title: Lymphatic metastasis in the absence of functional intratumor lymphatics.
abstract: Lymphatic metastasis contributes to mortality from solid tumors. Whether metastasizing cancer cells reach lymph nodes via intratumor lymphatic vessels is unknown. Here, we examine functional lymphatics associated with mouse tumors expressing normal or elevated levels of vascular endothelial growth factor-C (VEGF-C), a molecule that stimulates lymphangiogenesis. Although VEGF-C overexpression increased lymphatic surface area in the tumor margin and lymphatic metastasis, these tumors contained no functional lymphatics, as assessed by four independent functional assays and immunohistochemical staining. These findings suggest that the functional lymphatics in the tumor margin alone are sufficient for lymphatic metastasis and should be targeted therapeutically.
authors.affiliation: E. L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, 100 Blossom Street, Boston, MA 02114, USA.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Padera
authors.forename: Ananth
authors.initials: A
authors.lastname: Kadambi
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: di Tomaso
authors.forename: Carla Mouta
authors.initials: CM
authors.lastname: Carreira
authors.forename: Edward B
authors.initials: EB
authors.lastname: Brown
authors.forename: Yves
authors.initials: Y
authors.lastname: Boucher
authors.forename: Noah C
authors.initials: NC
authors.lastname: Choi
authors.forename: Douglas
authors.initials: D
authors.lastname: Mathisen
authors.forename: John
authors.initials: J
authors.lastname: Wain
authors.forename: Eugene J
authors.initials: EJ
authors.lastname: Mark
authors.forename: Lance L
authors.initials: LL
authors.lastname: Munn
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry / Q000473:pathology; D000818:Animals; D000954:Antigens, Surface / Q000032:analysis; D016228:Endothelial Growth Factors / Q000378:metabolism; D005110:Extracellular Space / Q000502:physiology; D005354:Fibrosarcoma / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology / Q000556:secondary; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000737:chemistry / Q000473:pathology / Q000503:physiopathology / Q000556:secondary; D008207:Lymphatic Metastasis; D008208:Lymphatic System / Q000737:chemistry / Q000473:pathology* / Q000502:physiology; D008220:Lymphography; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology / Q000556:secondary; D026901:Membrane Transport Proteins; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D008853:Microscopy / Q000379:methods; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D011312:Pressure; D014407:Tumor Cells, Cultured; D042582:Vascular Endothelial Growth Factor C; D033921:Vesicular Transport Proteins
chemical_list: D000954:Antigens, Surface; D016228:Endothelial Growth Factors; D006023:Glycoproteins; D026901:Membrane Transport Proteins; D042582:Vascular Endothelial Growth Factor C; D033921:Vesicular Transport Proteins; C119248:LYVE1 protein, human; C095910:MECA-32 antigen, mouse; C492273:LYVE1 protein, mouse