CELL-CELL INTERACTIONS IN MALIGNANCY

这项研究的总体目标是了解 特定粘附分子的变化有助于侵入性 或肿瘤细胞的转移能力。 研究重点 主要作用于神经细胞粘附分子N-CAM， 劳斯肉瘤病毒转化神经上皮细胞 (RSV)导致N-CAM的量显著减少， 相关的细胞凋亡以及细胞内 能动性 这些研究采用了生物化学和功能测定 基于针对特定CAM的特异性抗体， 使用克隆序列来分析它们的遗传调控， 表情 为了确定N-CAM表达的变化如何影响 细胞的恶性行为、粘附性、运动性和侵袭性 将比较已丢失N-CAM的完全转化细胞的 转化细胞中N-CAM水平已经降低， 是通过基因改造恢复的 为了确定N-CAM如何 水平降低，我们将测量转录，加工， N-CAM mRNA的稳定性和磷酸化， N-CAM蛋白质的稳定性，并将确定控制区域， N-CAM基因是RSV诱导的变化所必需的。 的 转换对其他定义的表达的影响 还将测定神经元粘附系统。 以识别 可能直接增强肿瘤细胞侵袭力的因素，我们将 测试转化细胞是否分泌 特别是改变CAM的合成和降解， 正常的周围细胞。 此外， 将评估CAM表达的转化， 引起癌的上皮细胞。 一个主要细胞粘附系统的丧失可能是一个诱因， 肿瘤细胞的脱落和局部侵袭。 的 拟议中的研究将测试这一想法，并将确定机制 从而改变肿瘤细胞的免疫功能。 研究结果可能表明， 临床干预转移扩散的新方法 人类肿瘤。

The overall goal of the proposed research is to understand how changes in specific adhesive molecules contribute to the invasive or metastatic capacity of tumor cells. The studies focus primarily on the neural cell adhesion molecule N-CAM because transformation of neuroepithelial cells by Rous sarcoma virus (RSV) results in a dramatic reduction in amount of N-CAM and associated cell adhesiveness together with an increase in cell motility. The studies employ biochemical and functional assays that are based on specific antibodies to defined CAMs, and make use of cloned sequences to analyze the genetic regulation of their expression. To determine how changes in N-CAM expression affect the malignant behavior of cell, the adhesion, motility and invasiveness of fully transformed cells that have lost N-CAM will be compared to that of transformed cells in which N-CAM levels have been restored by genetic manipulation. To determine how N-CAM levels are reduced, we will measure the transcription, processing, and stability of N-CAM mRNA and the phosphorylation and stability of N-CAM protein, and will define control regions in the N-CAM gene that are necessary for the RSV-induced change. The effect of transformation on the expression of other defined neuronal adhesion systems will also be determined. To identify factors that may directly enhance tumor cell invasiveness, we will test whether transformed cells secrete substances that specifically alter the synthesis and degradation of CAMs on normal surrounding cells. In addition, the effect of transformation on expression of CAMs will be assessed in epithelial cells that give rise to carcinomas. The loss of a major cell adhesion system may be a prime contributor to tumor cell detachment and local invasiveness. The proposed studies will test this idea and will define mechanisms that alter adhesiveness in tumor cells. The findings may suggest new approaches for clinical intervention in the metastatic spread of human tumors.