Novel Reg4-CD44 Signaling Pathway in Colon Cancer

 描述(由申请人提供)： 胃肠道(GI)恶性肿瘤占全球癌症死亡的近一半。一小部分细胞，称为肿瘤起始细胞或肿瘤干细胞(CSCs)，对肿瘤的维持、进展和治疗后的复发都很重要。据推测，这种特殊的细胞群介导了治疗耐药，这是胃肠道恶性肿瘤的一个标志。Reg4的表达是结肠癌、胃癌和胰腺癌发生的早期事件，与结直肠癌、胃癌和胰腺癌的不良临床预后独立相关。这一建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，Reg4受体可能在CSC的增殖和生存中发挥重要作用。由于这些通路还没有被现有的治疗药物所解决，靶向干细胞中的Reg4-CD44ICD信号可以极大地改变目前的治疗模式，并提高对化疗药物的反应性。这项建议有三个目的：一个是鉴定可作为Reg4受体的CD44亚型，一个是研究CD44ICD在结直肠癌中的作用，一个是临床上的目的，重点是确定CD44ICD信号与结直肠癌临床病理特征的关系。

 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.