title: Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis.
abstract: Formation of lymphatic metastasis is the initial step of generalized spreading of tumor cells and predicts poor clinical prognosis. Lymphatic vessels generally arise within the peritumoral stroma, although the lymphangiopoietic vascular endothelial growth factors (VEGF)-C and -D are produced by tumor cells. In a carefully selected collection of human cervical cancers (stage pT1b1) we demonstrate by quantitative immunohistochemistry and in situ hybridization that density of lymphatic microvessels is significantly increased in peritumoral stroma, and that a subset of stromal cells express large amounts of VEGF-C and VEGF-D. The density of cells producing these vascular growth factors correlates with peritumoral inflammatory stroma reaction, lymphatic microvessel density, and indirectly with peritumoral carcinomatous lymphangiosis and frequency of lymph node metastasis. The VEGF-C- and VEGF-D-producing stroma cells were identified in situ as a subset of activated tumor-associated macrophages (TAMs) by expression of a panel of macrophage-specific markers, including CD68, CD23, and CD14. These TAMs also expressed the VEGF-C- and VEGF-D-specific tyrosine kinase receptor VEGFR-3. As TAMs are derived from monocytes in the circulation, a search in peripheral blood for candidate precursors of VEGFR-3-expressing TAMs revealed a subfraction of CD14-positive, VEGFR-3-expressing monocytes, that, however, failed to express VEGF-C and VEGF-D. Only after in vitro incubation with tumor necrosis factor-alpha, lipopolysaccharide, or VEGF-D did these monocytes start to synthesize VEGF-C de novo. In conclusion VEGF-C-expressing TAMs play a novel role in peritumoral lymphangiogenesis and subsequent dissemination in human cancer.
authors.affiliation: Department of Pathology, University of Vienna-Allgemeines Krankenhaus, Austria.
authors.forename: Sebastian F
authors.initials: SF
authors.lastname: Schoppmann
authors.forename: Peter
authors.initials: P
authors.lastname: Birner
authors.forename: Johannes
authors.initials: J
authors.lastname: Stöckl
authors.forename: Romana
authors.initials: R
authors.lastname: Kalt
authors.forename: Robert
authors.initials: R
authors.lastname: Ullrich
authors.forename: Carola
authors.initials: C
authors.lastname: Caucig
authors.forename: Ernst
authors.initials: E
authors.lastname: Kriehuber
authors.forename: Katalin
authors.initials: K
authors.lastname: Nagy
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Dontscho
authors.initials: D
authors.lastname: Kerjaschki
mesh_terms: D015703:Antigens, CD / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D008207:Lymphatic Metastasis / Q000473:pathology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D020298:U937 Cells; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D040321:Vascular Endothelial Growth Factor Receptor-3
chemical_list: D015703:Antigens, CD; D016228:Endothelial Growth Factors; D017978:Receptors, Growth Factor; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D020794:Receptor Protein-Tyrosine Kinases; D040321:Vascular Endothelial Growth Factor Receptor-3