ORAL CANCER, RETINOIDS, AND ANTIANGIOGENESIS

描述(改编自《调查员摘要》)：头部和颈部 鳞状细胞癌是一种侵袭性的上皮性恶性肿瘤。 可怜的五年存活期。这在一定程度上是由于 这些患者的黏膜中都有多原发瘤。 因此，必须包括使用化学预防策略，以 彻底治好这种病。维甲酸是最多的 成功的预防新鳞状细胞生长的化学预防药物 细胞癌。维甲酸在体内的作用机制 化学预防环境仍不清楚。本实验室最近的工作 提示维甲酸的化学预防作用可能部分是由于 使内皮细胞对诱导剂产生抵抗性的能力 血管生成。然而，其特定的分子机制 内皮细胞变得难治性尚不清楚。假说 这项工作的基础是维甲酸的一个或多个成员 受体(RAR)家族直接参与内皮细胞的呈递 对血管生成诱导剂不敏感的细胞。我们的目标是确定 哪些RAR要对引起这种改变的反应负责 内皮细胞。这位调查员建议仔细确定 在内皮细胞中表达的功能性RARs的图谱 Northern和Western印迹以及电迁移率漂移分析 (EMSA)。受体特异性配体随后将在体外和体内使用 体内血管生成试验确定表达的哪些亚集 受体是改变内皮细胞的能力所必需的 对血管生成诱导剂有反应。最后，校长 研究人员建议转导人微血管内皮细胞 带有逆转录病毒载体的细胞含有显性阴性、野生型 类型，或嵌合体RARs。这些细胞将在体外进行测试，以确定 它们向各种血管生成物质迁移的能力也很强 作为纯化的血管生成因子，在存在或不存在各种 维甲酸类化合物。被转导的细胞也将被植入 小鼠及其结合成新血管的能力 在体内是否有维甲酸类物质被确定。这些 研究应该促进我们对生物和分子生物学的理解 一个人可以改变血管生成反应的机制 在大量的病理学和生理学研究中起着关键作用 条件，包括新的原代口腔鳞状细胞的发育 癌症。

DESCRIPTION (Adapted from investigator's Abstract): Head and neck squamous cell carcinoma is an aggressive epithelial malignancy that has a poor five-year survival. This is due, in part, to the development of multiple primary tumors throughout the mucosa of these patients. Therefore, the use of chemopreventive strategies must be included to completely treat this disease. Retinoic acid has been the most successful chemopreventive agent against the development of new squamous cell carcinomas. The mechanisms by which retinoic acid works in a chemopreventive setting remain unclear. Recent work by this lab suggests that retinoic acid's chemopreventive effects may be partly due to its ability to make endothelial cells refractory to the inducers of angiogenesis. However, the specific molecular mechanism by which endothelial cells become refractory is unknown. The hypothesis underlying this work is that one or more members of the retinoic acid receptor (RAR) family directly participate in rendering endothelial cells refractory to inducers of angiogenesis. The goal is to determine which RARs are responsible for causing this altered response of endothelial cells. This investigator proposes to carefully determine the profile of functional RARs expressed in endothelial cells, using both Northern and Western blots, as well as electromobility shift assays (EMSA). Receptor specific ligands will then be used in in vitro and in vivo angiogenesis assays to determine which subset of expressed receptors are required for altering the ability of endothelial cells to respond to inducers of angiogenesis. Finally, the Principal Investigator proposes to transduce human microvascular endothelial cells with retroviral vectors containing either dominant negative, wild type, or chimeric RARs. These cells will then be tested in vitro for their ability to migrate towards various angiogenic substances as well as purified angiogenic factors in the presence or absence of various retinoid compounds. The transduced cells will also be implanted into mice and their ability to incorporate into newly forming blood vessels in vivo in the presence or absence of retinoids determined. These studies should advance our understanding of the biologic and molecular mechanisms by which one can modify the angiogenic response which plays a critical role in a large array of both pathologic and physiologic conditions, including the development of new primary oral squamous cell carcinomas.