Tumor-induced sentinel lymph node lymphangiogenesis and increased lymph flow precede melanoma metastasis

Am J Pathol. 2007 Feb;170(2):774-86. doi: 10.2353/ajpath.2007.060761.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / pathology
  • Lymph Nodes / pathology
  • Lymph Nodes / physiopathology*
  • Lymph*
  • Lymphangiogenesis*
  • Lymphatic Metastasis
  • Lymphatic Vessels / pathology
  • Lymphatic Vessels / physiopathology*
  • Macrophages / pathology
  • Melanoma, Experimental / pathology
  • Melanoma, Experimental / physiopathology*
  • Mice
  • Microscopy, Fluorescence
  • Neoplasm Transplantation
  • Signal Transduction
  • Skin Neoplasms / pathology
  • Species Specificity