The c-myc proto-oncogene is de-regulated in many human cancers, and increased Myc expression is often associated with poor prognosis. We identified rapid growth of functional lymphatic and blood vessels during early stages of lymphomagenesis in E/mu-c-myc mice, where Myc is overexpressed in B cells. Myc induces vascular endothelial growth factor (VEGF-A) mRNA translation in B cells, which could mediate at least in part the growth of lymphatic and blood vessels, which both express VEGF receptor-2. We propose that the lymphangiogenesis and increased lymph flow through lymph nodes promotes the rapid formation of metastatic lymphomas in E/mu-c-myc mice. GFP-tagged E?-c-myc tumor cells will be transplanted into E/mu-c-myc or wild type mice, to test whether Myc-induced lymph node alterations promote lymphoma dissemination. We identified lymph node lymphangiogenesis in mouse models of metastatic solid tumors, suggesting that lymph node lymphatic vessel growth also supports solid tumor dissemination. Metastatic and non-metastatic B16 melanoma cell lines will be transplanted into E/mu-c-myc or wild type mice, to test whether lymph node lymphangiogenesis promotes solid tumor metastasis via the lymphatics. Myc will be overexpressed in non-metastatic melanomas using retroviral vectors to determine whether this oncogene promotes metastasis by inducing tumor and/or lymph node lymphangiogenesis. Several VEGF family members are expressed in E/mu-c-myc B cells, which could mediate lymphatic vessel growth and increased lymph flow within the lymph nodes. VEGF, VEGF-C, or VEGF-D activity will be inhibited in E/mu-c-myc or B16 tumors using a variety of approaches, to determine which factors mediate lymph node alterations. Treatments inhibiting lymph node lymphangiogenesis will test whether increased lymph flow is required for effective metastasis. Identification of the factors directing lymph node alterations and tumor dissemination will be useful in the development of diagnostic assays and therapies for metastasis via the lymph nodes.
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