c-Myc Expression during Lymphomagenesis

描述（由申请人提供）：c-myc原癌基因在许多人类癌症中失调，Myc表达增加通常与预后不良相关。 我们发现在E/mu-c-myc小鼠淋巴瘤发生的早期阶段，Myc在B细胞中过表达，功能性淋巴管和血管快速生长。 Myc诱导B细胞中的血管内皮生长因子（VEGF-A）mRNA翻译，其可至少部分介导淋巴管和血管的生长，淋巴管和血管均表达VEGF受体-2。 我们认为，淋巴管生成和淋巴流量增加通过淋巴结促进转移性淋巴瘤的快速形成E/mu-c-myc小鼠。 GFP标记的E？将c-myc肿瘤细胞移植到E/mu-c-myc或野生型小鼠中，以测试Myc诱导的淋巴结改变是否促进淋巴瘤扩散。 我们在转移性实体瘤小鼠模型中鉴定了淋巴结淋巴管生成，这表明淋巴结淋巴管生长也支持实体瘤扩散。 将转移性和非转移性B16黑素瘤细胞系移植到E/mu-c-myc或野生型小鼠中，以测试淋巴结淋巴管生成是否通过淋巴管生成促进实体瘤转移。 使用逆转录病毒载体将Myc在非转移性黑素瘤中过表达，以确定该癌基因是否通过诱导肿瘤和/或淋巴结淋巴管生成来促进转移。 几种VEGF家族成员在E/mu-c-myc B细胞中表达，其可介导淋巴管生长和增加淋巴结内的淋巴流量。 VEGF、VEGF-C或VEGF-D活性将使用多种方法在E/mu-c-myc或B16肿瘤中被抑制，以确定哪些因子介导淋巴结改变。 抑制淋巴结淋巴管生成的治疗将测试有效转移是否需要增加淋巴流量。 识别引导淋巴结改变和肿瘤扩散的因素将有助于开发通过淋巴结转移的诊断测定和治疗。

DESCRIPTION (provided by applicant): 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.