title: Tumor-induced sentinel lymph node lymphangiogenesis and increased lymph flow precede melanoma metastasis.
abstract: Lymphangiogenesis is associated with human and murine cancer metastasis, suggesting that lymphatic vessels are important for tumor dissemination. Lymphatic vessel alterations were examined using B16-F10 melanoma cells implanted in syngeneic C57Bl/6 mice, which form tumors metastasizing to draining lymph nodes and subsequently to the lungs. Footpad tumors showed no lymphatic or blood vessel growth; however, the tumor-draining popliteal lymph node featured greatly increased lymphatic sinuses. Lymph node lymphangiogenesis began before melanoma cells reached draining lymph nodes, indicating that primary tumors induce these alterations at a distance. Lymph flow imaging revealed that nanoparticle transit was greatly increased through tumor-draining relative to nondraining lymph nodes. Lymph node lymphatic sinuses and lymph flow were increased in mice implanted with unmarked or with foreign antigen-expressing melanomas, indicating that these effects are not due to foreign antigen expression. However, tumor-derived immune signaling could promote lymph node alterations, as macrophages infiltrated footpad tumors, whereas lymphocytes accumulated in tumor-draining lymph nodes. B lymphocytes are required for lymphangiogenesis and increased lymph flow through tumor-draining lymph nodes, as these alterations were not observed in mice deficient for B cells. Lymph node lymphangiogenesis and increased lymph flow through tumor-draining lymph nodes may actively promote metastasis via the lymphatics.
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Department of Comparative Medicine, University of Washington, 1100 Fairview Ave. N., MS-C2-023, P.O. Box 19024, Seattle, WA 98109, USA. aruddell@fhcrc.org.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Harrell
authors.forename: Brian M
authors.initials: BM
authors.lastname: Iritani
authors.forename: Alanna
authors.initials: A
authors.lastname: Ruddell
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology; D008196:Lymph; D008198:Lymph Nodes / Q000473:pathology / Q000503:physiopathology*; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000473:pathology / Q000503:physiopathology*; D008264:Macrophages / Q000473:pathology; D008546:Melanoma, Experimental / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000473:pathology; D013045:Species Specificity