{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T16:19:00Z","timestamp":1777997940257,"version":"3.51.4"},"reference-count":68,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T00:00:00Z","timestamp":1632787200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Malignant melanoma is one of the most aggressive skin cancers and is characterized by early lymph node metastasis and the capacity to develop resistance to therapies. Hence, understanding the regulation of lymphangiogenesis through mechanisms contributing to lymphatic vessel formation represents a treatment strategy for metastatic cancer. We have previously shown that CD147, a transmembrane glycoprotein overexpressed in melanoma, regulates the angiogenic process in endothelial cells. In this study, we show a correlation between high CD147 expression levels and the number of lymphatic vessels expressing LYVE-1, Podoplanin, and VEGFR-3 in human melanoma lymph nodes. CD147 upregulates in vitro lymphangiogenesis and its related mediators through the PROX-1 transcription factor. In vivo studies in a melanoma model confirmed that CD147 is involved in metastasis through a similar mechanism as in vitro. This study, demonstrating the paracrine role of CD147 in the lymphangiogenesis process, suggests that CD147 could be a promising target for the inhibition of melanoma-associated lymphangiogenesis.<\/jats:p>","DOI":"10.3390\/cancers13194859","type":"journal-article","created":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T12:29:14Z","timestamp":1632832154000},"page":"4859","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["CD147 Promotes Tumor Lymphangiogenesis in Melanoma via PROX-1"],"prefix":"10.3390","volume":"13","author":[{"given":"Coralie","family":"Reger de Moura","sequence":"first","affiliation":[{"name":"Inserm, UMR_S976, Universit\u00e9 de Paris, 75010 Paris, France"},{"name":"Pharmacogenomics Department, Saint Louis Hospital, AP-HP, 75010 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra","family":"Landras","sequence":"additional","affiliation":[{"name":"Inserm, UMR_S976, Universit\u00e9 de Paris, 75010 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Farah","family":"Khayati","sequence":"additional","affiliation":[{"name":"Inserm, UMR_S976, Universit\u00e9 de Paris, 75010 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Uwe","family":"Maskos","sequence":"additional","affiliation":[{"name":"Neurobiologie Int\u00e9grative des Syst\u00e8mes Cholinergiques, Institut Pasteur, Universit\u00e9 de Paris, CNRS, UMR_3571, 75724 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kamel","family":"Maouche","sequence":"additional","affiliation":[{"name":"Biology and Pathology of the Endocrine Pancreas, Universit\u00e9 de Paris, CNRS, UMR_8251, 75013 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maxime","family":"Battistella","sequence":"additional","affiliation":[{"name":"Inserm, UMR_S976, Universit\u00e9 de Paris, 75010 Paris, France"},{"name":"Pathology Department, Saint Louis Hospital, AP-HP, 75010 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suzanne","family":"Menashi","sequence":"additional","affiliation":[{"name":"Pharmacogenomics Department, Saint Louis Hospital, AP-HP, 75010 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C\u00e9leste","family":"Lebb\u00e9","sequence":"additional","affiliation":[{"name":"Inserm, UMR_S976, Universit\u00e9 de Paris, 75010 Paris, France"},{"name":"Dermatology Department, Saint Louis Hospital, AP-HP, 75010 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samia","family":"Mourah","sequence":"additional","affiliation":[{"name":"Inserm, UMR_S976, Universit\u00e9 de Paris, 75010 Paris, France"},{"name":"Pharmacogenomics Department, Saint Louis Hospital, AP-HP, 75010 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1177\/1947601911423028","article-title":"Lymphangiogenesis and Cancer","volume":"2","author":"Christiansen","year":"2011","journal-title":"Genes Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1387\/ijdb.103226ia","article-title":"Molecular mechanisms of lymphangiogenesis in development and cancer","volume":"55","author":"Albrecht","year":"2011","journal-title":"Int. J. Dev. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1158\/1078-0432.CCR-06-1324","article-title":"Determination of Microvessel Density by Quantitative Real-time PCR in Esophageal Cancer: Correlation with Histologic Methods, Angiogenic Growth Factor Expression, and Lymph Node Metastasis","volume":"13","author":"Loges","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Coso, S., Zeng, Y., Opeskin, K., and Williams, E.D. (2012). Vascular Endothelial Growth Factor Receptor-3 Directly Interacts with Phosphatidylinositol 3-Kinase to Regulate Lymphangiogenesis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0039558"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1182\/blood-2006-05-021758","article-title":"VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites","volume":"109","author":"Hirakawa","year":"2007","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1096\/fj.01-0945rev","article-title":"The role of tumor lymphangiogenesis in metastatic spread","volume":"16","author":"Stacker","year":"2002","journal-title":"FASEB J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"19420","DOI":"10.1074\/jbc.M011004200","article-title":"Mouse LYVE-1 Is an Endocytic Receptor for Hyaluronan in Lymphatic Endothelium","volume":"276","author":"Prevo","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_8","first-page":"270","article-title":"Podoplanin\u2014A specific marker for lymphatic endothelium expressed in angiosarcoma","volume":"83","author":"Soleiman","year":"1999","journal-title":"Verh. Dtsch. Ges. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.2353\/ajpath.2010.090703","article-title":"Tumor Lymphangiogenesis and Metastasis to Lymph Nodes Induced by Cancer Cell Expression of Podoplanin","volume":"177","author":"Cueni","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"18746","DOI":"10.1073\/pnas.1318346110","article-title":"BMP-9 balances endothelial cell fate","volume":"110","author":"Derynck","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/S0092-8674(00)81511-1","article-title":"Prox1 Function Is Required for the Development of the Murine Lymphatic System","volume":"98","author":"Wigle","year":"1999","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1016\/S0002-9440(10)64328-3","article-title":"Tumor Lymphangiogenesis: A novel prognostic indicator for cutaneous melanoma metastasis and survival","volume":"162","author":"Dadras","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1111\/j.1600-0560.2012.01955.x","article-title":"Expression of vascular endothelial growth factor-C in primary cutaneous melanoma predicts sentinel lymph node positivity","volume":"39","author":"Cianfarani","year":"2012","journal-title":"J. Cutan. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1111\/j.1600-0560.2008.01166.x","article-title":"Lymphatic invasion in cutaneous melanoma is associated with sentinel lymph node metastasis","volume":"36","author":"Doeden","year":"2009","journal-title":"J. Cutan. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1111\/cup.12571","article-title":"Peritumoral D2-40 Chalkley score independently predicts metastases and survival in patients with cutaneous malignant melanoma","volume":"42","author":"Pastushenko","year":"2015","journal-title":"J. Cutan. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1002\/1878-0261.12501","article-title":"Gene expression and promoter methylation of angiogenic and lymphangiogenic factors as prognostic markers in melanoma","volume":"13","author":"Monteiro","year":"2019","journal-title":"Mol. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1016\/j.ejca.2008.12.015","article-title":"Tumoural expression and circulating level of VEGFR-3 (Flt-4) in metastatic melanoma patients: Correlation with clinical parameters and outcome","volume":"45","author":"Mouawad","year":"2009","journal-title":"Eur. J. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Suresh, R., Ziemys, A., and Holder, A.M. (2020). Dissecting the Lymphatic System to Predict Melanoma Metastasis. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.576190"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1080\/17843286.2019.1629076","article-title":"Survival prediction in patients with cutaneous melanoma by tumour lymphangiogenesis","volume":"75","year":"2020","journal-title":"Acta Clin. Belg."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"9766","DOI":"10.18632\/oncotarget.2870","article-title":"EMMPRIN\/CD147 is a novel coreceptor of VEGFR-2 mediating its activation by VEGF","volume":"6","author":"Khayati","year":"2015","journal-title":"Oncotarget"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5547","DOI":"10.1182\/blood-2009-04-217380","article-title":"EMMPRIN promotes angiogenesis through hypoxia-inducible factor-2\u03b1\u2013mediated regulation of soluble VEGF isoforms and their receptor VEGFR-2","volume":"114","author":"Bougatef","year":"2009","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Landras, A., de Moura, C.R., Jouenne, F., Lebbe, C., Menashi, S., and Mourah, S. (2019). CD147 is a promising target of tumor progres-sion and a prognostic biomarker. Cancers, 11.","DOI":"10.3390\/cancers11111803"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1111\/exd.13022","article-title":"EMMPRIN\/CD147 is an independent prognostic biomarker in cutaneous melanoma","volume":"25","author":"Caudron","year":"2016","journal-title":"Exp. Dermatol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Liu, B., Wan, Z., Sheng, B., Lin, Y., Fu, T., Zeng, Q., and Qi, C. (2017). Overexpression of EMMPRIN is associated with lymph node metastasis and advanced stage of non-small cell lung cancer: A retrospective study. BMC Pulm. Med., 17.","DOI":"10.1186\/s12890-017-0540-1"},{"key":"ref_25","first-page":"4280","article-title":"CD147 promotes cervical cancer migration and invasion by up-regulating fatty acid synthase expression","volume":"12","author":"Guo","year":"2019","journal-title":"Int J Clin Exp Pathol"},{"key":"ref_26","first-page":"85","article-title":"Establishment and characterization of a human melanoma cell line (MV3) which is highly metastatic in nude mice","volume":"48","author":"Jansen","year":"2007","journal-title":"Int. J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/BF01753729","article-title":"Antigen expression of metastasizing and non-metastasizing human melanoma cells xenografted into nude mice","volume":"9","author":"Cornelissen","year":"1991","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_28","first-page":"103","article-title":"Cell Membrane Vesicles as a Tool for the Study of Direct Epithelial\u2013Stromal Interaction: Lessons from CD147","volume":"1066","author":"Gabison","year":"2013","journal-title":"Adv. Struct. Saf. Stud."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/S0002-9440(10)62245-6","article-title":"Differential Expression of Extracellular Matrix Metalloproteinase Inducer (CD147) in Normal and Ulcerated Corneas: Role in Epithelio-Stromal Interactions and Matrix Metalloproteinase Induction","volume":"166","author":"Gabison","year":"2005","journal-title":"Am. J. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1152\/physrev.00005.2002","article-title":"Vascular Growth Factors and Lymphangiogenesis","volume":"82","author":"Jussila","year":"2002","journal-title":"Physiol. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/S0002-9440(10)65285-6","article-title":"Angiosarcomas Express Mixed Endothelial Phenotypes of Blood and Lymphatic Capillaries: Podoplanin as a Specific Marker for Lymphatic Endothelium","volume":"154","author":"Soleiman","year":"1999","journal-title":"Am. J. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Stump, B., Shrestha, S., LaMattina, A.M., Louis, P.H., Cho, W., Perrella, M.A., Ai, X., Rosas, I.O., Wagner, F.F., and Priolo, C. (2019). Glycogen synthase kinase 3-\u03b2 inhibition induces lymphangiogenesis through \u03b2-catenin-dependent and mTOR-independent pathways. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0213831"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Shi, F., Wang, Y.-C., Zhao, T.-Z., Zhang, S., Du, T.-Y., Yang, C.-B., Li, Y.-H., and Sun, X.-Q. (2012). Effects of Simulated Microgravity on Human Umbilical Vein Endothelial Cell Angiogenesis and Role of the PI3K-Akt-eNOS Signal Pathway. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0040365"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"E231","DOI":"10.1038\/35046659","article-title":"Paxillin and focal adhesion signalling","volume":"2","author":"Turner","year":"2000","journal-title":"Nat. Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1007\/s10456-013-9386-1","article-title":"Src contributes to IL6-induced vascular endothelial growth factor-C expression in lymphatic endothelial cells","volume":"17","author":"Huang","year":"2014","journal-title":"Angiogenesis"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Huang, Y.-H., Yang, H.-Y., Huang, S.-W., Ou, G., Hsu, Y.-F., and Hsu, M.-J. (2016). Interleukin-6 Induces Vascular Endothelial Growth Factor-C Expression via Src-FAK-STAT3 Signaling in Lymphatic Endothelial Cells. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0158839"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S0092-8674(00)00116-1","article-title":"Signal Transduction by the JNK Group of MAP Kinases","volume":"103","author":"Davis","year":"2000","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4739","DOI":"10.1038\/s41598-019-41299-7","article-title":"Non-canonical WNT-signaling controls differentiation of lymphatics and extension lymphangiogenesis via RAC and JNK signaling","volume":"9","author":"Lutze","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_39","unstructured":"Lockshin, A., Giovanella, B.C., De Ipolyi, P.D., Williams, L.J., Mendoza, J.T., O Yim, S., and Stehlin, J.S. (1985). Exceptional lethality for nude mice of cells derived from a primary human melanoma. Cancer Res., 45."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1111\/j.0022-202X.2004.22531.x","article-title":"Truncation of Activated Leukocyte Cell Adhesion Molecule: A Gateway to Melanoma Metastasis","volume":"122","author":"Meier","year":"2004","journal-title":"J. Investig. Dermatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1002\/1097-0215(200102)9999:9999<::AID-IJC1173>3.0.CO;2-L","article-title":"The pattern of metastasis of human melanoma to the central nervous system is not influenced by integrin \u03b1v\u03b23 expression","volume":"92","author":"Westphal","year":"2001","journal-title":"Int. J. Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.bbrc.2016.08.017","article-title":"Blockade of FLT4 suppresses metastasis of melanoma cells by impaired lymphatic vessels","volume":"478","author":"Lee","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2997","DOI":"10.1038\/sj.onc.1210114","article-title":"Chemokine-mediated migration of melanoma cells towards lymphatics\u2014A mechanism contributing to metastasis","volume":"26","author":"Shields","year":"2006","journal-title":"Oncogene"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/s41586-020-2623-z","article-title":"Lymph protects metastasizing melanoma cells from ferroptosis","volume":"585","author":"Ubellacker","year":"2020","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1800","DOI":"10.1002\/ijc.22062","article-title":"High incidence of EMMPRIN expression in human tumors","volume":"119","author":"Riethdorf","year":"2006","journal-title":"Int. J. Cancer"},{"key":"ref_46","first-page":"55","article-title":"The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily","volume":"55","author":"Biswas","year":"1995","journal-title":"Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4187","DOI":"10.1111\/febs.13414","article-title":"Soluble extracellular matrix metalloproteinase inducer (EMMPRIN, EMN) regulates cancer-related cellular functions by homotypic interactions with surface CD147","volume":"282","author":"Knutti","year":"2015","journal-title":"FEBS J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3193","DOI":"10.1158\/0008-5472.CAN-04-3605","article-title":"Extracellular Matrix Metalloproteinase Inducer Stimulates Tumor Angiogenesis by Elevating Vascular Endothelial Cell Growth Factor and Matrix Metalloproteinases","volume":"65","author":"Tang","year":"2005","journal-title":"Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"37576","DOI":"10.1074\/jbc.M606993200","article-title":"Membrane Type 1 Matrix Metalloproteinase (MT1-MMP\/MMP-14) Cleaves and Releases a 22-kDa Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) Fragment from Tumor Cells","volume":"281","author":"Egawa","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1111\/jgh.13148","article-title":"Circulating CD147 predicts mortality in advanced hepatocellular carcinoma","volume":"31","author":"Lee","year":"2016","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1093\/jmcb\/mju047","article-title":"Tumor-derived microvesicles mediate human breast cancer invasion through differentially glycosylated EMMPRIN","volume":"7","author":"Menck","year":"2015","journal-title":"J. Mol. Cell Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1038\/sj.onc.1207070","article-title":"The microvesicle as a vehicle for EMMPRIN in tumor\u2013stromal interactions","volume":"23","author":"Sidhu","year":"2004","journal-title":"Oncogene"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1111\/jcmm.13996","article-title":"CD147 promotes progression of head and neck squamous cell carcinoma via NF-kappa B signaling","volume":"23","author":"Yu","year":"2019","journal-title":"J. Cell. Mol. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4670","DOI":"10.3892\/ol.2017.6808","article-title":"CD147 expression correlates with lymph node metastasis in T1-T2 squamous cell carcinoma of the tongue","volume":"14","author":"Suzuki","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"4593","DOI":"10.1093\/emboj\/cdf470","article-title":"Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor","volume":"21","author":"Petrova","year":"2002","journal-title":"EMBO J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"6139","DOI":"10.21873\/anticanres.12966","article-title":"PROX1 Is Associated with Cancer Progression and Prognosis in Gastric Cancer","volume":"38","author":"Ueta","year":"2018","journal-title":"Anticancer Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"6416","DOI":"10.1158\/1078-0432.CCR-12-0832","article-title":"Prospero Homeobox 1 Promotes Epithelial\u2013Mesenchymal Transition in Colon Cancer Cells by Inhibiting E-cadherin via miR-9","volume":"18","author":"Lu","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1245\/s10434-015-4831-6","article-title":"Nuclear PROX1 is Associated with Hypoxia-Inducible Factor 1\u03b1 Expression and Cancer Progression in Esophageal Squamous Cell Carcinoma","volume":"22","author":"Yokobori","year":"2015","journal-title":"Ann. Surg. Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1007\/s10555-012-9390-8","article-title":"Transcription factor PROX1: Its role in development and cancer","volume":"31","author":"Elsir","year":"2012","journal-title":"Cancer Metastasis Rev."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"29914","DOI":"10.1038\/srep29914","article-title":"Tumour hypoxia promotes melanoma growth and metastasis via High Mobility Group Box-1 and M2-like macrophages","volume":"6","author":"Huber","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.leukres.2010.07.038","article-title":"Antiangiogenic therapy accelerates tumor metastasis","volume":"35","author":"Ribatti","year":"2011","journal-title":"Leuk. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.ccr.2009.01.027","article-title":"Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis","volume":"15","author":"Allen","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1007\/s00280-016-3134-3","article-title":"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","volume":"78","author":"Saif","year":"2016","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Jones, D. (2020). Parallels of Resistance between Angiogenesis and Lymphangiogenesis Inhibition in Cancer Therapy. Cells, 9.","DOI":"10.3390\/cells9030762"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1002\/med.21496","article-title":"Potential lymphangiogenesis therapies: Learning from current antiangiogenesis therapies-A review","volume":"38","author":"Yamakawa","year":"2018","journal-title":"Med. Res. Rev."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1001\/jamaoncol.2018.3039","article-title":"Effect of Anlotinib as a Third-Line or Further Treatment on Overall Survival of Patients with Advanced Non-Small Cell Lung Cancer: The ALTER 0303 Phase 3 Randomized Clinical Trial","volume":"4","author":"Han","year":"2018","journal-title":"JAMA Oncol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"753","DOI":"10.20892\/j.issn.2095-3941.2020.0024","article-title":"Anlotinib suppresses lymphangiogenesis and lymphatic metastasis in lung adenocarcinoma through a process potentially involving VEGFR-3 signaling","volume":"17","author":"Qin","year":"2020","journal-title":"Cancer Biol. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.addr.2015.12.011","article-title":"Tumor lymphangiogenesis and new drug development","volume":"99","author":"Dieterich","year":"2016","journal-title":"Adv. Drug Deliv. Rev."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/19\/4859\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:06:26Z","timestamp":1760166386000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/19\/4859"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,28]]},"references-count":68,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["cancers13194859"],"URL":"https:\/\/doi.org\/10.3390\/cancers13194859","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,28]]}}}