Tumor and lymph node lymphangiogenesis-impact

The extent of lymph node (LN) metastasis is a major determinant for the staging and the prognosis of most human malignancies and often guides therapeutic decisions. Although the clinical significance of LN involvement is well clocumentecl, little has been known about the molecular mechanisms that promote tmnor spread via lymphatic vessels to sentinel and £listal LN and beyond. However, recent discoveries have identified novel lymphatic-specific markers, and the newly discovered lymphangiogenesis factors vascular endothelial growth factor-C (VEGF-C) and VEGF-D were found to promote tumor-associated lymphatic vessel growth in mouse tumor models, leading to enhanced tumor spread to sentinel LN. Our t•ecent findings indicate that VEGF -A also acts as a potent tumor lymphangiogenesis factor that pt·omotes lymphatic tmnor spread. VEGF-A overexpressing primary tumors induced sentinel LN lyntphangiogenesis even before metastasizing and maintained theit· lymphangiogenic activity after m e tastasis to draining LN. Our recent studies showed that primary human melanomas that later metastasized wet·e chm·acterized hy increased lymphangiogenesis and that the degree of tumor lymphangiogenesis can serve as a novel predictor of LN metastasis and overall patient survival, independently of tumot· thickness. Tumor lymphangiogenesis also signifieantly predicted the presence of sentinel LN metastases at the time of surgical excision of the primary melanoma. Together, these findings suggest that tmnor lymphangiogenesis actively contributes to cancer dissemination, that blockade of lymphatic vessel growth might inhibit tumor metastasis to LN, and that the extent of tumor-associated lymphangiogenesis could serve as a novel, prognostic parameter for the metastatic risk of human cancers. J, Leukoc. Biol. 80: 691-696; 2006.