Induced Glycan Alterations in Sub-populations of Pancreatic Tumors

胰腺肿瘤亚群中诱导的聚糖改变

基本信息

批准号：
7641158
负责人：
Brian B. Haab
金额：
$ 9.1万
依托单位：
VAN ANDEL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2011-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Glycan alterations are known to be critical for several processes that contribute to cancer progression, particularly in pancreatic cancer, where glycosylation alterations are highly prevalent. Little is known about the conditions that give rise to those alterations, or whether they distinctly occur in particular subpopulations of cancer cells. Preliminary data have shown that pro-inflammatory cytokine signaling induces glycan alterations in pancreatic cancer cells, suggesting the possibility that the inflammatory environment typically seen in pancreatic cancer induces cancer cells to modify their extracellular glycan structures. Furthermore, the preliminary data suggest that the induced glycan alterations are different between groups of cell lines, as defined by the presence or absence of cell-surface markers that are associated with tumorigenicity in pancreatic cancer. That finding suggests that induced glycan alterations are distinct between cell types, and that these glycan alterations contribute to the particular behavior of each cell type. In order to gain insight into the relevance of these behaviors to cancer biology, the next step is to investigate these hypotheses in primary tumor cells, rather than in the cell line models used for the preliminary studies. A good system for that work is mouse xenografts from human primary tumors, which have been established for pancreatic cancer and can provide enough material for experiments on sorted cell subpopulations. In the first aim, we will determine whether the glycosylation or expression status of several mucins is different between the tumorigenic and non-tumorigenic subpopulations. In the second aim, we will determine whether these subpopulations display different glycan alterations in response to cytokine signaling. A significant aspect of this project is the unique experimental approach of using antibody arrays with glycan detection to measure protein and glycan variation on several specific proteins. The micro-scale nature of that assay also is valuable for the study of small subpopulations of cells. This work is well suited to a pilot-project mechanism since it will give insights into a possibly transformative research direction. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is a devastating disease with very low survival rates. It is known that alterations to the carbohydrates on the surfaces of cancer cells are important for disease progression, but the factors that give rise to those alterations, and the particular cancer cell types on which they appear, are incompletely understood. This proposal addresses that question, which has implications for treating or controlling pancreatic cancer.

描述（由申请人提供）：已知聚糖改变对于导致癌症进展的几个过程至关重要，特别是在胰腺癌中，糖基化改变非常普遍。对于引起这些改变的条件，或者它们是否明显发生在特定的癌细胞亚群中，人们知之甚少。初步数据表明，促炎细胞因子信号传导会诱导胰腺癌细胞中的聚糖改变，这表明胰腺癌中常见的炎症环境可能会诱导癌细胞改变其细胞外聚糖结构。此外，初步数据表明，不同细胞系组之间诱导的聚糖改变是不同的，这是通过与胰腺癌致瘤性相关的细胞表面标记物的存在或不存在来定义的。这一发现表明，诱导的聚糖改变在细胞类型之间是不同的，并且这些聚糖改变有助于每种细胞类型的特定行为。为了深入了解这些行为与癌症生物学的相关性，下一步是在原发性肿瘤细胞中研究这些假设，而不是在用于初步研究的细胞系模型中。这项工作的一个很好的系统是来自人类原发性肿瘤的小鼠异种移植物，该系统已针对胰腺癌建立，并且可以为分选细胞亚群的实验提供足够的材料。在第一个目标中，我们将确定几种粘蛋白的糖基化或表达状态在致瘤性和非致瘤性亚群之间是否不同。在第二个目标中，我们将确定这些亚群是否响应细胞因子信号传导而表现出不同的聚糖改变。该项目的一个重要方面是使用具有聚糖检测功能的抗体阵列来测量蛋白质和几种特定蛋白质的聚糖变异的独特实验方法。该测定的微尺度性质对于研究小细胞亚群也很有价值。这项工作非常适合试点项目机制，因为它将深入了解可能的变革性研究方向。公众健康相关性：胰腺癌是一种毁灭性的疾病，存活率非常低。众所周知，癌细胞表面碳水化合物的改变对于疾病进展很重要，但引起这些改变的因素以及它们出现的特定癌细胞类型尚不完全清楚。该提案解决了这个问题，这对治疗或控制胰腺癌具有重要意义。