metastasis by promoting lymphangiogenesis and angiogenesis inside and around tumors. Stimulation of VEGF-C/VEGFR-3 signaling promotes tumor metastasis in tumors, such as ovarian, renal, pancreatic, prostate, lung, skin, gastric, colorectal, cervical, leukemia, mesothelioma, Kaposi sarcoma, and endometrial carcinoma. We discuss and update the role of VEGF-C/VEGFR-3 signaling in tumor development and the research is still needed to completely comprehend this multifunctional receptor.

Similar content being viewed by others
References
Achen MG, Jeltsch M, Kukk E, Mäkinen 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 USA 95(2):548–553. https://doi.org/10.1073/pnas.95.2.548
Alishekevitz D, Gingis-Velitski S, Kaidar-Person O, Gutter-Kapon L, Scherer SD, Raviv Z, Merquiol E et al (2014) Thalidomide suppresses breast cancer tumor growth by inhibiting tumor-associated macrophage accumulation in breast tumor-bearing mice. Clin Genitourin Cancer 15(4):105302. https://doi.org/10.1016/j.clgc.2015.12.014
Alishekevitz D, Gingis-Velitski S, Kaidar-Person O, Gutter-Kapon L, Scherer SD, Raviv Z, Merquiol E, Ben-Nun Y, Miller V, Rachman-Tzemah C, Timaner M, Mumblat Y, Ilan N, Loven D, Hershkovitz D, Satchi-Fainaro R, Blum G, Sleeman JP, Vlodavsky I, Shaked Y (2016) Macrophage-induced lymphangiogenesis and metastasis following paclitaxel chemotherapy is regulated by VEGFR3. Cell Rep 17(5):1344–1356. https://doi.org/10.1016/j.celrep.2016.09.083
Apte RS, Chen DS, Ferrara N (2019) VEGF in signaling and disease: beyond discovery and development. Cell 176(6):1248–1264. https://doi.org/10.1016/j.cell.2019.01.021
Arinaga M, Noguchi T, Takeno S, Chujo M, Miura T, Uchida Y (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(2):457–464
Baeyens N, Nicoli S, Coon BG, Ross TD, Van den Dries K, Han J, Lauridsen HM, Mejean CO, Eichmann A, Thomas JL, Humphrey JD, Schwartz MA (2015) Vascular remodeling is governed by a VEGFR3-dependent fluid shear stress set point. Elife 4:e04645
Ball SG, Shuttleworth CA, Kielty CM (2007) Vascular endothelial growth factor can signal through platelet-derived growth factor receptors. J Cell Biol 177(3):489–500. https://doi.org/10.1083/jcb.200608093. (Epub 2007 Apr 30)
Benedito R, Rocha SF, Woeste M, Zamykal M, Radtke F, Casanovas O, Duarte A, Pytowski B, Adams RH (2012) Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signaling. Nature 484:110–114
Brand TM, Iida M, Luthar N, Starr MM, Huppert EJ, Wheeler DL (2013) Nuclear EGFR as a molecular target in cancer. Radiother Oncol 108(3):370–377. https://doi.org/10.1016/j.radonc.2013.06.010. (Epub 2013 Jul 3. Erratum in: Radiother Oncol. 2019 Jan;130:195)
Cadamuro M, Brivio S, Mertens J, Vismara M, Moncsek A, Milani C, Fingas C et al (2019) Platelet-derived growth factor-D Enables liver myofibroblasts to promote tumor lymphangiogenesis in cholangiocarcinoma. J Hepatol 70(4):700–709. https://doi.org/10.1016/j.jhep.2018.12.004
Chang TM, Chu PY, Lin HY, Huang KW, Hung WC, Shan YS, Chen LT, Tsai HJ (2022) PTEN regulates invasiveness in pancreatic neuroendocrine tumors through DUSP19-mediated VEGFR3 dephosphorylation. J Biomed Sci 29(1):92. https://doi.org/10.1186/s12929-022-00875-2
Chaudary N, Milosevic M, Hill RP (2011) Suppression of vascular endothelial growth factor receptor 3 (VEGFR3) and vascular endothelial growth factor C (VEGFC) inhibits hypoxia-induced lymph node metastases in cervix cancer. Gynecol Oncol 123(2):393–400. https://doi.org/10.1016/j.ygyno.2011.07.006
Chen Z, Varney ML, Backora MW, Cowan K, Solheim JC, Talmadge JE, Singh RK (2005) Down-regulation of vascular endothelial cell growth factor-C expression using small interfering RNA vectors in mammary tumors inhibits tumor lymphangiogenesis and spontaneous metastasis and enhances survival. Cancer Res 65(19):9004–9011. https://doi.org/10.1158/0008-5472.CAN-05-0885
Coso S, Zeng Y, Opeskin K, Williams ED (2012) Vascular endothelial growth factor receptor-3 directly interacts with phosphatidylinositol 3-kinase to regulate lymphangiogenesis. PLoS ONE 7(6):e39558. https://doi.org/10.1371/journal.pone.0039558. (Epub 2012 Jun 22)
Davis JA, Koenig AL, Lubert A, Chestnut B, Liu F, Desai SP, Winkler T, Pociute K, Choi K, Sumanas S (2018) ETS transcription factor Etsrp/Etv2 is required for lymphangiogenesis and directly regulates Vegfr3/Flt4 expression. Dev Biol 440(1):40–52. https://doi.org/10.1016/j.ydbio.2018.05.003
Decio A, Taraboletti G, Patton V, Alzani R, Perego P, Fruscio R, Jürgensmeier JM, Giavazzi R, Belotti D (2014) Vascular endothelial growth factor C promotes ovarian carcinoma progression through paracrine and autocrine mechanisms. Am J Pathol 184(4):1050–1061. https://doi.org/10.1016/j.ajpath.2013.12.030
Dias S, Choy M, Alitalo K, Rafii S (2002) Vascular endothelial growth factor (VEGF)-C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy. Blood 99(6):2179–2184. https://doi.org/10.1182/blood.v99.6.2179
Dixelius J, Makinen T, Wirzenius M, Karkkainen MJ, Wernstedt C, Alitalo K, Claesson-Welsh L (2003) Ligand-induced vascular endothelial growth factor receptor-3 (VEGFR-3) heterodimerization with VEGFR-2 in primary lymphatic endothelial cells (LECs) regulates tyrosine phosphorylation sites. J Biol Chem 278:40973–40979
Duffy AM, Bouchier-Hayes DJ, Harmey JH (2000–2013) Vascular endothelial growth factor (VEGF) and its role in non-endothelial cells: autocrine signaling by VEGF. In: Madame Curie Bioscience Database [Internet]. Landes Bioscience, Austin. Available from: https://www.ncbi.nlm.nih.gov/books/NBK6482/
Filho L, Adhemar AM, Costa SMA, Schmitt FC (2005) VEGFR-3 expression in breast cancer tissue is not restricted to lymphatic vessels. Pathol Res Pract 201(2):93–99. https://doi.org/10.1016/j.prp.2004.11.008
Fischer I, Schulze S, Kuhn C, Friese K, Walzel H, Markert UR, Jeschke U (2009) Inhibiton of RET and JAK2 Signals and upregulation of VEGFR3 phosphorylation in vitro by galectin-1 in trophoblast tumor cells BeWo. Placenta 30(12):1078–1082. https://doi.org/10.1016/j.placenta.2009.10.003
Gauvrit S, Villasenor A, Strilic B, Kitchen P, Collins MM, Marin-Juez R, Guenther S, Maischein HM, Fukuda N, Canham MA, Brickman JM, Bogue CW, Jayaraman PS, Stainier DYR (2018) HHEX is a transcriptional regulator of the VEGFC/FLT4/PROX1 signaling axis during vascular development. Nat Commun 9:2704
Gogate PN, Kurenova EV, Ethirajan M, Liao J, Yemma M, Sen A, Pandey RK, Cance WG (2014) Targeting the C-terminal focal adhesion kinase scaffold in pancreatic cancer. Cancer Lett 353(2):281–289. https://doi.org/10.1016/j.canlet.2014.07.032
Gombos Z, Xu X, Chu CS, Zhang PJ, Acs G (2005) Peritumoral lymphatic vessel density and vascular endothelial growth factor C expression in early-stage squamous cell carcinoma of the uterine cervix. Clin Cancer Res 11(23):8364–8371. https://doi.org/10.1158/1078-0432.CCR-05-1238
Graziosi L, Mencarelli A, Santorelli C, Renga B, Cipriani S, Cavazzoni E, Palladino G et al (2012) Mechanistic role of P38 MAPK in gastric cancer dissemination in a rodent model peritoneal metastasis. Eur J Pharmacol 674(2–3):143–152. https://doi.org/10.1016/j.ejphar.2011.11.015
Hamada K, Oike Y, Takakura N, Ito Y, Jussila L, Dumont DJ, Alitalo K (2000) Suda T (2000) VEGF-C signaling pathways through VEGFR-2 AND VEGFR-3 in vasculoangiogenesis and hematopoiesis. Blood 96:3793–3800
Hanrahan V, Currie MJ, Gunningham SP, Morrin HR, Scott PA, Robinson BA, Fox SB (2003) The angiogenic switch for vascular endothelial growth factor (VEGF)-A, VEGF-B, VEGF-C, and VEGF-D in the adenoma-carcinoma sequence during colorectal cancer progression. J Pathol 200(2):183–194. https://doi.org/10.1002/path.1339
Hao S, Han W, Ji Y, Sun H, Shi H, Ma J, Yip J, Ding Y (2022) BANCR positively regulates the HIF-1α/VEGF-C/VEGFR-3 pathway in a hypoxic microenvironment to promote lymphangiogenesis in pancreatic cancer cells. Oncol Lett 24(6):422. https://doi.org/10.3892/ol.2022.13542
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(11):819–825. https://doi.org/10.1093/jnci/94.11.819
Hlophe YN, Joubert AM (2022) Vascular endothelial growth factor-C in activating vascular endothelial growth factor receptor-3 and chemokine receptor-4 in melanoma adhesion. J Cell Mol Med 26(23):5743–5754. https://doi.org/10.1111/jcmm.17571. (Epub 2022 Nov 17)
Hoshida T, Isaka N, Hagendoorn J, di Tomaso E, Chen YL, Pytowski B, Fukumura D, Padera TP, Jain RK (2006) Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications. Cancer Res 66(16):8065–8075. https://doi.org/10.1158/0008-5472.CAN-06-1392
Huang J, Mei H, Tang Z, Li J, Zhang X, Yixiang Lu, Huang F, Jin Q, Wang Z (2017) Triple-AmiRNA VEGFRs inhibition in pancreatic cancer improves the efficacy of chemotherapy through EMT regulation. J Control Release 245:1–14. https://doi.org/10.1016/j.jconrel.2016.11.024
Hughes DC (2001) Alternative splicing of the human VEGFGR-3/FLT4 gene as a consequence of an integrated human endogenous retrovirus. J Mol Evol 53:77–79
Jeltsch M, Karpanen T, Strandin T, Aho K, Lankinen H, Alitalo K (2006) Vascular endothelial growth factor (VEGF)/VEGF-C mosaic molecules reveal specificity determinants and feature novel receptor binding patterns. J Biol Chem 281(17):12187–12195. https://doi.org/10.1074/jbc.M511593200. (Epub 2006 Feb 27)
Jennbacken K, Vallbo C, Wang W, Damber J-E (2005) Expression of vascular endothelial growth factor C (VEGF-C) and VEGF receptor-3 in human prostate cancer is associated with regional lymph node metastasis. Prostate 65(2):110–116
Jha SK, Rauniyar K, Jeltsch M (2018) Key molecules in lymphatic development, function, and identification. Ann Anat 219:25–34. https://doi.org/10.1016/j.aanat.2018.05.003. (Epub 2018 May 26)
Jüttner S, Wiβmann C, Jöns T, Vieth M, Hertel J, Gretschel S, Schlag PM, Kemmner W, Höcker M (2006) Vascular endothelial growth factor-D and its receptor VEGFR-3: two novel independent prognostic markers in gastric adenocarcinoma. J Clin Oncol 24(2):228–240
Kojima H, Shijubo N, Yamada G, Ichimiya S, Abe S, Satoh M, Sato N (2005) Clinical significance of vascular endothelial growth factor-C and vascular endothelial growth factor receptor 3 in patients with T1 lung adenocarcinoma. Cancer 104(8):1668–1677
Koyama Y, Kaneko K, Akazawa K, Kanbayashi C, Kanda T, Hatakeyama K (2003) Vascular endothelial growth factor-C and vascular endothelial growth factor-D messenger RNA expression in breast cancer: association with lymph node metastasis. Clin Breast Cancer 4(5):354–360. https://doi.org/10.3816/cbc.2003.n.041
Lampinen AM, Virman JP, Bono P, Luukkaala TH, Sunela KL, Kujala PM, Saharinen P, Kellokumpu-Lehtinen PLI (2017) Novel angiogenesis markers as long-term prognostic factors in patients with renal cell cancer. Clin Genitourin Cancer 15(1):e15-24. https://doi.org/10.1016/j.clgc.2016.07.008
Leppänen VM, Tvorogov D, Kisko K, Prota AE, Jeltsch M, Anisimov A, Markovic-Mueller S, Stuttfeld E, Goldie KN, Ballmer-Hofer K, Alitalo K (2013) Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation. Proc Natl Acad Sci USA 110(32):12960–12965. https://doi.org/10.1073/pnas.1301415110. (Epub 2013 Jul 22)
Li Q, Dong X, Wei Gu, Qiu X, Wang E (2003) Clinical significance of co-expression of VEGF-C and VEGFR-3 in non-small cell lung cancer. Chin Med J 116(05):727–730
Li R, Younes M, Wheeler TM, Scardino P, Ohori M, Frolov A, Ayala G (2004) Expression of vascular endothelial growth factor receptor-3 (VEGFR-3) in human prostate. Prostate 58(2):193–199
Lian L, Li XL, Xu MD, Li XM, Wu MY, Zhang Y, Tao M, Li W, Shen XM, Zhou C, Jiang M (2019) VEGFR2 promotes tumorigenesis and metastasis in a pro-angiogenic-independent way in gastric cancer. BMC Cancer 19(1):183. https://doi.org/10.1186/s12885-019-5322-0
Lim J, Yang K, Barbie Taylor-Harding W, Wiedemeyer R, Buckanovich RJ (2014) VEGFR3 inhibition chemosensitizes ovarian cancer stemlike cells through down-regulation of BRCA1 and BRCA2. Neoplasia (united States) 16(4):343-353.e2. https://doi.org/10.1016/j.neo.2014.04.003
Lin Y, Zhai E, Liao B, Xu L, Zhang X, Peng S, He Y, Cai S, Zeng Z, Chen M (2017) Autocrine VEGF signaling promotes cell proliferation through a PLC-dependent pathway and modulates Apatinib treatment efficacy in gastric cancer. Oncotarget 8(7):11990–12002. https://doi.org/10.18632/oncotarget.14467
Marchio S, Primo L, Pagano M, Palestro G, Albini A, Veikkola T, Cascone I, Alitalo K, Bussolino F (1999) Vascular endothelial growth factor-C stimulates the migration and proliferation of Kaposi’s sarcoma cells. J Biol Chem 274(39):27617–27622. https://doi.org/10.1074/jbc.274.39.27617
Martins SF, Garcia EA, Luz MA, Pardal F, Rodrigues M, Filho AL (2013) Clinicopathological correlation and prognostic significance of VEGF-A, VEGF-C, VEGFR-2 and VEGFR-3 expression in colorectal cancer. Cancer Genomics Proteomics 10(2):55–67
Maruyama K, Ii M, Cursiefen C, Jackson DG, Keino H, Tomita M, Van Rooijen N, Takenaka H, D’Amore PA, Stein-Streilein J, Losordo DW, Streilein JW (2005) Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages. J Clin Invest 115(9):2363–2372. https://doi.org/10.1172/JCI23874
Masood R, Kundra A, Zhu ST, Xia G, Pierluigi Scalia D, Smith L, Gill PS (2003) Malignant mesothelioma growth inhibition by agents that target the VEGF and VEGF-C autocrine loops. Int J Cancer 104(5):603–610. https://doi.org/10.1002/ijc.10996
Miller B, Sewell-Loftin MK (2022) Mechanoregulation of vascular endothelial growth factor receptor 2 in angiogenesis. Front Cardiovasc Med 8:804934. https://doi.org/10.3389/fcvm.2021.804934
Moe K, Heidecke H, Dechend R, Staff AC (2017) Dysregulation of circulating autoantibodies against VEGF-A, VEGFR-1 and PlGF in preeclampsia—a role in placental and vascular health? Pregnancy Hypertens 10:83–89. https://doi.org/10.1016/j.preghy.2017.06.002. (Epub 2017 Jun 27)
Monaghan RM, Page DJ, Ostergaard P, Keavney BD (2021) The physiological and pathological functions of VEGFR3 in cardiac and lymphatic development and related diseases. Cardiovasc Res 117(8):1877–1890. https://doi.org/10.1093/cvr/cvaa291
Moser A, Range K, York DM, Manuscript A (2008) The small molecule chloropyramine hydrochloride (C4) targets the binding site of focal adhesion kinase and vascular endothelial growth factor receptor 3 and suppresses breast cancer growth in vivo. Bone 23(1):1–7. https://doi.org/10.1021/jm900159g.The
Neuchrist C, Erovic BM, Handisurya A, Fischer MB, Steiner GE, Hollemann D, Gedlicka C, Saaristo A, Burian M (2003) Vascular endothelial growth factor c and vascular endothelial growth factor receptor 3 expression in squamous cell carcinomas of the head and neck. Head Neck J Sci Spec Head Neck 25(6):464–474
Ong HS, Gokavarapu S, Xu Q, Tian Z, Li J, Ji T, Zhang CP (2017) Cytoplasmic neuropilin 2 is associated with metastasis and a poor prognosis in early tongue cancer patients. Int J Oral Maxillofac Surg 46(10):1205–1219. https://doi.org/10.1016/j.ijom.2017.03.035
Onimaru M, Yonemitsu Y (2011) Angiogenic and lymphangiogenic cascades in the tumor microenvironment. Front Biosci (schol Ed) 3(1):216–225. https://doi.org/10.2741/s146
Pak KH, Park KC, Cheong JH (2019) VEGF-C induced by TGF-β1 signaling in gastric cancer enhances tumor-induced lymphangiogenesis. BMC Cancer 19(1):799. https://doi.org/10.1186/s12885-019-5972-y
Pan MR, Chang TM, Chang HC, Su JL, Wang HW, Hung WC (2009) Sumoylation of Prox1 controls its ability to induce VEGFR3 expression and lymphatic phenotypes in endothelial cells. J Cell Sci 122(Pt 18):3358–3364. https://doi.org/10.1242/jcs.050005. (Epub 2009 Aug 25)
Peach CJ, Mignone VW, Arruda MA, Alcobia DC, Hill SJ, Kilpatrick LE, Woolard J (2018) Molecular pharmacology of VEGF-A isoforms: binding and signaling at VEGFR2. Int J Mol Sci 19(4):1264. https://doi.org/10.3390/ijms19041264
Pentheroudakis G, Nicolaou I, Kotoula V, Fountzilas E, Markou K, Eleftheraki AG, Fragkoulidi A et al (2012) Prognostic utility of angiogenesis and hypoxia effectors in patients with operable squamous cell cancer of the larynx. Oral Oncol 48(8):709–716. https://doi.org/10.1016/j.oraloncology.2012.02.002
Saharinen P, Helotera H, Miettinen J, Norrmen C, D’Amico G, Jeltsch M, Langenberg T, Vandevelde W, Ny A, Dewerchin M, Carmeliet P, Alitalo K (2010) Claudin-like protein 24 interacts with the VEGFR-2 and VEGFR-3 pathways and regulates lymphatic vessel development. Genes Dev 24:875–880
Saif MW, Knost JA, Gabriela Chiorean E, Kambhampati SRP, Danni Yu, Pytowski B, Qin A, Kauh JS, O’Neil BH (2016) Phase 1 study of the anti-vascular endothelial growth factor receptor 3 monoclonal antibody LY3022856/IMC-3C5 in patients with advanced and refractory solid tumors and advanced colorectal cancer. Cancer Chemother Pharmacol 78(4):815–824. https://doi.org/10.1007/s00280-016-3134-3
Sarkar J, Luo Y, Zhou Q, Ivakhnitskaia E, Lara D, Katz E, Sun MG, Guaiquil V, Rosenblatt M (2022) VEGF receptor heterodimers and homodimers are differentially expressed in neuronal and endothelial cell types. PLoS ONE 17(7):e0269818. https://doi.org/10.1371/journal.pone.0269818
Schoppmann SF, Fenzl A, Nagy K, Unger S, Bayer G, Geleff S, Gnant M, Horvat R, Jakesz R, Birner P (2006) VEGF-C expressing tumor-associated macrophages in lymph node positive breast cancer: impact on lymphangiogenesis and survival. Surgery 139(6):839–846. https://doi.org/10.1016/j.surg.2005.12.008
Shah AA, Kamal MA, Akhtar S (2021) Tumor angiogenesis and VEGFR-2: mechanism, pathways and current biological therapeutic interventions. Curr Drug Metab 22(1):50–59. https://doi.org/10.2174/1389200221666201019143252
Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, Riccardi L, Alitalo K, Claffey K, Detmar M (2001) Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 7(2):192–198. https://doi.org/10.1038/84643
Su J-L, Yang P-C, Shih J-Y, Yang C-Y, Wei L-H, Hsieh C-Y, Chou C-H, Jeng Y-M, Wang M-Y, Chang K-J (2006) The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells. Cancer Cell 9(3):209–223
Su JL, Yen CJ, Chen PS, Chuang SE, Hong CC, Kuo IH, Chen HY, Hung MC, Kuo ML (2007) The role of the VEGF-C/VEGFR-3 axis in cancer progression. Br J Cancer 96(4):541–545. https://doi.org/10.1038/sj.bjc.6603487. (Epub 2006 Dec 12)
Suksawat M, Techasen A, Namwat N, Yongvanit P, Khuntikeo N, Titapun A, Koonmee S, Loilome W (2017) Upregulation of endothelial nitric oxide synthase (ENOS) and its upstream regulators in opisthorchis viverrini associated cholangiocarcinoma and its clinical significance. Parasitol Int 66(4):486–493. https://doi.org/10.1016/j.parint.2016.04.008
Suzuki H, Watabe T, Kato M, Miyazawa K, Miyazono K (2005) Roles of vascular endothelial growth factor receptor 3 signaling in differentiation of mouse embryonic stem cell-derived vascular progenitor cells into endothelial cells. Blood 105:2372–2379
Tacconi C, Correale C, Gandelli A, Spinelli A, Dejana E, D’Alessio S, Danese S (2015) Vascular endothelial growth factor C disrupts the endothelial lymphatic barrier to promote colorectal cancer invasion. Gastroenterology 148(7):1438-1451.e8. https://doi.org/10.1053/j.gastro.2015.03.005
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
Torres-Ruiz S, Tormo E, Garrido-Cano I, Lameirinhas A, Rojo F, Madoz-Gúrpide J, Burgués O, Hernando C, Bermejo B, Martínez MT, Lluch A, Cejalvo JM, Eroles P (2023) High VEGFR3 expression reduces doxorubicin efficacy in triple-negative breast cancer. Int J Mol Sci 24(4):3601. https://doi.org/10.3390/ijms24043601
Tvorogov D, Anisimov A, Zheng W, Leppanen VM, Tammela T, Laurinavicius S, Holnthoner W, Helotera H, Holopainen T, Jeltsch M, Kalkkinen N, Lankinen H, Ojala PM, Alitalo K (2010) Effective suppression of vascular network formation by combination of antibodies blocking VEGFR ligand binding and receptor dimerization. Cancer Cell 18:630–640
Uemura A, Fruttiger M, D’Amore PA, De Falco S, Joussen AM, Sennlaub F, Brunck LR, Johnson KT, Lambrou GN, Rittenhouse KD, Langmann T (2021) VEGFR1 signaling in retinal angiogenesis and microinflammation. Prog Retin Eye Res 84:100954. https://doi.org/10.1016/j.preteyeres.2021.100954. (Epub 2021 Feb 25)
Valiulienė G, Vitkevičienė A, Navakauskienė R (2020) The epigenetic treatment remodel genome-wide histone H4 hyper-acetylation patterns and affect signaling pathways in acute promyelocytic leukemia cells. Eur J Pharmacol. https://doi.org/10.1016/j.ejphar.2020.173641
Van Trappen PO, Steele D, Lowe DG, Baithun S, Beasley N, Thiele W, Weich H, Krishnan J, Shepherd JH, Pepper MS (2003) Expression of vascular endothelial growth factor (VEGF)-C and VEGF-D, and their receptor VEGFR-3, during different stages of cervical carcinogenesis. J Pathol 201(4):544–554. https://doi.org/10.1002/path.1467
Virman JP, Bono P, Luukkaala TH, Sunela KL, Kujala PM, Kellokumpu-Lehtinen PLI (2016) Combined angiogenesis and proliferation markers’ expressions as long-term prognostic factors in renal cell cancer. Clin Genitourin Cancer 14(4):e283–e289. https://doi.org/10.1016/j.clgc.2015.12.014
Wang J, Taylor A, Showeil R, Trivedi P, Horimoto Y, Bagwan I, Ewington L, Lam EWF, El-Bahrawy MA (2014) Expression profiling and significance of VEGF-A, VEGFR2, VEGFR3 and related proteins in endometrial carcinoma. Cytokine 68(2):94–100. https://doi.org/10.1016/j.cyto.2014.04.005
Wang QS, He R, Yang F, Kang LJ, Li XQ, Li Fu, Sun B, Feng YM (2018) FOXF2 deficiency permits basal-like breast cancer cells to form lymphangiogenic mimicry by enhancing the response of VEGF-C/VEGFR3 signaling pathway. Cancer Lett 420:116–126. https://doi.org/10.1016/j.canlet.2018.01.069
Wang X, Tang L, Zhang Z, Li W, Chen Y (2020) Keratocytes promote corneal neovascularization through VEGFr3 induced by PPARα-inhibition. Exp Eye Res 193:107982. https://doi.org/10.1016/j.exer.2020.107982
Weninger W, Partanen TA, Breiteneder-Geleff S, Mayer C, Kowalski H, Mildner M, Pammer J, Stürzl M, Kerjaschki D, Alitalo K, Tschachler E (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 79(2):243–251
Witte D, Thomas A, Ali N, Carlson N, Younes M (2002) Expression of the vascular endothelial growth factor receptor-3 (VEGFR-3) and its ligand VEGF-C in human colorectal adenocarcinoma. Anticancer Res 22(3):1463–1466
Xu Y, Yuan L, Mak J, Pardanaud L, Caunt M, Kasman I, Larrivée B, Del Toro R, Suchting S, Medvinsky A, Silva J, Yang J, Thomas JL, Koch AW, Alitalo K, Eichmann A, Bagri A (2010) Neuropilin-2 mediates VEGF-C-induced lymphatic sprouting together with VEGFR3. J Cell Biol 188(1):115–130. https://doi.org/10.1083/jcb.200903137
Yang GL, Li LY (2018) Counterbalance: modulation of VEGF/VEGFR activities by TNFSF15. Signal Transduct Target Ther 10(3):21. https://doi.org/10.1038/s41392-018-0023-8
Yang J, Hong-Fei Wu, Qian L-X, Zhang W, Hua L-X, Mei-Lin Yu, Wang Z, Zheng-Quan Xu, Sui Y-G, Wang X-R (2006) Increased expressions of vascular endothelial growth factor (VEGF), VEGF-C and VEGF receptor-3 in prostate cancer tissue are associated with tumor progression. Asian J Androl 8(2):169–175
Yokoyama Y, Stephen Charnock-Jones D, Licence D, Yanaihara A, Hastings JM, Holland CM, Emoto M, Sakamoto A, Sakamoto T, Maruyama H (2003) Expression of vascular endothelial growth factor (VEGF)-D and its receptor, VEGF receptor 3, as a prognostic factor in endometrial carcinoma. Clin Cancer Res 9(4):1361–1369
Yonemura Y, Fushida S, Bando E, Kinoshita K, Miwa K, Endo Y, Sugiyama K, Partanen T, Yamamoto H, Sasaki T (2001) Lymphangiogenesis and the vascular endothelial growth factor receptor (VEGFR)-3 in gastric cancer. Eur J Cancer 37(7):918–923. https://doi.org/10.1016/S0959-8049(01)00015-6
Zarkada G, Heinolainen K, Makinen T, Kubota Y, Alitalo K (2015) VEGFR3 does not sustain retinal angiogenesis without VEGFR2. Proc Natl Acad Sci USA 112:761–766
Zhan P, Wang J, Lv XJ, Wang Q, Qiu LX, Lin XQ, Li Ke Yu, Song Y (2009) Prognostic value of vascular endothelial growth factor expression in patients with lung cancer: a systematic review with meta-analysis. J Thorac Oncol 4(9):1094–1103. https://doi.org/10.1097/JTO.0b013e3181a97e31
Zhang X, Zheng Z, Shin YK, Kim KY, Rha SY, Noh SH, Chung HC, Jeung HC (2014) Angiogenic factor thymidine phosphorylase associates with angiogenesis and lymphangiogenesis in the intestinal-type gastric cancer. Pathology 46(4):316–324. https://doi.org/10.1097/PAT.0000000000000094
Zhang P, He D, Chen Z, Pan Q, Fangfang Du, Zang X, Wang Y et al (2016) Chemotherapy enhances tumor vascularization via notch signaling-mediated formation of tumor-derived endothelium in breast cancer. Biochem Pharmacol 118:18–30. https://doi.org/10.1016/j.bcp.2016.08.008
Zhou J, He Z, Guo Le, Zeng J, Liang P, Ren L, Zhang M, Zhang P, Huang X (2018) MiR-128-3p directly targets VEGFC/VEGFR3 to modulate the proliferation of lymphatic endothelial cells through Ca2+ signaling. Int J Biochem Cell Biol 102:51–58. https://doi.org/10.1016/j.biocel.2018.05.006
Acknowledgements
This work was supported by the Department of Science and Technology, Science and Engineering Research Board (SERB) - Research Scientist Scheme, Government of India for the research Grant to S. Vimalraj (Grant no. SB/SRS/2022-23/109/LS). The authors acknowledge the Researchers Supporting Project Number (RSPD2023R674), King Saud University, Riyadh, Saudi Arabia for funding this research work.
Author information
Authors and Affiliations
Contributions
SV: conceptualization, methodology, writing—original draft preparation, supervision, and validation. KNGH, MR, PG, KP, SS, and DG: original draft preparation.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Vimalraj, S., Hariprabu, K.N.G., Rahaman, M. et al. Vascular endothelial growth factor-C and its receptor-3 signaling in tumorigenesis. 3 Biotech 13, 326 (2023). https://doi.org/10.1007/s13205-023-03719-4
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s13205-023-03719-4