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被去调控，Myc表达增加通常与不良预后相关。我们发现，在E/mu-c-myc小鼠淋巴瘤形成的早期阶段，功能性淋巴管和血管快速生长，其中Myc在B细胞中过度表达。Myc诱导血管内皮生长因子（VEGF- a） mRNA在B细胞中的翻译，至少部分介导淋巴管和血管的生长，淋巴管和血管都表达VEGF受体-2。我们认为在E/mu-c-myc小鼠中，淋巴管生成和淋巴结淋巴流量的增加促进了转移性淋巴瘤的快速形成。GFP-tagged E ?将-c-myc肿瘤细胞移植到E/mu-c-myc或野生型小鼠体内，检测myc诱导的淋巴结改变是否促进淋巴瘤传播。我们在转移性实体瘤小鼠模型中发现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的传播。转移性和非转移性B16黑色素瘤细胞系将被移植到E/mu-c-myc或野生型小鼠体内，以检测淋巴结淋巴管生成是否通过淋巴管促进实体瘤转移。Myc将在非转移性黑色素瘤中过度表达，使用逆转录病毒载体来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。VEGF家族的几个成员在E/mu-c-myc B细胞中表达，可以介导淋巴管生长和淋巴结内淋巴流量增加。VEGF、VEGF- c或VEGF- d活性将在E/mu-c-myc或B16肿瘤中被多种方法抑制，以确定哪些因素介导淋巴结改变。抑制淋巴结淋巴管生成的治疗将测试是否需要增加淋巴流量才能有效转移。确定指导淋巴结改变和肿瘤扩散的因素将有助于通过淋巴结转移的诊断分析和治疗的发展。

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.