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Inhibition of tumor progression by inhibition of ganglioside biosynthesis: Models and mechanisms.

机译：通过抑制神经节苷脂的生物合成来抑制肿瘤的进展：模型和机制。

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摘要

Gangliosides are complex sphingolipids containing polar head groups, located primarily in cell membranes. They have long been recognized as sites of biological recognition and are involved in complex signal transduction processes, cell proliferation, differentiation, adhesion and apoptosis. Thus, gangliosides are potentially influential in tumor development and progression. Our laboratory and this study have established that gangliosides have the potential to influence tumor growth, and that experimental manipulation of ganglioside synthesis is able to slow down tumor progression and delay tumor onset. We found that treatment with the iminosugar OGT2378, an inhibitor of ganglioside synthesis at the level of glucosylceramide synthase, significantly impedes neuroectodermal tumor growth in an orthotopic, syngeneic MEB4 melanoma tumor model and, in exploratory studies, in an orthotopic, xenogeneic SKNSH neuroblastoma tumor model. In addition, in an orthotopic, xenogeneic LAN-1 neuroblastoma tumor model, treatment decreased the propensity of the tumor to metastasize.Morphology, growth characteristics, or apoptosis of these cells were not altered in response to OGT2378 treatment in vitro. Histopathologically, tumor tissue from ganglioside depleted MEB4 melanoma tumors appeared more highly differentiated and showed a strong reduction of PCNA expression indicating decreased mitotic activity. To further investigate the mechanism involved, ganglioside depleted neuroectodermal tumor cells were cultured in normoxic and hypoxic conditions. Ganglioside depleted neuroectodermal tumor cells exhibited a significant increase in apoptosis when cultured in severe hypoxia, an effect that was partly reversed by both the addition of exogenous gangliosides and inhibition of the de novo ceramide synthesis. Ganglioside depletion had no effect on the activation of either HIF-1alpha, protein kinase B/Akt or mTOR caused by hypoxia, while VEGF secretion was moderately augmented.Our results establish that ganglioside inhibition significantly inhibits tumor growth. We have implicated cell proliferation, differentiation, cell signaling, apoptosis, and host immune responses as processes all altered by interference with tumor ganglioside metabolism. Both tumor cell membrane gangliosides as well as gangliosides shed in the tumor microenvironment play important roles in tumor development, suppressing host immune function and enhancing microenvironmental stromal cells (fibroblasts, endothelial cells) to provide favorable conditions for tumor growth, whereas ganglioside depletion impedes the tumor cell's stress response.
机译：神经节苷脂是复杂的鞘脂，包含极性头基，主要位于细胞膜中。长期以来，它们一直被认为是生物识别的场所，并参与复杂的信号转导过程，细胞增殖，分化，粘附和凋亡。因此，神经节苷脂可能对肿瘤的发展和进展有影响。我们的实验室和这项研究已经确定，神经节苷脂有可能影响肿瘤的生长，而神经节苷脂合成的实验操作能够减缓肿瘤的进展并延缓肿瘤的发作。我们发现，在糖原神经酰胺合酶水平上神经节苷脂合成抑制剂亚氨基糖OGT2378的治疗在原位同基因MEB4黑色素瘤模型中以及在原位异种SKNSH神经母细胞瘤模型中探索性地阻碍了神经外胚层肿瘤的生长。 。此外，在异位LAN-1神经母细胞瘤原位肿瘤模型中，治疗降低了肿瘤转移的倾向。这些细胞的形态，生长特征或凋亡在响应OGT2378体外治疗后并未改变。组织病理学上，来自神经节苷脂耗尽的MEB4黑色素瘤肿瘤的肿瘤组织表现出更高的分化程度，并显示PCNA表达强烈降低，表明有丝分裂活性降低。为了进一步研究涉及的机制，在常氧和低氧条件下培养了神经节苷脂耗尽的神经外胚层肿瘤细胞。在严重缺氧条件下培养时，神经节苷脂耗尽的神经外胚层肿瘤细胞显示出明显的凋亡增加，这种作用在一定程度上被添加外源神经节苷脂和抑制新生神经酰胺合成所逆转。神经节苷脂的耗竭对缺氧引起的HIF-1α，蛋白激酶B / Akt或mTOR的激活没有影响，而VEGF的分泌却适度增加。我们的结果证明，神经节苷脂的抑制作用显着抑制了肿瘤的生长。我们已经暗示了细胞增殖，分化，细胞信号转导，凋亡和宿主免疫反应，因为这些过程均因干扰肿瘤神经节苷脂代谢而改变。肿瘤细胞膜神经节苷脂以及在肿瘤微环境中脱落的神经节苷脂均在肿瘤发展，抑制宿主免疫功能和增强微环境基质细胞（成纤维细胞，内皮细胞）中发挥重要作用，为肿瘤生长提供有利条件，而神经节苷脂耗竭则阻碍了肿瘤的发展。细胞的应激反应。

著录项

  • 作者

    Weiss, Michael.;

  • 作者单位

    The George Washington University.;

  • 授予单位 The George Washington University.;
  • 学科 Biology Cell.Health Sciences Oncology.Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 225 p.
  • 总页数 225
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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