GLYCOLIPIDS IN DIFFERENTATION AND ONCOGENESIS

糖脂在分化和癌发生中的作用

• 批准号: 3479309
• 负责人: Sen-itiroh Hakomori
• 金额: $ 66.23万
• 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 1993-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3479309
• 关键词: blood group antigens; carbohydrate structure; cell differentiation; cell growth regulation; complementary DNA; early embryonic stage; epidermal growth factor; gangliosides; genetic manipulation; glycolipids; histochemistry /cytochemistry; human tissue; immunochemistry; laboratory mouse; laboratory rabbit; mammalian embryology; membrane lipids; molecular cloning; monoclonal antibody; neoplasm /cancer classification /staging; neoplastic growth; neoplastic transformation; platelet derived growth factor; teratoma; tumor antigens

The dramatic changes in glycolipid composition and metabolism associated with cellular differentiation and oncogenesis suggest a specific role of membrane glycolipids in these processes. Previous studies have revealed that many tumor-associated antigens as well as developmentally-regulated antigens are glycolipids. Some of these antigens are modified or incompatible blood group antigens. On the other hand, ubiquitous gangliosides such as GM3 or GM1 may have a basic function in regulating cell proliferation and cell adhesing. Some evidence has been provided for a possible effect of membranes gangliosides on growth factor receptors such as EGF, PDGF, FGF, and transferrin. GM3 or GM1 inhibit tyrosine phosphorylation of the PDGF receptor, while GM3 inhibits that of the EGF receptor. Based on these findings, we propose to study the following projects: (1) A search for new glycolipid tumor-associated markers and their expression as related to various stages of cancer progression. (2) Specificities of blood group determinants as influenced by their carrier carbohydrates. (3) Oncofetal alteration of blood group determinants and their carrier carbohydrates, particularly expression of the globo-series blood group antigens and incompatible A-like antigens in human cancer. (4) A possible role of glycolipids in cell recognition during embryogenesis and differentiation of teratocarcinoma. (5) Cell growth inhibition and differentiation induction by exogenous addition of gangliosides, and the mechanism of such effects. (6) The effect of anti-carbohydrate antibodies on cell growth and differentiation. These studies may greatly enrich our knowledge of: (1) the molecular basis of tumor markers, their heterogeneity as related to phenotypic variation of human tumor cell population, and the steps of cancer progression; and (2) the molecular basis of cell recognition and adhesion through glycolipids, and the mechanism of aberrant cell proliferation of cancer cells.

糖脂组成和代谢的巨大变化相关 细胞分化和肿瘤发生表明了特定的作用 这些过程中的膜糖脂。 之前的研究表明 许多肿瘤相关抗原以及发育调节的抗原 抗原是糖脂。 其中一些抗原被修饰或 血型抗原不相容。 另一方面，无处不在 神经节苷脂如 GM3 或 GM1 可能具有调节神经节苷脂的基本功能 细胞增殖和细胞粘附。 已提供一些证据 膜神经节苷脂对生长因子受体的可能影响，例如 如 EGF、PDGF、FGF 和转​​铁蛋白。 GM3 或 GM1 抑制酪氨酸 PDGF 受体的磷酸化，而 GM3 抑制 EGF 的磷酸化 受体。 基于这些发现，我们建议研究以下项目：（1）A 寻找新的糖脂肿瘤相关标志物及其表达 与癌症进展的各个阶段有关。 (2) 血型决定因素的特异性受其影响 载体碳水化合物。 (3) 血型决定因子及其携带者的肿瘤胎儿改变 碳水化合物，特别是 Globo 系列血型的表达 抗原和人类癌症中不相容的A样抗原。 (4) 糖脂在胚胎发生过程中细胞识别中的可能作用 和畸胎癌的分化。 (5) 外源性细胞生长抑制和分化诱导 添加神经节苷脂，以及这种作用的机制。 (6) 抗碳水化合物抗体对细胞生长和生长的影响 差异化。 这些研究可能会极大地丰富我们的知识：（1）分子基础 肿瘤标志物的异质性与表型变异有关 人类肿瘤细胞群，以及癌症进展的步骤；和（2） 通过糖脂进行细胞识别和粘附的分子基础， 以及癌细胞异常细胞增殖的机制。