Mechanisms of Notch Signalling in Colon Cancer Initiating Cells

描述（由申请人提供）：最近的研究表明，结直肠癌起始细胞（CCIC）在结直肠癌（CRC）的肿瘤发生和转移中起重要作用。在初步研究中，我们从原发性crc和转移性crc中获得了多个新的CCIC系。我们发现，与常用的CRC细胞系相比，CCIC具有显著升高的NOTCH信号水平，并且当NOTCH被抑制时，CCIC发生细胞周期阻滞和凋亡。本课题的总体目标是了解NOTCH信号在结肠癌起始细胞中的作用机制以及NOTCH在人类结肠癌中的作用。这一目标具有重要意义，因为确定CCIC的关键药物靶点和生物标志物是改善当前结直肠癌化学预防和化疗的创新方法。因此，我们提出(1)确定CCIC抗凋亡、异种移植物形成和自我更新的关键NOTCH通路组分；(2)验证非甾体抗炎药（NSAIDs）抑制结肠癌起始细胞3-分泌酶活性和NOTCH信号传导的假设。

DESCRIPTION (provided by applicant): Recent studies have provided evidence that colorectal cancer initiating cells (CCIC) are important in colorectal cancer (CRC) tumorigenesis and metastasis. In Preliminary Studies, we derived multiple new CCIC lines from both primary CRCs and metastases. We show that CCIC have significantly elevated NOTCH signaling levels vs. commonly used CRC cell lines, and that CCIC undergo cell cycle arrest and apoptosis when NOTCH is inhibited. The overall goal of this proposal is to understand the mechanism of NOTCH signaling in colon cancer initiating cells and the role of NOTCH in human colon cancer. This goal is significant because identifying critical drug targets and biomarkers for CCIC is an innovative approach to improve current CRC chemoprevention and chemotherapy. We therefore propose to (1) Identify critical NOTCH pathway components in CCIC anti- apoptosis, xenograft formation and self-renewal and (2) Test the hypothesis that Non-Steroidal Anti- Inflammatory Drugs (NSAIDs) inhibit 3-secretase activity and NOTCH signaling in Colon Cancer Initiating Cells. PUBLIC HEALTH RELEVANCE: Recent studies have provided evidence that colorectal cancer initiating cells (CCIC) are important in colorectal cancer (CRC) tumorigenesis and metastasis. In Preliminary Studies, we derived multiple new CCIC lines from both primary CRCs and metastases. We show that CCIC have significantly elevated NOTCH signaling levels vs. commonly used CRC cell lines, and that CCIC undergo cell cycle arrest and apoptosis when NOTCH is inhibited. The overall goal of this proposal is to understand the mechanism of NOTCH signaling in colon cancer initiating cells and the role of NOTCH in human colon cancer. Understanding the mechanism of NOTCH signaling in CCIC has the potential to identify more effective drug targets for CRC chemoprevention and chemotherapy and identify biomarkers directly involved in the mechanisms of tumorigenesis and metastasis.