GLYCOLIPIDS IN DIFFERENTATION AND ONCOGENESIS

糖脂在分化和癌发生中的作用

• 批准号: 3479308
• 负责人: Sen-itiroh Hakomori
• 金额: $ 64.91万
• 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/3479308
• 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与 与细胞分化和肿瘤发生有关的研究表明， 这些过程中的细胞膜糖脂。此前的研究表明， 许多肿瘤相关抗原以及发育调节的 抗原是糖脂。这些抗原中的一些被修饰或 血型抗原不相容。另一方面，无处不在的 神经节苷脂如GM3或GM1可能具有基本的调节功能 细胞增殖和细胞黏附。已经提供了一些证据来证明 膜神经节苷脂对生长因子受体的可能影响 如EGF、PDGF、成纤维细胞生长因子和转铁蛋白。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 与癌症进展的不同阶段有关。 (2)血型决定因素受其影响的特异性 载体碳水化合物。 (3)肿瘤胎儿血型决定因素及其携带者的改变 碳水化合物，特别是Globo系列血型的表达 人类癌症中的抗原和不相容的A类抗原。 (4)糖脂在胚胎发育过程中对细胞识别的可能作用 畸胎癌的分化。 (5)外源对细胞生长的抑制和诱导分化 神经节苷脂的添加及其作用机制。 (6)抗碳水化合物抗体对细胞生长和 差异化。 这些研究可以极大地丰富我们对以下方面的知识：(1)分子基础 肿瘤标志物的异质性与肿瘤的表型变异有关 人类肿瘤细胞的数量和癌症进展的步骤；和(2) 细胞通过糖脂识别和黏附的分子基础， 以及癌细胞异常增殖的机制。