THE ROLE OF A BONE MORPHOGENETIC PROTEIN IN LUNG CANCER

骨形态发生蛋白在肺癌中的作用

• 批准号: 6604004
• 负责人: JOHN LANGENFELD
• 金额: $ 15.69万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-08 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6604004
• 关键词: angiogenesis; athymic mouse; bone morphogenetic proteins; clinical research; growth factor receptors; human subject; insulinlike growth factor; interleukin 1; interleukin 8; lung neoplasms; migration inhibition factor; molecular oncology; neoplastic process; patient oriented research; receptor expression; tissue /cell culture; transfection; vascular endothelial growth factors

DESCRIPTION (provided by applicant): Lung cancer remains a devastating disease with the majority of patients developing distant metastasis. To identify genes that may regulate metastasis, we used representational differential analysis (RDA) to identify genes highly expressed in human lung carcinomas. RDA identified bone morphogenetic protein 2 (BMP-2) expression in lung cancer and subsequent studies showed BMP-2 is highly expressed in the majority of lung cancers with low levels of expression in normal lung tissue. We show that the inhibition of BMP-2 activity of the A549 lung cancer cell line injected into nude mice causes a significant decrease in tumor growth. We hypothesize that the mechanism(s) by which BMP-2 promotes the development of tumor growth occurs through stimulation of angiogenesis and production of growth promoting cytokines. We will test this hypothesis by performing the following studies. (1) To analyze BMP-2 regulation of angiogenesis, lung cancer cell lines will be co-injected into nude mice with Affi-blue agarose beads coated with albumin, recombinant BMP-2, or the BMP-2 antagonist, noggin. Differences in vessel cooption, regression, and proliferation will be assessed in developing tumors using immunohistochemistry. To determine the mechanism by which BMP-2 stimulates angiogenesis by assessing both the regulation of vascular endothelial growth factor (VEGF) and activation of BMP-2 specific receptors. Cell lines transfected with dominant negative BMP receptors will be used to determine which BMP receptor is activated to induce angiogenesis. (2) To examine the paracrine and autocrine regulation of BMP-2 on known growth promoting cytokines and assess the role of the identified cytokine in promoting bmp-2 stimulation of tumor growth and angiogenesis. (3) To examine in patient derived tissue samples whether the level of BMP-2 ligand and receptor expression in primary and metastatic lung tumors correlates with vascular invasion, tumor grade, cell differentiation, monocyte infiltration, and the frequency of distant metastatic spread. Our long-term goal is to use BMP-2 inhibiting therapy as a modality to prevent the progression of lung cancer.

描述（由申请人提供）：肺癌仍然是一个毁灭性的 大多数患者发生远处转移。到 鉴定可能调节转移的基因，我们使用代表性的 差异分析（RDA），以鉴定在人肺中高表达的基因 癌RDA鉴定了骨形态发生蛋白2（BMP-2）在 随后的研究表明，BMP-2在肺癌中高度表达， 大多数肺癌在正常肺组织中表达水平低。 我们发现，抑制A549肺癌细胞BMP-2的活性， 注射到裸鼠中的线导致肿瘤生长的显著减少。 我们推测BMP-2促进肿瘤生长的机制可能是 肿瘤生长的发生是通过刺激血管生成和产生 促生长细胞因子。我们将通过执行 继研究。(1)为了分析BMP-2对血管生成的调节， 将癌细胞系与Affi-蓝琼脂糖共注射到裸鼠中 用白蛋白、重组BMP-2或BMP-2拮抗剂头蛋白包被的珠。 将评估血管融合、消退和增殖的差异 在肿瘤发展中的作用。为了确定机制 BMP-2刺激血管生成的方法， 血管内皮生长因子（VEGF）和BMP-2特异性激活 受体。用显性阴性BMP受体转染的细胞系将 用于确定哪种BMP受体被激活以诱导血管生成。 (2)检测BMP-2对已知生长的旁分泌和自分泌调节 促进细胞因子，并评估所鉴定的细胞因子在 促进BMP-2刺激肿瘤生长和血管生成。(3)审查 在患者来源的组织样品中，BMP-2配体和 原发性和转移性肺肿瘤中的受体表达与 血管浸润、肿瘤分级、细胞分化、单核细胞浸润， 和远处转移的频率。我们的长期目标是利用 BMP-2抑制疗法作为预防肺损伤进展的方式 癌