Novel Reg4-CD44 Signaling Pathway in Colon Cancer

结肠癌中的新型 Reg4-CD44 信号通路

• 批准号: 9339585
• 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
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9339585
• 关键词: Address; Aftercare; Agar; Animal Model; Antibodies; Apoptosis; Apoptotic; Behavior; Binding; Biological Assay; CD44 gene; Cancer Etiology; Cancer Patient; Caring; 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; Human; In Vitro; Large Intestine Carcinoma; Legal patent; Ligands; Link; Maintenance; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of pancreas; Mediating; Microscopic; Modeling; 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; Screening for cancer; 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; cancer therapy; carcinogenesis; cell growth; chemotherapeutic agent; clinically relevant; cost; gamma secretase; improved; in vivo; inhibitor/antagonist; innovation; malignant stomach neoplasm; neoplastic cell; novel; osteopontin; palliative; programs; public health relevance; radiation resistance; receptor; response; screening; self-renewal; stem; stem-like cell; stemness; therapeutic target; therapy resistant; tool; treatment response; tumor; tumorigenesis

 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）恶性肿瘤几乎占全球癌症死亡的一半。一小部分细胞，称为肿瘤发射细胞或癌变干细胞（CSC），对于维持肿瘤，进展和治疗后复发很重要。据推测，这种专门的细胞群介导了胃肠道恶性肿瘤的标志的治疗耐药性。 Reg4表达是结肠，胃和胰腺癌中癌变的早期事件，与结直肠癌，胃和胰腺癌的临床结局不良相关。该提案遵循我们最近发现REG4受体的发现，以及我们的初步数据表明，它可能在CSC的增殖和生存中起重要作用。由于这些途径未通过现有疗法来解决，因此靶向干细胞中的REG4-CD44ICD信号传导可能会大大改变当前的治疗范式并提高对化学治疗剂的反应性。该提议有三个目标。一个重点是鉴定可以用作REG4受体的CD44同工型，这是一个侧重于检查CD44ICD在CSC中的作用的实验目的，临床目的侧重于确定CD44ICD信号传导与结直肠癌临床病理学特征之间的关系。