Mechanisms of Wnt-1-induced reduction of VEGF-C expression in melanoma

Wnt-1 is a proto-oncogene that targets beta-catenin. Hyper-activation of Wnt/ beta-catenin signaling is associated with the formation and progression of a variety of cancers. We found Wnt-1 expressed in human melanoma. Unexpectedly, employing a metastatic melanoma mouse model, Wnt-1 over-expression reduced lymph- angiogenesis and delayed melanoma metastasis. This was largely based on the ability of Wnt-1 to prevent melanoma cell-derived VEGF-C secretion. Wnt-1-induced VEGF-C suppression and anti-lymph-angiogenesis was calcineurin-dependent, but in-dependent from beta-catenin. We now wish to define pathways responsible for beneficial effects of Wnt-1 in melanoma and specifically define the link between calcineurin and repression of VEGF-C expression. In melanoma, the probability of metastatic spread correlates with lymphatic vessel densities. Efforts to therapeutically reduce tumor-induced lymph-angiogenesis and therefore to reduce metastasis are just at the horizon. The unexpected effects of Wnt-1 that over-expression severely impaired the ability of melanoma to secrete VEGF- C and to recruit lymph vessels, opens a new option; Wnt-1 could be considered as a potential anti-lymph- angiogenic factor for adjuvant treatment of melanoma and potentially also for other malignancies.

Melanoma metastasizes primarily through lymphatic vessels to the sentinel lymph node. The probability of this event correlates with the amount of locally produced VEGF-C and the resulting amount of lymphangiogenesis. However, the critical parameters responsible for this event are largely unknown. Here we describe signal transduction pathways, which on the one hand - are able to suppress VEGF-C secretion and the resulting lymphangiogenesis and metastasis. On the other hand, we describe pathways, which induce VEGF-C expression, lymphangiogensis and melanoma progression. Significance Currently the probability for metastasis of the primary melanoma can be only determined by sentinel node biopsy. Our results have the potential to predict metastasis by analyzing the protein expression profile of the primary tumor thereby avoiding sentinel node biopsy and the resulting risk for morbidity.