title: Inhibition of TGFBIp expression reduces lymphangiogenesis and tumor metastasis.
abstract: Transforming growth factor-β-induced protein (TGFBIp) is an extracellular matrix protein that has a role in a wide range of pathological conditions. However, the role of TGFBIp signaling in lymphangiogenesis is poorly understood. The purpose of this study was therefore to analyze the effects of TGFBIp on lymphangiogenesis and determine whether TGFBIp-related lymphangiogenesis is important for the metastasis of tumor cells. TGFBIp increased adhesion, migration, and morphologic differentiation of human lymphatic endothelial cells (LECs), consistent with an increase in lymphatic vessel sprouting in a three-dimensional lymphatic ring assay. TGFBIp also induced phosphorylation of intracellular signaling molecules SRC, FAK, AKT, JNK and ERK. TGFBIp-induced lymphatic vessel sprouting was inhibited by addition of anti-integrin β3 antibody and pharmacologic inhibitors of FAK, AKT, JNK or ERK. TGFBIp increased both CCL21 expression in LECs, a chemokine that actively recruits tumor cells expressing the cognate chemokine receptors to lymphatic vessels and LEC permeability by inducing the dissociation of VE-cadherin junctions between LECs via the activation of SRC signaling. In vivo, inhibition of TGFBIp expression in SW620 cancer cells dramatically reduced tumor lymphangiogenesis and metastasis. Collectively, our findings demonstrate that TGFBIp is a lymphangiogenic factor contributing to tumor dissemination and represents a potential target to inhibit metastasis.
authors.affiliation: Corneal Dystrophy Research Institute, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Y-S
authors.initials: YS
authors.lastname: Maeng
authors.affiliation: Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Aguilar
authors.affiliation: Corneal Dystrophy Research Institute, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: S-I
authors.initials: SI
authors.lastname: Choi
authors.affiliation: Corneal Dystrophy Research Institute, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea.|Severance Biomedical Science Institute, Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: E K
authors.initials: EK
authors.lastname: Kim
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D054421:Chemokine CCL21 / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D042583:Lymphangiogenesis / Q000502:physiology*; D008207:Lymphatic Metastasis / Q000473:pathology*; D016688:Mice, Inbred NOD; D010539:Permeability; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000378:metabolism; D000099222:betaIG-H3 Protein; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D054421:Chemokine CCL21; D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; D019061:src-Family Kinases; D000099222:betaIG-H3 Protein; D000099152:Cadherin 5; C515478:CCL21 protein, human