IL-10 Regulation of Lymphangiogenesis in Prostate Cancer

IL-10 对前列腺癌淋巴管生成的调节

• 批准号: 6890003
• 负责人: Mark E Stearns
• 金额: $ 33.75万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-11-11 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6890003
• 关键词: SCID mouse; angiogenesis; biological signal transduction; cell line; clinical research; cytokine receptors; enzyme linked immunosorbent assay; gel mobility shift assay; gene expression; human tissue; interleukin 10; lymphopoiesis; male; metastasis; neoplasm /cancer diagnosis; neoplasm /cancer genetics; neoplastic cell; neoplastic process; pathologic process; polymerase chain reaction; prostate neoplasms; transfection; vascular endothelial growth factors

DESCRIPTION (provided by applicant): We postulate, based on preliminary studies, that the IL-10/IL-10R axis controls a 'lymphangiogenesis switch' leading to microvessel formation and the transformation of tumors from 'latent cancers' to actively growing cancers, which exhibit localized metastases to the perineural fibers and lymph nodes.. In this grant application, the overall goal is to assess whether IL-10 selectively targets lymphangiogenesis (and/or angiogenesis) to block microvessel formation, prostate tumor growth and localized metastases by primary prostate tumor sublines, HPCA-10a, 10b, 10c, 10d, 10e and 10f. The goals are three foal, including: Aim 1a: to characterize the IL-10R axis signaling pathway, which down regulates VEGF D synthesis; Aim 1b: to evaluate the role of the IL-10 receptor axis in controlling VEGF D/VEGF C expression in primary tumor cell lines and tumor explants; Aim lc: to determine the influence of IL-10 on tumor cell induced lymphangiogenesis (and angiogenesis) in vitro. Aim 2. To test whether IL-10 transfection blocks IL-10S1- VEGF D signaling and VEGF D and VEGF C expression to prevent lymphangiogenesis and/or angiogenesis, and localized metastases in an orthotopic SCID mouse model. Aim 3: to evaluate the expression by immunoassays of the genes/proteins regulated by the IL-10R axis, which are associated with lymphangiogenesis (and angiogenesis) in human prostate tumor studies. The labeling studies will be done with 'tissue arrays' blocks generated from approximately 1294 prostate cancer specimens and approximately 400 biopsies (e.g. including archival material collected over the past 5 yrs), plus fresh frozen sections of whole mount prostates. We will compare the expression profiles relative to the pathology of putative 'latent' cancers, and malignant cancers as well as localized metastases to the lymph nodes, neural, muscle, and seminal vesicles. Lymphatic and blood microvessel distributions will be measured by immunolabeling with LYVE-1, Podoplanin and Factor VIII antibodies. A 3-D reconstruction imaging software program termed ACIS will be employed for measuring microvessel density in serial sections. Evaluation of the data with respect to the pathology and patient outcome over a 5-10 yr period will permit evaluation of the importance of gene expression profiles. Overall, the studies should demonstrate whether the IL-10R axis and down stream effector genes (and specifically IL-10S1-VEGF D, and VEGF D) play a pivotal role in lymphangiogenesis and/or angiogenesis processes.

描述（由申请人提供）：根据初步研究，我们假设 IL-10/IL-10R 轴控制着“淋巴管生成开关”，导致微血管形成以及肿瘤从“潜伏癌症”转变为活跃生长的癌症，这些癌症表现出局部转移到神经周围纤维和淋巴结。在本拨款申请中，总体目标是评估 IL-10 是否 选择性靶向淋巴管生成（和/或血管生成），以阻断原发性前列腺肿瘤亚系 HPCA-10a、10b、10c、10d、10e 和 10f 的微血管形成、前列腺肿瘤生长和局部转移。目标是三个小马驹，包括： 目标 1a：表征 IL-10R 轴信号通路，下调 VEGF D 合成；目标1b：评估IL-10受体轴在原代肿瘤细胞系和肿瘤外植体中控制VEGF D/VEGF C表达中的作用；目标1c：确定IL-10对体外肿瘤细胞诱导的淋巴管生成（和血管生成）的影响。目标 2. 在原位 SCID 小鼠模型中测试 IL-10 转染是否阻断 IL-10S1-VEGF D 信号传导以及 VEGF D 和 VEGF C 表达以预防淋巴管生成和/或血管生成以及局部转移。目标 3：通过免疫分析评估受 IL-10R 轴调节的基因/蛋白质的表达，这些基因/蛋白质与人类前列腺肿瘤研究中的淋巴管生成（和血管生成）相关。标记研究将使用约 1294 个前列腺癌样本和约 400 个活组织检查（例如，包括过去 5 年收集的档案材料）生成的“组织阵列”块，以及全前列腺的新鲜冷冻切片进行。我们将比较与假定的“潜伏”癌症和恶性肿瘤以及淋巴结、神经、肌肉和精囊局部转移的病理学相关的表达谱。将通过 LYVE-1、Podoplanin 和因子 VIII 抗体的免疫标记来测量淋巴和血液微血管分布。称为 ACIS 的 3D 重建成像软件程序将用于测量连续切片中的微血管密度。对 5-10 年期间病理学和患者结果的数据评估将允许评估基因表达谱的重要性。总体而言，这些研究应证明 IL-10R 轴和下游效应基因（特别是 IL-10S1-VEGF D 和 VEGF D）是否在淋巴管生成和/或血管生成过程中发挥关键作用。