THE ROLE OF A BONE MORPHOGENETIC PROTEIN IN LUNG CANCER

骨形态发生蛋白在肺癌中的作用

基本信息

批准号：
6792062
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
项目类别：
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/6792062
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

项目摘要

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）：肺癌仍然是毁灭性的大多数患者发生远处转移的疾病。到识别可能调节转移的基因，我们使用了代表性差异分析（RDA）鉴定在人肺中高度表达的基因癌。 RDA确定了骨形态发生蛋白2（BMP-2）的表达肺癌和随后的研究表明，BMP-2在大多数肺癌在正常肺组织中表达较低。我们表明，A549肺癌细胞BMP-2活性的抑制注射到裸鼠的线导致肿瘤生长显着减少。我们假设BMP-2促进发展的机制肿瘤生长是通过刺激血管生成和生产而发生的促进细胞因子的生长。我们将通过执行以下研究。（1）分析BMP-2调节血管生成，肺癌细胞系将与亲密蓝琼脂糖共同注射到裸鼠中珠子涂有白蛋白，重组BMP-2或BMP-2拮抗剂Noggin。船只库房，回归和增殖的差异将被评估使用免疫组织化学发展肿瘤。确定机制 BMP-2通过评估调节血管内皮生长因子（VEGF）和BMP-2特异性的激活受体。用主要负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）检查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已鉴定的细胞因子在促进BMP-2刺激肿瘤生长和血管生成。（3）检查在患者衍生的组织样品中，无论是BMP-2配体的水平和原发性和转移性肺肿瘤中的受体表达与血管浸润，肿瘤等级，细胞分化，单核细胞浸润，以及远处转移扩散的频率。我们的长期目标是使用 BMP-2抑制疗法作为预防肺发展的一种方式癌症。