Mechanisms of NOTCH, NUMB and MET signaling in Colon Cancer Initiating Cell Asymm

NOTCH、NUMB 和 MET 信号在结肠癌引发细胞不对称中的机制

• 批准号: 8287536
• 负责人: Steven M Lipkin
• 金额: $ 18.38万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8287536
• 关键词: Blood Circulation; Cancer Etiology; Cancer Patient; Cancer cell line; Cell Count; Cell Line; Cell surface; Cells; Cessation of life; Clinical Data; Colon; Colon Carcinoma; Colorectal Cancer; Cytotoxic Chemotherapy; Data; Diagnosis; Equilibrium; Fluorescence Microscopy; Goals; Hepatocyte Growth Factor; Individual; Inherited; Life; Ligand Binding; Link; Measures; Minority; Mitosis; Modeling; Neoplasm Metastasis; Organ; Outcome; Parents; Patients; Play; Role; Signal Transduction; Signal Transduction Inhibitor; Solid Neoplasm; Stem cells; Techniques; Testing; United States; base; cancer cell; cancer chemoprevention; chemotherapy; daughter cell; drug development; improved; inhibitor/antagonist; innovation; insight; leukemia; molecular marker; mutant; neoplastic cell; novel; receptor; research study; self-renewal; success; theories; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Almost half a million new cases of colorectal cancer (CRC) worldwide are diagnosed each year. Studies from our lab and others have shown that CRC initiating cells (CCIC) are important for CRC formation. In contrast to commonly used CRC cell lines, CCIC serially maintain tumors with the pathological and molecular markers of the primary CRCs from which they were derived. However, the mechanism of CCIC tumor formation, and how it differs from that used by commonly used CRC cell lines to form tumors, is poorly characterized. We recently derived new CCIC lines and made several novel findings. These include data that (1) CCIC have 30X+ higher NOTCH signaling levels than commonly used CRC cell lines, (2) NOTCH signaling is critical for CCIC self-renewal and tumor formation and (3) CCIC use a NOTCH driven mechanism to mitose asymmetrically (similar to the mechanism used by normal colon stem cells to form colon crypts) and generate distinct daughter cells. This is the first example of CRC cell asymmetric mitosis. Asymmetric mitosis is critical for leukemia CIC tumor formation and self-renewal and is likely to play a similar role for CCIC. Since commonly used CRC cell lines do not mitose asymmetrically this study will provide unique insights into the mechanism of CCIC tumor formation and how it differs from that used by commonly used CRC cell lines. The overall goal of this proposal is to understand the mechanism that regulates the balance between colon cancer initiating cell symmetric and asymmetric mitosis and the role of each in CCIC self-renewal and tumor formation. Based on the role of NOTCH in normal colon stem cell asymmetric mitosis and our preliminary data we hypothesize that NOTCH, NUMB and HGF/MET critically regulate colon cancer initiating cell asymmetric/symmetric mitosis, tumor formation and self-renewal. We propose AIM 1 Identify the mechanism of NOTCH driven CCIC asymmetric mitosis and tumor formation and AIM 2 Test hypotheses that NUMB and HGF/MET regulate CCIC symmetric and asymmetric mitosis

描述（由申请人提供）：每年诊断出全球近半百万个新的结直肠癌（CRC）病例。我们实验室和其他人的研究表明，CRC启动细胞（CCIC）对于CRC形成很重要。与常用的CRC细胞系相比，CCIC串行与衍生的主要CRC的病理和分子标记物保持肿瘤。然而，CCIC肿瘤形成的机制及其与常用的CRC细胞系形成肿瘤的机制不同。我们最近得出了新的CCIC线条，并做出了一些新颖的发现。这些数据包括（1）CCIC比常用的CRC细胞系具有30倍以上的Notch信号传导水平，（2）Notch信号对于CCIC的自我更新和肿瘤形成至关重要，并且（3）CCIC使用凹槽驱动的机制不对称地构成线索（类似于正常的结肠干细胞与形成结肠crage的机制相似），并形成了结肠crage的生成差异）。这是CRC细胞不对称有丝分裂的第一个例子。不对称有丝分裂对于白血病CIC肿瘤的形成和自我更新至关重要，并且可能对CCIC发挥相似的作用。由于常用的CRC细胞系并非不对称地有丝分裂，因此该研究将提供有关CCIC肿瘤形成机理的独特见解，以及它与常用CRC细胞系所使用的机理的不同之处。该提案的总体目标是了解调节结肠癌启动细胞对称性和不对称有丝分裂之间平衡的机制，以及每种细胞在CCIC自我更新和肿瘤形成中的作用。基于Notch在正常结肠干细胞不对称有丝分裂和我们的初步数据中的作用，我们假设Notch，Numb和HGF/MET严重调节结肠癌的结肠癌启动细胞不对称/对称有丝分裂，肿瘤形成和自我更新。我们提出的目标1确定Notch驱动的CCIC不对称有丝分裂和肿瘤形成的机制，AIM 2测试假设假设麻木和HGF/MET调节CCIC对称和不对称有丝分裂