ORAL CANCER, RETINOIDS, AND ANTIANGIOGENESIS

描述（改编自研究者摘要）：头部和颈部 鳞状细胞癌是一种侵袭性上皮恶性肿瘤， 五年生存率很低 部分原因是， 在这些患者的整个粘膜中存在多个原发性肿瘤。 因此，必须包括化学预防策略的使用， 彻底治疗这种疾病。维生素A酸是最常见的 成功的化学预防剂对新的鳞状细胞癌的发展 细胞癌 视黄酸的作用机制， 化学预防设置仍不清楚。 本实验室最近的工作 表明视黄酸的化学预防作用可能部分是由于 它的能力，使内皮细胞难治的诱导剂 血管生成 然而，特定的分子机制， 内皮细胞变得难治性是未知的。 的假设 这项工作的基础是视黄酸的一个或多个成员 RAR受体（RAR）家族直接参与内皮细胞的形成， 对血管生成诱导剂不敏感的细胞。 目标是确定 哪些RAR负责引起这种改变的反应， 内皮细胞 本调查员建议仔细确定 内皮细胞中表达的功能性RAR谱，使用 北方和西方印迹，以及电迁移率变动分析 （EMSA）。 然后将受体特异性配体用于体外和体内。 体内血管生成测定以确定表达的 受体是改变内皮细胞 对血管生成的诱导物有反应。 最后，校长 研究者建议将人微血管内皮细胞 细胞与逆转录病毒载体含有显性阴性，野生 型或嵌合型RAR。 然后将这些细胞在体外进行测试， 它们向各种血管生成物质迁移的能力 作为纯化的血管生成因子， 类维生素A化合物 转导的细胞也将被植入 小鼠及其融入新形成血管的能力 在有或没有类维生素A的情况下测定体内。 这些 这些研究应该会促进我们对生物和分子的理解， 通过这种机制，人们可以改变血管生成反应， 在一系列的病理和生理的 条件，包括新的初级口腔鳞状细胞的发展 癌

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.