Novel Reg4-CD44 Signaling Pathway in Colon Cancer

结肠癌中的新型 Reg4-CD44 信号通路

基本信息

批准号：
9795436
负责人：
BRIAN Keith DIECKGRAEFE
金额：
--
依托单位：
ST. LOUIS VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9795436
关键词：
Address Aftercare Agar Animal Model Antibodies Apoptosis Apoptotic Binding Biological Assay CD44 gene Cancer Etiology Cancer Patient Cell Nucleus Cell Proliferation Cell Surface Receptors Cell Survival Cell surface Cells Cessation of life Clinical Colon Carcinoma Colorectal Colorectal Adenocarcinoma Colorectal Cancer Critical Pathways Cyclic AMP-Responsive DNA-Binding Protein Cyclin D1 Data Diagnosis Disease Early Diagnosis Esophageal Adenocarcinoma Event Excision Gallbladder Carcinoma Gallbladder adenocarcinoma Gastric Adenocarcinoma Genes Glioma Growth In Vitro Large Intestine Carcinoma Legal patent Ligands Link Maintenance Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Malignant neoplasm of pancreas Mediating Microscopic Modeling Monoclonal Antibodies Natural regeneration Neoplastic Processes Outcome Pancreas Pancreatic Adenocarcinoma Pancreatic carcinoma Pathway interactions Patients Play Population Premalignant Probability Protein Isoforms Proteolysis RNA Interference RNA Splicing Radiation Receptor Protein-Tyrosine Kinases Receptor Signaling Recurrence Relapse Resistance Role Signal Pathway Signal Transduction Specimen Stem cells Stomach Stomach Carcinoma Symptoms Testing Therapeutic Time Transcription Coactivator Transcriptional Activation Transfection Tumor Cell Line Tumor Initiators Variant Xenograft Model advanced disease cancer biomarkers cancer cell cancer survival carcinogenesis care costs cell growth chemotherapeutic agent clinically relevant colon cancer screening colon cancer treatment gamma secretase human model improved in vivo inhibitor/antagonist innovation malignant stomach neoplasm neoplastic cell novel off-patent osteopontin palliative public health relevance radiation resistance receptor response screening program self-renewal stem stem-like cell stemness therapeutic target therapy resistant tool treatment response tumor tumor behavior tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Gastrointestinal (GI) malignancies account for nearly half of worldwide cancer deaths. A small population of cells, termed tumor-initiating cells or cancer stem-like cells (CSCs), are important for tumor maintenance, progression and post-treatment recurrence. It is speculated that this specialized population of cells mediates the treatment resistance that is a hallmark of GI malignancy. Reg4 expression is an early event in carcinogenesis in colon, gastric and pancreatic carcinomas and is independently associated with poor clinical outcomes from colorectal, gastric and pancreatic cancers. This proposal follows our recent discovery of the Reg4 receptor, and our preliminary data that suggests that it may play an important role in the proliferation and survival of the CSC. Since these pathways are not addressed by existing therapeutics, targeting Reg4-CD44ICD signaling in the stem cell could dramatically change the current treatment paradigm and enhance responsiveness to chemotherapeutic agents. This proposal has three Aims; one focused on identification of the CD44 isoforms that can serve as the Reg4 receptor, an experimental Aim focused on examining the role of CD44ICD in the CSC, and a clinical Aim focused on determining the relationship between CD44ICD signaling and clinicopathologic features in colorectal cancer.

描述（由申请人提供）：胃肠道 (GI) 恶性肿瘤占全球癌症死亡人数的近一半，称为肿瘤起始细胞或癌症干细胞样细胞 (CSC) 的一小群细胞对于肿瘤的维持、进展和治疗后复发至关重要。推测这种特殊的细胞群介导治疗抵抗，这是胃肠道恶性肿瘤的一个标志，Reg4 表达是结肠癌、胃癌和胰腺癌癌变的早期事件，并且与不良临床结果独立相关。这项提议是在我们最近发现 Reg4 受体之后提出的，我们的初步数据表明它可能在 CSC 的增殖和存活中发挥重要作用，因为现有的治疗方法无法解决这些途径，靶向干细胞中的 Reg4-CD44ICD 信号传导可以极大地改变当前的治疗模式并增强对化疗药物的反应性。该提案有三个目标：其中一个重点是鉴定可作为化疗药物的 CD44 同工型。 Reg4 受体，实验目标侧重于检查 CD44ICD 在 CSC 中的作用，临床目标侧重于确定 CD44ICD 信号传导与结直肠癌临床病理特征之间的关系。