THE ROLE OF A BONE MORPHOGENETIC PROTEIN IN LUNG CANCER

描述(申请人提供)：肺癌仍是一种毁灭性疾病 大多数患者发生远处转移的疾病。至 确定可能调节转移的基因，我们使用代表性 差异分析(RDA)用于鉴定人肺中高表达的基因 癌症。RDA鉴定骨形态发生蛋白2(BMP-2)在牙周炎中的表达 肺癌和后续研究表明，BMP-2在肺癌组织中高表达 大多数肺癌在正常肺组织中低水平表达。 我们发现对A549肺癌细胞BMP-2活性的抑制 LINE注射到裸鼠体内可显著降低肿瘤的生长。 我们推测骨形态发生蛋白-2促进发育的机制(S) 肿瘤的生长是通过刺激血管生成和产生 促进生长的细胞因子。我们将通过执行 随后进行的研究。(1)分析BMP-2对肺血管生成的调节作用 癌细胞株将与Affi-Blue琼脂糖共注射到裸鼠体内 包被白蛋白、重组BMP-2或BMP-2拮抗剂Noggin的珠子。 将评估血管合并、退化和增殖方面的差异。 用免疫组织化学的方法来发展肿瘤。确定其作用机制 BMP-2通过评估BMP-2对血管生成的调节 血管内皮生长因子与骨形态发生蛋白-2的特异性激活 感受器。转染显性负性BMP受体的细胞株将 用来确定哪个BMP受体被激活以诱导血管生成。 (2)研究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识别的细胞因子在 促进BMP-2刺激肿瘤生长和血管生成。(三)审查 在患者来源的组织样本中BMP-2配体和 原发和转移性肺肿瘤中受体表达与 血管侵犯，肿瘤分级，细胞分化，单核细胞浸润， 以及远处转移扩散的频率。我们的长期目标是利用 骨形态发生蛋白-2抑制治疗作为预防肺部疾病进展的一种手段 癌症。

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.