GROWTH REGULATION OF HUMAN COLONIC NEOPLASMS

一个多学科小组将描述生长调节， 人结肠肿瘤的生长调节靶点 抗结肠癌治疗剂的开发。 的in 体外模型系统将由在以下中发现的细胞类型组成： 正常结肠;增生性息肉、腺瘤性息肉和 癌 生物学比较分析 每种类型的细胞的特性将被制作，包括 致瘤性，不依赖锚定生长的能力， 转移能力和分化标志物分析。 一 生长调节机制的表达谱将是 为每个生长表型建立。 该配置文件将提供 为了表征生长的依赖性， 特异性自分泌生长因子的细胞表型， 外源性生长因子和癌基因。 细胞表型 这三种分子之间的特定相互关系 也将被定性。 这些特征将确定 自分泌因子，如果解偶联（通过抗体或 类似物）可能导致依赖性的显著变化 细胞的生物学特性向更良性的表型发展 或者细胞死亡 解偶联的协同互- 这些类型的分子之间的关系也可以产生 同样的结果。 将确定是否调制 与细胞表型相关的生长调节表型 也将导致生物特性的调节 与表型相关。 这将通过 开发合适的转染载体， 生长调节相关自分泌因子的过表达 和癌基因。 成功转染的细胞将 进行生物学和生长调节的改变测试 表型 一些致癌基因与 结肠和其他系统中分化功能的表达。 这些也将在转染系统中进行测试，以确定 它们的过度表达是否会调节恶性表型 更温和的状态。 还将确定是否有一系列 或抑制剂可以影响 生物学和生长调节表型。 特别令人感兴趣的将是分化的影响 促进转染和抑制剂对 生长调节分子的表达及其相互关系 因为模拟这些效应的试剂的开发可以 进行有效的治疗干预。

A multidisciplinary group will characterize growth regulation in human colon neoplasms to identify growth regulatory targets for development of anticolon cancer therapeutic agents. The in vitro model system will consist of the types of cells found in normal colon; hyperplastic polyps, adenomatous polyps and carcinomas. Comparative analysis of the biological characteristics of each type of cell will be made and include tumorigenicity, ability to grow with anchorage independence, metastatic capability and analysis of differentiation markers. A profile of expression of growth regulatory mechanisms will be established for each growth phenotype. This profile will provide for the characterization of the dependence of the growth of cellular phenotypes on specific autocrine growth factors, exogenous growth factors and oncogenes. Cellular phenotype specific interrelationships among these three types of molecules will also be characterized. These characterizations will identify autocrine factors which if uncoupled (either by antibodies or analogues) could lead to a significant change in the dependent cell's biological characteristics toward a more benign phenotype or perhaps cell death. Uncoupling of synergistic inter- relationships among these types of molecules could also produce the same result. It will be determined whether modulation of the growth regulatory phenotype associated with a cellular phenotype will also result in the modulation of the biological properties associated with the phenotype. This will be accomplished by developing appropriate transfection vectors for the overexpression of growth regulatory associated autocrine factors and oncogenes in benign cells. Successfully transfected cells will be tested for alterations in biological and growth regulatory phenotypes. Some oncogenes have been associated with the expression of differentiated functions in colon and other systems. These will also be tested in transfection systems to determine whether their overexpression will modulate malignant phenotypes to more benign states. It will also be determined whether a series of putative differentiation or inhibitory agents can affect the biological and growth regulatory phenotypes in a similar manner. Of particular interest will be the effects of differentiation promoting transfections and the inhibitory agents on the expression of growth regulatory molecules and their relationships since the development of agents to mimic these effects could allow for effective therapeutic intervention.