GROWTH REGULATION OF HUMAN COLONIC NEOPLASMS

一个多学科小组将以增长调控为特征 为人类结肠肿瘤确定生长调控靶点 抗结肠癌治疗药物的研究进展。入内 体外模型系统将由下列类型的细胞组成 正常结肠；增生性息肉、腺瘤性息肉和 癌症。生物多样性的比较分析 将制作每种类型的电池的特征，并包括 致瘤性，与锚地独立生长的能力， 肿瘤转移能力与分化标记物分析。一个 生长调节机制的表达概况将是 为每种生长表型建立的。此配置文件将提供 为了刻画对经济增长的依赖性 特定自分泌生长因子的细胞表型， 外源生长因子和癌基因。细胞表型 这三种分子之间的特定相互关系 也将被描述为。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)可以导致依赖关系的显著变化 细胞的生物学特性向更良性的表型转变 或者可能是细胞死亡。协同关系的解偶性 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 也会导致对生物特性的调节 与表型相关。这将通过以下方式实现 开发合适的转导载体 生长调节相关自分泌因子的过表达 良性细胞中的癌基因。成功转导的细胞将 接受生物和生长调节方面的变化检测 表型。一些癌基因已被认为与 分化功能在结肠等系统中的表达。 这些也将在转基因系统中进行测试，以确定 它们的过度表达是否会调节恶性表型 更良性的状态。还将确定一个系列是否 可能的分化或抑制剂会影响 生物和生长调节表型以类似的方式。 尤其令人感兴趣的是差异化的影响 促转染剂及其对细胞生长的抑制作用 生长调节分子的表达及其相互关系 由于模拟这些影响的试剂的开发可以 允许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.