The Role of Semaphorin 4D and Plexin-B1 in Tumor-Induced Angiogenesis.

Semaphorin 4D 和 Plexin-B1 在肿瘤诱导的血管生成中的作用。

• 批准号: 7936808
• 负责人: John R. Basile
• 金额: $ 31.13万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-21 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936808
• 关键词: Angiogenesis Inhibitors; Binding; Biological; Blood Vessels; CD100 antigen; Cells; Chemotaxis; Cleaved cell; Complex; Cues; Development; Employee Strikes; Endothelial Cells; Gene Transfer; Genes; Growth; Growth Cones; Head and Neck Squamous Cell Carcinoma; Home environment; Human; Hypoxia; Hypoxia Inducible Factor; In Vitro; Investigation; Knockout Mice; Ligands; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Metabolic; Modeling; Muscle fasciculation; Nature; Neoplasm Metastasis; Neoplasms; Nerve; Neurons; Paracrine Communication; Pathway interactions; Phenotype; Play; Process; Production; Proliferating; Proteins; Regulation; Resistance; Role; Semaphorins; Signal Transduction; Solid Neoplasm; Surface; Testing; Transcriptional Regulation; Tumor Pathology; Tumor Promotion; Up-Regulation; Vascular Endothelial Growth Factors; Work; Xenograft Model; Xenograft Model Antitumor Assays; angiogenesis; autocrine; axonal guidance; cancer therapy; cell stroma; cell transformation; chemotherapy; human MMP14 protein; hypoxia inducible factor 1; in vivo; malignant mouth neoplasm; meetings; men; migration; mouse model; neoplastic cell; paracrine; plexin; promoter; public health relevance; receptor; research study; response; retroviral-mediated; trait; transcription factor; treatment strategy; tumor; tumor growth; tumor vascular supply; tumor xenograft; tumorigenesis

DESCRIPTION (provided by applicant): Oral cancer is common among men in the developed world and among the most difficult neoplasms to treat. The growth and metastasis of all solid tumors requires induction of angiogenesis, the creation and remodeling of new blood vessels, to meet the increasing metabolic demands of rapidly dividing transformed cells, thus making the development of anti-angiogenic agents an appealing treatment strategy. Recent studies have identified increased expression of hypoxia- inducible factor (HIF)-1, a transcription factor that promotes angiogenesis, in many different primary and metastatic tumors, suggesting that its activation is common in human cancer (1). We now know that proteins involved in transmitting axonal guidance cues can also play a role in tumor-induced angiogenesis. For example, we were the first to show that Plexin-B1, a protein previously identified as a regulator of neuron growth cone progression and migration and nerve bundle fasciculation, is also highly expressed in endothelial cells and promotes a pro-angiogenic response when bound by its ligand Semaphorin 4D (Sema4D) (3), a protein expressed in head and neck squamous cell carcinomas (HNSCC) and many other solid tumors that enhances their growth and vascularity (4). The broad, long-term objectives of this application are to elucidate the mechanisms of regulation of Sema4D and the implications for tumor- induced angiogenesis. The hypothesis to be tested is that Sema4D is upregulated in hypoxia due to HIF-1- mediated pathways, and that its expression acts with other HIF-1-regulated gene products such as membrane type 1-matrix metalloproteinase (MT1-MMP) and vascular endothelial growth factor (VEGF) to induce a more vascular and consequently a more aggressive tumor phenotype. The specific aims are: 1) to establish the mechanism of transcriptional regulation of Sema4D and its biological relevance in hypoxia- mediated tumorigenesis. This will be accomplished by analyzing Sema4D protein and message levels in normoxic and hypoxic cells expressing reduced or constitutively active HIF, thorough promoter analysis of the Sema4D gene and through in vitro and in vivo angiogenesis assays and tumor xenograft experiments; 2) to determine the importance of hypoxia-mediated induction of MT1-MMP on the ability of Sema4D to induce angiogenesis. This will be studied through analysis of MT1-MMP levels in cells with altered HIF activity and the biological significance of MT1-mediated processing of Sema4D in a tumor xenograft model, and; 3) to determine VEGF and Sema4D contributions to HNSCC-induced angiogenesis through retroviral-mediated gene transfer directly into tumor cells in a conditional knockout mouse model. I believe that these investigations into Sema4D/Plexin-B1-mediated angiogenesis will support a newly emerging model of tumor-induced angiogenesis and present possible new targets for cancer therapy. PUBLIC HEALTH RELEVANCE: By their very nature, tumor cells are genetically unstable, a trait that contributes to their ability to proliferate inappropriately, avoid natural defenses and acquire resistance to chemotherapy. The development of anti-angiogenic agents capable of blocking a tumor's blood supply has become an intriguing way to circumvent this problem. If successful, our proposed project may uncover an important mechanism for tumor-induced angiogenesis, thereby presenting new targets for the development of anti- angiogenic therapies for the management of aggressive tumors.

描述（由申请人提供）：口腔癌在发达国家的男性中很常见，并且是最难治疗的肿瘤之一。所有实体瘤的生长和转移都需要诱导血管生成、新血管的产生和重塑，以满足快速分裂的转化细胞日益增加的代谢需求，因此使得抗血管生成剂的开发成为一种有吸引力的治疗策略。最近的研究已经确定了缺氧诱导因子（HIF）-1（一种促进血管生成的转录因子）在许多不同的原发性和转移性肿瘤中的表达增加，表明其激活在人类癌症中是常见的（1）。我们现在知道，参与传递轴突导向信号的蛋白质也可以在肿瘤诱导的血管生成中发挥作用。例如，我们首次证明丛蛋白-B1，一种先前被鉴定为神经元生长锥进展和迁移以及神经束成束的调节剂的蛋白质，也在内皮细胞中高度表达，并且当与其配体脑信号蛋白4D（Sema 4D）结合时促进促血管生成反应（3），一种在头颈部鳞状细胞癌（HNSCC）和许多其他实体瘤中表达的蛋白质，可增强其生长和血管分布（4）。本申请的广泛的长期目标是阐明Sema 4D的调节机制和对肿瘤诱导的血管生成的影响。待检验的假设是Sema 4D在缺氧中由于HIF-1介导的途径而上调，并且其表达与其他HIF-1调节的基因产物如膜型1-基质金属蛋白酶（MT 1-MMP）和血管内皮生长因子（VEGF）起作用，以诱导更多的血管，从而诱导更侵袭性的肿瘤表型。具体目标是：1）建立Sema 4D的转录调控机制及其在缺氧介导的肿瘤发生中的生物学意义。这将通过分析Sema 4D蛋白和表达减少或组成型活性HIF的常氧和缺氧细胞中的信息水平、Sema 4D基因的彻底启动子分析以及通过体外和体内血管生成测定和肿瘤异种移植实验来实现; 2）确定缺氧介导的MT 1-MMP诱导对Sema 4D诱导血管生成能力的重要性。这将通过分析具有改变的HIF活性的细胞中的MT 1-MMP水平和肿瘤异种移植模型中MT 1介导的Sema 4D加工的生物学意义来研究; 3）通过逆转录病毒介导的基因转移直接进入条件性敲除小鼠模型中的肿瘤细胞来确定VEGF和Sema 4D对HNSCC诱导的血管生成的贡献。我相信这些对Sema 4D/丛蛋白B1介导的血管生成的研究将支持一个新出现的肿瘤诱导的血管生成模型，并为癌症治疗提供可能的新靶点。 公共卫生相关性：就其本质而言，肿瘤细胞在遗传上是不稳定的，这一特性有助于它们不适当地增殖，避免自然防御并获得对化疗的抵抗力。能够阻断肿瘤血液供应的抗血管生成剂的开发已经成为规避这一问题的一种有趣的方法。如果成功的话，我们提出的项目可能会揭示肿瘤诱导血管生成的重要机制，从而为开发用于管理侵袭性肿瘤的抗血管生成疗法提供新的靶点。