权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

An Untested Approach: Biomarkers for Colon Cancer

未经测试的方法：结肠癌的生物标志物

基本信息

批准号：
7339673
负责人：
KHUSHI L MATTA
金额：
$ 14.55万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7339673
关键词：
American Cancer Society Anabolism Antibodies Antigens Area Biochemistry Biological Assay Biological Markers Biology Blood Vessels CA-19-9 Antigen Cancer Patient Cancer cell line Cancerous Carbohydrates Carcinoembryonic Antigen Carrier Proteins Cell Line Cells Cessation of life Chemicals Clinical Colon Colon Carcinoma Data Detection Development Diagnosis Disease Early Diagnosis Enzymes Epitopes Evaluation Exhibits Future Galactose Binding Lectin Generations Genus Cola Glycoconjugates Glycolipids Glycoproteins Haptens Human Inorganic Sulfates Keyhole Limpet Hemocyanin Knowledge Lead Lectin Link Malignant Neoplasms Measures Mediating Medicine Methods Modification Mono-S Monoclonal Antibodies Mucinous Mucins Mus Normal Cell Oligosaccharides Outcome Pathway interactions Patients Pattern Polysaccharides Publishing Reagent Research Personnel Screening for cancer Series Serum Serum Markers Specificity Specimen Standards of Weights and Measures Structure Techniques Testing Time Tissues Tumor Antigens Unspecified or Sulfate Ion Sulfates anticancer research base cancer cell cancer therapy carbohydrate structure colon cancer cell line concept drug development glycosylation glycosyltransferase improved interest novel novel strategies outcome forecast preference prognostic programs research study sulfotransferase

项目摘要

One of the most demanding areas of cancer research is finding biomarkers for the early detection of cancer. It is known that cancer is associated with alterations in the glycosylation patterns of glycoconjugates including glycolipids and glycoproteins. Based on this observation, the objective of this project is to identify novel mucinous biomarkers for the early detection and prognostic evaluation of colon cancer. Our approach differs from conventional methods of identifying cancer-associated glycans in that we examine the level of cellular glycosylation and use this information along with our knowledge of glyean biosynthetic pathways to predict likely candidate biomarkers. The overall hypothesis of the study is that "Changes in the structures of cancer-associated glycans are driven by fundamental changes in the cellular expression of the glycosyltransferases involved in their biosynthesis. Cancer cells express different glycosyltransferases leading to disticnt glyean signatures." In support of the above concept, we performed studies to assay the activity of fucosyl-,(3-N- acetylgalactosaminyl-, sialyl- and sulfotransferases in different colon cancer cell lines, and normal and cancerous colon tissue. These studies focused on those enzymes that generate the outer ends of the oligosaccharide chains in glycans. In these studies, we consistently observed elevated levels of two distinct Gal:3-O-sulfotransferases in cancerous tisue. One of these enzymes mediated formation of SE3- Gal|31¿>3GalNAca- type structure and the other mediated formation of SE3-Gal|31¿>4GlcNAc terminal units in the mucin core 2 tetrasaccharide Gal(31,4GlcNAc(31,6(Gal(31,3)GalNAca-. These tissues also exhibited appreciable levels of a(1,3)fucoyltranferase and a(2,3)sialyltranferase. Based on these studies from cancer cell lines and tissues, we have selected uniquely expressed novel sulfated carbohydrate epitopes that are likely present on colon cancer but not normal cells. We propose that these sulfated glycans provide novel targets for treatment and detection of colon cancer. In order to confirm this possibility, we propose to synthesize selected sulfated carbohydrate antigens and link them to KLH. Monoclonal antibodies will be developed against these target structures. Finally, these antibodies will be applied to colon cell lines and clinical specimens to assess their efficacy in identifying novel colon associated antigens. Our synthetic capability also provides a series of oligosaccharides to determine the specificity of the new antibody reagents, and thus these reagents are likely to be useful not only for studies of colon cancer.but also other problems in the fields of cancer and vascular biology. Generation of monoclonal antibodies unique to sulfated glycans of colon cancer cells can lead to new diagnosis strategies. There are currently no serum markers of colon cancer, and thus our project will also study if sulfated glycans in serum are elevated during colon cancer. The successful outcome of this program will lead us to a future program on colon cancer that includes the use of glycans expressed on cancer cells as targets for cancer therapy.

癌症研究中要求最高的领域之一是寻找用于早期检测的生物标志物癌症。众所周知，癌症与糖复合物的糖基化模式的改变有关包括糖脂和糖蛋白。根据这一观察，该项目的目标是确定用于结肠癌早期检测和预后评估的新型粘液生物标志物。我们的方法与识别癌症相关聚糖的传统方法不同，我们检查细胞糖基化，并利用这些信息以及我们对聚糖生物合成途径的了解预测可能的候选生物标志物。该研究的总体假设是“结构的变化癌症相关聚糖是由细胞表达的根本变化驱动的糖基转移酶参与其生物合成。癌细胞表达不同的糖基转移酶导致独特的聚糖特征。” 为了支持上述概念，我们进行了研究来测定岩藻糖基-,(3-N- 不同结肠癌细胞系中的乙酰半乳糖胺基、唾液酸和磺基转移酶以及正常和癌性结肠组织。这些研究集中于那些产生外端的酶聚糖中的寡糖链。在这些研究中，我们一致观察到两种不同的水平升高 Gal:癌组织中的3-O-磺基转移酶。其中一种酶介导 SE3- 的形成 Gal|31>>3GalNAca-型结构和 SE3-Gal|31>>4GlcNAc 末端单元的其他介导形成粘蛋白核心 2 四糖 Gal(31,4GlcNAc(31,6(Gal(31,3)GalNAca-)。这些组织还表现出 α(1,3)岩藻酰转移酶和α(2,3)唾液酸转移酶的水平较高。基于这些癌症研究细胞系和组织，我们选择了独特表达的新型硫酸化碳水化合物表位，它们是可能存在于结肠癌中，但不存在于正常细胞中。我们认为这些硫酸化聚糖提供了新的结肠癌治疗和检测的目标。为了确认这种可能性，我们建议合成选定的硫酸化碳水化合物抗原并将其与 KLH 连接。单克隆抗体将针对这些目标结构开发的。最后，这些抗体将应用于结肠细胞系并临床标本以评估其鉴定新型结肠相关抗原的功效。我们的合成能力还提供了一系列寡糖来确定新抗体的特异性试剂，因此这些试剂可能不仅可用于结肠癌的研究，而且还可用于其他癌症和血管生物学领域的问题。产生独特的单克隆抗体结肠癌细胞的硫酸化聚糖可以带来新的诊断策略。目前没有血清结肠癌的标志物，因此我们的项目还将研究血清中的硫酸聚糖是否在结肠癌。该计划的成功结果将引导我们开展未来的结肠癌计划包括使用癌细胞上表达的聚糖作为癌症治疗的靶标。