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。一小群细胞，称为肿瘤起始细胞或癌症干细胞样细胞（CSC），对肿瘤的维持、进展和治疗后复发至关重要。据推测，这种特化的细胞群介导作为GI恶性肿瘤的标志的治疗抗性。Reg 4表达是结肠癌、胃癌和胰腺癌癌变的早期事件，并且与结直肠癌、胃癌和胰腺癌的不良临床结局独立相关。这一建议遵循我们最近发现的Reg 4受体，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。由于现有的治疗方法无法解决这些途径，因此靶向干细胞中的Reg 4-CD 44 ICD信号传导可能会显著改变目前的治疗模式并增强对化疗药物的反应性。这项建议有三个目的;一个目标集中于鉴定可作为Reg 4受体的CD 44同种型，一个实验目标集中于检查CD 44 ICD在CSC中的作用，以及一个临床目标集中于确定CD 44 ICD信号传导与结肠直肠癌临床病理学特征之间的关系。

 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.