Molecular Analysis of CD44 on Colon Cancer Cells

结肠癌细胞 CD44 的分子分析

基本信息

批准号：
7630414
负责人：
ROBERT SACKSTEIN
金额：
$ 33.25万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
2007-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7630414
关键词：
Adherence Adhesions Adhesives Affect Affinity Binding Biological Assay CD44 gene Carbohydrates Cell Adhesion Molecules Cell Communication Cells Characteristics Chimera organism Clinical Colon Carcinoma Colorectal Cancer Development Disease Disease Progression Distant Drops Drug or chemical Tissue Distribution E-Selectin Electron Microscopy Endothelial Cells Endothelium Environment Epitopes Flow Cytometry Fucosyltransferase Hematogenous Homing Human Hyaluronic Acid Hyaluronic Acid Binding Hypoxia Immunohistochemistry Infiltration Investigation Laboratories Lead Ligands Liver Lung Malignant Epithelial Cell Malignant Neoplasms Measures Mediating Modeling Modification Molecular Molecular Analysis Mus NIH Program Announcements Neoplasm Metastasis Normal tissue morphology Organ Oxygen Pathway interactions Pattern Phenotype Play Polysaccharides Prevention Prevention therapy Process Protein Isoforms RNA Splicing Research Personnel Role Seeds Simulate Site Skin Small Interfering RNA Staging Structure Surface Survival Rate System Testing Time Tissue Sample Tissues Umbilical vein Variant Vascular Endothelium Western Blotting Woman base cancer cell cancer stem cell cell motility circulating cancer cell colon cancer cell line glycosylation glycosyltransferase hemodynamics in vivo information gathering intravital microscopy men migration neoplastic cell novel novel therapeutics outcome forecast prevent programs therapeutic target tumor

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer is the third most common cancer in both men and women. The 5 year survival rate for this malignancy drops to 8% once the cancer has spread hematogenously to distant organs such as the liver or the lung. An increased understanding of the molecular basis of colon cancer metastasis is needed in order to devise novel therapies for prevention of late-stage disease. The critical first step in hematogenous metastasis of target organs is the "tethering and rolling" attachment of circulating cancer cells onto vascular endothelium. Among the principal effectors of tethering and rolling interactions of cells under shear flow conditions are E-selectin/E-selectin ligands and the CD44/hyaluronic acid (HA) axis. While HA is the principal ligand for CD44, studies from our laboratory have revealed that specialized glycoforms of CD44 (known as HCELL) bind E-selectin with high affinity. We have recently found that CD44 on human colon cancer cells express the HCELL glycoform and binds both E-selectin and HA. Importantly, expression of CD44 variants and tumor cell binding to E-selectin have each been correlated with poor prognosis in colon cancer. The studies proposed herein seek to elucidate the relationship between HCELL/CD44 binding to its ligands E-selectin and HA, and the role these adhesive pathways play in the promotion of the metastatic cascade, from the initial tethering/rolling of tumor cells on endothelium through transmigration and tissue infiltration. With respect to this Program Announcement, we seek to define how the cancer microenvironment affects expression and function of CD44 (including glycosylations rendering E-selectin binding determinant(s)), a molecule expected to promote metastasis of colon cancer "stem" cells. The Specific Aims of this proposal are: (1) To analyze the expression level, surface distribution, and function of CD44 on colon carcinoma cells; (2) To determine whether microenvironmental factors can influence expression and distribution of isoforms/glycoforms of CD44 on colon carcinoma cells; and (3) To analyze the capacity of colon carcinoma cells to transmigrate and seed tissue sites by manipulating tumor cell CD44 expression/function and carbohydrate modifications. It is anticipated that results of the studies proposed herein will lead to a greater understanding of the role of CD44 as a molecular effector of colon cancer cell-endothelial interactions under hydrodynamic shear conditions. This information is fundamental to devising new therapeutic strategies to prevent colon cancer dissemination, and thus has profound implications for prevention of late-stage disease. Lay summary: The underlying molecular basis of colon cancer metastasis is poorly understood. The proposed studies will focus on CD44, a molecule that is associated with poor prognosis and disease progression. It is anticipated that information gathered from these studies will form the basis for development of therapeutics targeting CD44 in colon cancer.

描述（由申请人提供）：结肠癌是男性和女性中第三大常见的癌症。一旦癌症将血源性扩散到肝脏或肺等远处的器官，这种恶性肿瘤的5年生存率下降到8％。为了制定新的预防晚期疾病疗法，需要对结肠癌转移的分子基础的分子基础进行越来越多的了解。目标器官血源转移的关键第一步是循环癌细胞的“绑扎和滚动”附着在血管内皮上。在剪切流条件下细胞的束缚和滚动相互作用的主要效应子中，E-选择蛋白/E-选择蛋白配体和CD44/透明质酸（HA）轴。尽管HA是CD44的主要配体，但我们实验室的研究表明，CD44（称为HCELL）的专门糖型结合具有高亲和力的E-选择素。我们最近发现，人类结肠癌细胞上的CD44表达HCELL糖衣并结合E-选择素和HA。重要的是，CD44变异和与E-选择素结合的肿瘤细胞的表达与结肠癌预后不良相关。本文提出的研究旨在阐明HCELL/CD44与其配体E-选择蛋白和HA结合的关系，以及这些粘合剂途径在促进转移性级联反应中所起的作用，从肿瘤细胞的最初绑扎/滚动通过肿瘤细胞通过肿瘤细胞通过肿瘤细胞通过肿瘤细胞的最初通过，迁移和组织浸润。关于此计划公告，我们试图定义癌症微环境如何影响CD44的表达和功能（包括糖基化呈现E-选择蛋白结合剂（S）），这是一种预期促进结肠癌转移的分子。该提案的具体目的是：（1）分析CD44在结肠癌细胞上的表达水平，表面分布和功能；（2）确定微环境因素是否可以影响CD44在结肠癌细胞上的同工型/糖型的表达和分布；（3）通过操纵肿瘤细胞CD44表达/功能和碳水化合物的修饰来分析结肠癌细胞对迁移和种子组织部位的能力。可以预料，本文提出的研究的结果将导致对CD44作为在流体动力剪切条件下结肠癌细胞 - 细胞内皮相互作用的分子效应的作用有更深入的了解。该信息是设计新的治疗策略以防止结肠癌传播的基础，因此对预防晚期疾病具有深远的影响。摘要：结肠癌转移的基本分子基础知之甚少。拟议的研究将集中于CD44，这是一种与预后不良和疾病进展相关的分子。预计从这些研究中收集的信息将构成针对结肠癌中CD44的治疗剂的基础。