{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nVascular endothelial growth factor‐C (VEGF‑C) is emerging as a master regulator of lymphatic vessel growth that fuels the earliest steps of tumor dissemination. It is produced by both malignant cells and components of the tumor microenvironment—including activated macrophages—and its enhanced expression is associated with increased peritumoral lymphangiogenesis and lymph node metastasis in a variety of cancers such as cervical, mesothelioma, papillary thyroid, bladder, and even glioblastoma. In these settings, VEGF‑C fuels not only the expansion of lymphatic networks but also facilitates the efficient transit of tumor cells into draining lymph nodes, thereby contributing to poor clinical outcome."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe regulation and activation of VEGF‑C involve multiple, interrelated molecular mechanisms. Proteolytic processing by extracellular enzymes (for example, plasmin) converts its full‐length inactive precursor into a mature form with high receptor affinity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Its expression is induced by growth factors and cytokines such as heregulin‑β1"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "and cyclooxygenase‑2–dependent pathways"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", while specific integrin interactions (via α9β1;"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "and structural determinants revealed by crystallographic studies"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "further refine its bioactivity. In addition, transcriptional regulators such as SIX1 in concert with TGF‑β"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "and"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", as well as post‐transcriptional modulation by microRNAs (for example, miR‑27b, miR‑101, and miR‑128;"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ", help fine‑tune its levels. Furthermore, inflammatory mediators—notably interleukin‑6—can stimulate its expression"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ", and emerging evidence suggests that additional pathways, such as those modulated by tumor‐associated macrophages (with inhibitory inputs via cannabinoid receptor activation;"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "and"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": ", contribute to its regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}, {"type": "fg_f", "ref": "10"}, {"type": "fg_fs", "start_ref": "12", "end_ref": "16"}, {"type": "fg_f", "ref": "18"}, {"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its pro‐lymphangiogenic role, VEGF‑C exerts additional functions that contribute to tumor progression and cellular homeostasis. 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"}, {"type": "b", "children": [{"type": "t", "text": "Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/S0002-9440(10)64255-1"}], "href": "https://doi.org/10.1016/S0002-9440(10"}, {"type": "t", "text": "64255-1) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12213723"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12213723"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Rizwan Masood, Ajay Kundra, SuTao Zhu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Malignant mesothelioma growth inhibition by agents that target the VEGF and VEGF-C autocrine loops."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.10996"}], "href": "https://doi.org/10.1002/ijc.10996"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12594815"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12594815"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Ricardo López de Cicco, James C Watson, Daniel E Bassi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Simultaneous expression of furin and vascular endothelial growth factor in human oral tongue squamous cell carcinoma progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-03-0670"}], "href": "https://doi.org/10.1158/1078-0432.CCR-03-0670"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15240540"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15240540"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Panayiotis A Kyzas, Dimitrios Stefanou, Niki J Agnantis "}, {"type": "b", "children": [{"type": "t", "text": "COX-2 expression correlates with VEGF-C and lymph node metastases in patients with head and neck squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mod Pathol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/modpathol.3800244"}], "href": "https://doi.org/10.1038/modpathol.3800244"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15272284"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15272284"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "A Alitalo, M Detmar "}, {"type": "b", "children": [{"type": "t", "text": "Interaction of tumor cells and lymphatic vessels in cancer progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2011.602"}], "href": "https://doi.org/10.1038/onc.2011.602"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22179834"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22179834"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Dan Liu, Li Li, Xiao-Xue Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SIX1 promotes tumor lymphangiogenesis by coordinating TGFβ signals that increase expression of VEGF-C."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-13-3598"}], "href": "https://doi.org/10.1158/0008-5472.CAN-13-3598"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25142796"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25142796"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Wang He, Guangzheng Zhong, Ning Jiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Long noncoding RNA BLACAT2 promotes bladder cancer-associated lymphangiogenesis and lymphatic metastasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI96218"}], "href": "https://doi.org/10.1172/JCI96218"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29355840"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29355840"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Eric Song, Tianyang Mao, Huiping Dong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41586-019-1912-x"}], "href": "https://doi.org/10.1038/s41586-019-1912-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31942068"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31942068"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Bradley K McColl, Megan E Baldwin, Sally Roufail, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20030361"}], "href": "https://doi.org/10.1084/jem.20030361"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12963694"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12963694"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Pei-Wen Tsai, Shine-Gwo Shiah, Ming-Tsan Lin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Up-regulation of vascular endothelial growth factor C in breast cancer cells by heregulin-beta 1. A critical role of p38/nuclear factor-kappa B signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M204863200"}], "href": "https://doi.org/10.1074/jbc.M204863200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12471041"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12471041"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Jen-Liang Su, Jin-Yuan Shih, Men-Luh Yen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cyclooxygenase-2 induces EP1- and HER-2/Neu-dependent vascular endothelial growth factor-C up-regulation: a novel mechanism of lymphangiogenesis in lung adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.can-03-1301"}], "href": "https://doi.org/10.1158/0008-5472.can-03-1301"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14744769"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14744769"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Nicholas E Vlahakis, Bradford A Young, Amha Atakilit, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The lymphangiogenic vascular endothelial growth factors VEGF-C and -D are ligands for the integrin alpha9beta1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M412816200"}], "href": "https://doi.org/10.1074/jbc.M412816200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15590642"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15590642"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Veli-Matti Leppänen, Andrea E Prota, Michael Jeltsch, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural determinants of growth factor binding and specificity by VEGF receptor 2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0914318107"}], "href": "https://doi.org/10.1073/pnas.0914318107"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20145116"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20145116"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Chu-An Wang, Paul Jedlicka, Aaron N Patrick, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SIX1 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in mouse models of breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI59858"}], "href": "https://doi.org/10.1172/JCI59858"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22466647"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22466647"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Jun Ye, Xianguo Wu, Dang Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miRNA-27b targets vascular endothelial growth factor C to inhibit tumor progression and angiogenesis in colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0060687"}], "href": "https://doi.org/10.1371/journal.pone.0060687"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23593282"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23593282"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Guibin Zhao, Guangwei Zhu, Yongjian Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IL-6 mediates the signal pathway of JAK-STAT3-VEGF-C promoting growth, invasion and lymphangiogenesis in gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/or.2016.4544"}], "href": "https://doi.org/10.3892/or.2016.4544"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26750536"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26750536"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Hong Ji, Renhai Cao, Yunlong Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms5944"}], "href": "https://doi.org/10.1038/ncomms5944"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25229256"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25229256"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Rosaria I Staiano, Stefania Loffredo, Francesco Borriello, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human lung-resident macrophages express CB1 and CB2 receptors whose activation inhibits the release of angiogenic and lymphangiogenic factors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Leukoc Biol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1189/jlb.3HI1214-584R"}], "href": "https://doi.org/10.1189/jlb.3HI1214-584R"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26467187"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26467187"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Shinichi Aishima, Yunosuke Nishihara, Tomohiro Iguchi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Lymphatic spread is related to VEGF-C expression and D2-40-positive myofibroblasts in intrahepatic cholangiocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mod Pathol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/modpathol.3800985"}], "href": "https://doi.org/10.1038/modpathol.3800985"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18192971"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18192971"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Satyan S Kalkunte, Teddy F Mselle, Wendy E Norris, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Vascular endothelial growth factor C facilitates immune tolerance and endovascular activity of human uterine NK cells at the maternal-fetal interface."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.0803769"}], "href": "https://doi.org/10.4049/jimmunol.0803769"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19299706"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19299706"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Ming-Hsien Chien, Chia-Chi Ku, Gunnar Johansson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Vascular endothelial growth factor-C (VEGF-C) promotes angiogenesis by induction of COX-2 in leukemic cells via the VEGF-R3/JNK/AP-1 pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Carcinogenesis (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/carcin/bgp244"}], "href": "https://doi.org/10.1093/carcin/bgp244"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19825968"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19825968"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Hendrik J M de Jonge, Peter J M Valk, Nic J G M Veeger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High VEGFC expression is associated with unique gene expression profiles and predicts adverse prognosis in pediatric and adult acute myeloid leukemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2010-03-270991"}], "href": "https://doi.org/10.1182/blood-2010-03-270991"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20522712"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20522712"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Dariush Moussai, Hiroshi Mitsui, Julia S Pettersen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The human cutaneous squamous cell carcinoma microenvironment is characterized by increased lymphatic density and enhanced expression of macrophage-derived VEGF-C."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Invest Dermatol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/jid.2010.266"}], "href": "https://doi.org/10.1038/jid.2010.266"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20827282"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20827282"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Chandrasekharam N Nagineni, Vijay K Kommineni, Abitha William, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of VEGF expression in human retinal cells by cytokines: implications for the role of inflammation in age-related macular degeneration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Physiol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcp.22708"}], "href": "https://doi.org/10.1002/jcp.22708"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21374591"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21374591"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Renhai Cao, Hong Ji, Ninghan Feng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1208324109"}], "href": "https://doi.org/10.1073/pnas.1208324109"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22967508"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22967508"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Marissa J Stanton, Samikshan Dutta, Heyu Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Autophagy control by the VEGF-C/NRP-2 axis in cancer and its implication for treatment resistance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-11-3635"}], "href": "https://doi.org/10.1158/0008-5472.CAN-11-3635"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23149913"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23149913"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Kristiana Gordon, Dörte Schulte, Glen Brice, et al. "}, {"type": "b", "children": [{"type": "t", "text": "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."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.113.300350"}], "href": "https://doi.org/10.1161/CIRCRESAHA.113.300350"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23410910"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23410910"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Veli-Matti Leppänen, Denis Tvorogov, Kaisa Kisko, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Vascular endothelial growth factor C disrupts the endothelial lymphatic barrier to promote colorectal cancer invasion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2015.03.005"}], "href": "https://doi.org/10.1053/j.gastro.2015.03.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25754161"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25754161"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Hai-Ting Liu, Ai-Yan Xing, Xu Chen, et al. 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