GLYCOLIPIDS--CELL INTERACTION/PROLIFERATION/ONCOGENESIS

糖脂——细胞相互作用/增殖/癌发生

• 批准号: 2090768
• 负责人: Sen-itiroh Hakomori
• 金额: $ 89.64万
• 依托单位: BIOMEMBRANE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-01 至 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2090768
• 关键词: biological signal transduction; blood group antigens; cell adhesion molecules; cell cell interaction; cell cycle; cell growth regulation; epidermal growth factor; gangliosides; glycosphingolipids; human subject; oncoproteins; protein kinase C; sphingosine; tumor antigens

Dramatic changes in composition and metabolism of glycosphingolipids (GSLs) have been observed in essentially all experimental and human cancers, resulting in formation of a variety of tumor-associated antigens defined by monoclonal antibodies, although the functional significance of tumor-associated GSL antigens is not known. On the other hand, a number of concurrent studies have suggested two distinct functional roles of GSLs, i.e., (1) GSLs as adhesion molecules based on GSL-GSL interactions, and synergistic effect of this system with other cell adhesion systems based on integrin receptors or leccams. Tumor-associated GSLs could be the targets of leccam recognition. . (2) GSLs and their metabolites as modulators of transmembrane signaling. E.g., GM3, together with lyso-PC, lyso-GM3, and N,N-dimethylsphingosine (derived from sphingosine), were found to be strong functional modulators of key molecules playing roles in transmembrane signaling (e.g., protein kinase C, EGF receptor kinase). They may also be modulators of functional units (e.g., "oncoproteins") which regulate cell proliferation. Studies along lines 1 and 2 above are expected to provide new means of correcting or blocking tumor cell proliferation, invasiveness, and metastasis, e.g., application of GSLs, their modified structures, or MAbs directed to them for inhibiting interaction of tumor cells with capillary endothelial cells of specific organs, or blocking interaction of tumor cells with cells of neighboring tissues (this direction of study could be called "anti-adhesion therapy"). We may also discover ways to block transmembrane signaling mechanisms which are apparently enhanced in a variety of tumor cells. These mechanisms can be suppressed by employing physiological inhibitors (e.g., metabolites of GSLs, phospholipids, and SPN), with consequent preferential blocking of tumor cell proliferation. A preliminary experiment indicated that this "anti-signaling" approach indeed inhibited tumor cell malignancy. Aberrant expression of A antigen (deletion, overexpression of A antigen in A tumors, or expression of incompatible A in O or B tumors) is a topic of long-standing interest in clinical immunology, in view of the close association between aberrant A antigen expression and patient prognosis. Since we have cloned the A and B genes, in-depth understanding of the molecular genetic basis of aberrant ABO status in human cancer is another specific goal of this proposal.

糖脂脂的组成和代谢的急剧变化 （GSL）在所有实验和人类中都观察到了 癌症，导致形成多种肿瘤相关抗原 由单克隆抗体定义，尽管功能意义 与肿瘤相关的GSL抗原尚不清楚。另一方面，许多 并发研究表明，GSL的两个不同的功能作用， 即，（1）GSL作为基于GSL-GSL相互作用的粘附分子，并且 该系统与其他基于细胞粘附系统的协同作用 在整联蛋白受体或鳞茎上。肿瘤相关的GSL可能是 鳞茎识别的靶标。 。 （2）GSL及其代谢物作为 跨膜信号的调节剂。例如，GM3与Lyso-PC一起 Lyso-GM3和N，N-二甲基肾上腺素（源自鞘氨醇）为 发现关键分子的强大功能调节剂在 跨膜信号传导（例如蛋白激酶C，EGF受体激酶）。 它们也可能是功能单元的调节剂（例如，“癌蛋白”） 调节细胞增殖。沿着第1行的研究是 预计将提供纠正或阻止肿瘤细胞的新方法 增殖，侵入性和转移，例如GSL的应用， 它们的修改结构或针对它们的mab抑制 肿瘤细胞与特异性毛细血管内皮细胞的相互作用 器官，或阻止肿瘤细胞与相邻细胞的相互作用 组织（该研究方向可以称为“抗粘附 疗法”）。我们还可能发现阻止跨膜信号传导的方法 在多种肿瘤细胞中显然增强的机制。 这些机制可以通过使用生理抑制剂来抑制 （例如，GSL，磷脂和SPN的代谢产物），因此 优先阻断肿瘤细胞增殖。初步 实验表明，这种“反信号”方法确实抑制了 肿瘤细胞恶性肿瘤。 抗原的异常表达（缺失，抗原的过表达 O或B肿瘤中A肿瘤或表达A的表达）是一个主题 鉴于结束，对临床免疫学的长期兴趣 异常的抗原表达与患者预后之间的关联。 由于我们已经克隆了A和B基因，因此对 人类癌症异常ABO状态的分子遗传基础是另一种 该提案的具体目标。