Tumor lymphangiogenesis and melanoma metastasis

Abstract

Malignant melanomas of the skin primarily metastasize to lymph nodes, and the detection of sentinel lymph node metastases serves as an important prognostic parameter. There is now compelling evidence that melanomas can induce lymphangiogenesis (growth of lymphatic vessels), mainly at the tumor-stroma interface, and that the level of tumor lymphangiogenesis is correlated with the incidence of sentinel lymph node metastases and with disease-free survival. Thus, tumor lymphangiogenesis can serve as a novel prognostic predictor in melanoma. Vascular endothelial growth factor (VEGF)-C, released by melanoma cells and by tumor-associated macrophages, likely represents the major lymphangiogenic factor in melanoma, although other members of the VEGF family might also be involved. The recent discovery that tumors can induce a premetastatic niche, by inducing lymphatic vessel growth in sentinel lymph nodes even before metastasis, and that lymph node lymphangiogenesis enhances metastatic spread, indicates that activated lymphatic vessels represent novel targets for the detection and/or therapy of melanoma metastases.

Lymphatic vessel density is associated with CD8+ T cell infiltration and immunosuppressive factors in human melanoma

“…17 , 33 , 41-43 Lymphatic vessels may support migration of tumor cells, but may also modulate immune cells, as recently demonstrated in primary tumors and draining LNs in mice, 24 , 25 , 44 raising the possibility that lymphatics mediate immune suppression and poor clinical outcome in cancer patients. 19 , 31 , 42 Because corresponding human data are missing, we performed a very wide IHC analysis. Our findings reveal multiple correlations between lymphatic vessels and host immunity, suggesting immune mechanisms that act locally as well as loco-regionally in melanoma patients (Fig.…”

In vivo imaging of lymphatic vessels in development, wound healing, inflammation, and tumor metastasis

“…Melanoma is one of the tumors that metastasize mainly through invasion of the regional lymph nodes (46)(47)(48)(49). To explore the capacity of the reporter to track lymphangiogenesis in a highly metastatic tumor context, we used a xenograft assay by s.c. injection of the metastatic mouse melanoma cell line (B16-V5) (50) in Vegfr3 EGFPLuc +/KI females, backcrossed into the B6(Cg)-Tyr c-2J /J genetic background for 5 generations.…”

Exosomes Released by Melanoma Cells Prepare Sentinel Lymph Nodes for Tumor Metastasis

“…Alternatively, sentinel or regional nodes play an active role in the progression of melanoma metastasis. The observation that regional lymph nodes downstream of melanomas undergo reactive lymphangiogenesis prior to metastasis (6) suggest that melanoma metastasis is facilitated by preparation of a premetastatic niche within lymph nodes. This process is believed to be mediated by tumor secretion of paracrine angiogenic growth factors.…”