TRANSFORMING GROWTH FACTORS IN COLONIC NEOPLASIA

这些研究的总体目标是评估 刺激和抑制自分泌生长因子活性的研究 正常和肿瘤结肠上皮细胞的生长调控。在……里面 此外，这些通路的改变对肿瘤的影响 进展将得到解决。已建立的息肉细胞的使用 表型范围为 从高分化到低分化将允许 生长因子需求和产量调查， 生长因子受体的表达和潜在的受体后 与配体相关的信号转导所必需的事件 有约束力的。此外，从这些方法中获得的答案在 将培养的细胞应用于正常皮肤的原代标本 结肠组织、息肉和癌症样本 相关的体外和体内的研究结果。具体来说，转化生长因子α 转化生长因子β的活性将在所有类型的细胞中进行表征 关于转录和反应中的生产和反应 翻译级别。北方和南方印迹等工具 分析、放射受体分析、放射免疫分析和 免疫沉淀法将被用来检测 这些生长因子在生长控制中，以及解剖 肿瘤细胞成功地通过其潜在的机制 改变这些机制。生产潜力放大 刺激分子(转化生长因子α)和/或反应减弱 对抑制信号(转化生长因子β)可能是标志性事件 肿瘤形成的发生和发展。结肠 上皮细胞是研究这种进展的有用的模型系统。 因为正常、癌前病变(息肉)和几个阶段的 有肿瘤组织可用。如果这些推定的角色 自分泌监管机构成立，可能有方法阻止积极 信号或增加对抑制信号的反应将是 检查过了。在这些研究中，针对生长的特定抗体 将使用因子或其受体。这项提案的范围 不仅包括确定增长因素 对维持正常的结肠上皮是必要的，但也 正常控制通路中的顺序变化具有 导致结肠发育不良，并最终形成肿瘤。这些 研究的目的是增加我们对正常和 结肠上皮的肿瘤性增殖，从而提供 洞察可能的方法将肿瘤细胞重定向到 正常的生长控制过程。

The overall objective of these studies is to evaluate the role of stimulatory and inhibitory autocrine growth factor activities in growth regulation of normal and neoplastic colonic epithelia. In addition, the effects of alterations in these pathways on tumor progression will be addressed. The use of established polyp cell lines and colon carcinoma cell lines which phenotypically range from well differentiated to poorly differentiated will allow investigation of growth factor requirements and production, growth factor receptor expression, and potential post receptor events necessary for signal transduction consequential to ligand binding. Furthermore, answers obtained from these approaches in cultured cells will be applied to primary specimens of normal colon tissue, polyp and carcinoma samples in an effort to correlate in vitro and in vivo findings. Specifically, TGF alpha and TGF beta activities will be characterized in all cell types with regard to production and response at the transcriptional and translational levels. Tools such as Northern and Southern blot analyses, radioreceptor assay, radioimmunoassay, and immunoprecipitation will be employed to examine the role of these growth factors in growth control, as well as dissect potential mechanisms by which neoplastic cells have managed to alter these mechanisms. Potential amplification of production of stimulatory molecules (TGF alpha) and/or diminution of response to inhibitory signals (TGF beta) could be hallmark events in the establishment and progression of tumor formation. The colonic epithelium is a useful model system to study such progression because normal, preneoplastic (polyp) and several stages of neoplastic tissue are available. If a role for these putative autocrine regulators is established, possible ways to block positive signals or increase responses to inhibitory signals will be examined. In these studies, specific antibodies to the growth factors or their receptors will be used. The scope of this proposal encompasses not only the identification of growth factors necessary for maintenance of normal colonic epithelia, but also the sequential alterations in normal control pathways that have contributed to colonic dysplasia and ultimately neoplasia. These studies are designed to increase our understanding of normal and neoplastic proliferation of colonic epithelia, and thus provide insight into possible ways to redirect neoplastic cells onto a normal course of growth control.