title: Hepatocyte growth factor is a lymphangiogenic factor with an indirect mechanism of action.
abstract: Hepatocyte growth factor (HGF) has previously been reported to act as a hemangiogenic factor, as well as a mitogenic factor for a variety of tumor cells. Here, we demonstrate that HGF is a lymphangiogenic factor, which may contribute to lymphatic metastasis when overexpressed in tumors. In a mouse corneal lymphangiogenesis model, implantation of HGF induces sprouting and growth of new lymphatic vessel expressing the lymphatic vessel endothelial specific marker hyaluronan receptor-1 (Lyve-1). Unlike blood vessels, the Lyve-1-positive structures consist of blunt-ended vessels of large diameters that generally lack expression of CD31. The growth of HGF-induced lymphatic vessels can be partially blocked by a soluble VEGFR-3, suggesting that HGF may stimulate lymphatic vessel growth through an indirect mechanism. Consistent with this finding, the HGF receptor (c-Met) is only localized on corneal blood vessels but is absent on lymphatic vessels in a mouse corneal assay. In a transgenic mouse model that expresses HGF under the control of the whey acidic protein (WAP) gene promoter, transgenic females develop tumors in the mammary glands after several pregnancies. Interestingly, dilated Lyve-1-positive lymphatic vessels accumulate in the peritumoral area and occasionally penetrate into the tumor tissue. Our findings indicate that HGF may play a critical role in lymphangiogenesis and potentially contribute to lymphatic metastasis.
authors.affiliation: Microbiology and Tumor Biology Center, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Renhai
authors.initials: R
authors.lastname: Cao
authors.forename: Meit A
authors.initials: MA
authors.lastname: Björndahl
authors.forename: Marta I
authors.initials: MI
authors.lastname: Gallego
authors.forename: Shaohua
authors.initials: S
authors.lastname: Chen
authors.forename: Piotr
authors.initials: P
authors.lastname: Religa
authors.forename: Anker J
authors.initials: AJ
authors.lastname: Hansen
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
mesh_terms: D000818:Animals; D003315:Cornea / Q000098:blood supply / Q000254:growth & development; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000502:physiology*; D042583:Lymphangiogenesis / Q000235:genetics / Q000502:physiology*; D008207:Lymphatic Metastasis / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000556:secondary; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D011247:Pregnancy; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D006023:Glycoproteins; D017228:Hepatocyte Growth Factor; D026901:Membrane Transport Proteins; D019859:Proto-Oncogene Proteins c-met; D040321:Vascular Endothelial Growth Factor Receptor-3; C492273:LYVE1 protein, mouse