Regulation of Wnt Signaling in Invasive Colon Cancer

侵袭性结肠癌中 Wnt 信号转导的调控

• 批准号: 8984015
• 负责人: George Tsun-Te Chen
• 金额: $ 3.67万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-20 至 2018-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8984015
• 关键词: Address; Autocrine Communication; Biological Assay; Cancer Etiology; Cell Mobility; Cell Nucleus; Cells; Cessation of life; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Colon; Colon Carcinoma; Diagnosis; Disease; Distant; Endothelial Cells; Epithelium; Fibroblasts; Gene Silencing; Gene Targeting; Growth; Growth Factor; Health; Heterogeneity; Immune; Ligands; Link; Malignant Neoplasms; Measures; Microfluidic Microchips; Mucous Membrane; Mutation; Neoplasm Metastasis; Organ; Pathway interactions; Patients; Phenotype; Proteins; Publishing; RORA gene; Regulation; Research; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Stromal Cells; TCF Transcription Factor; Testing; Therapeutic; United States; Woman; autocrine; base; beta catenin; cancer cell; cancer therapy; cell motility; colon cancer patients; extracellular; inhibitor/antagonist; men; migration; neoplastic cell; novel; overexpression; paracrine; prevent; receptor; small hairpin RNA; small molecule; therapeutic target; tumor; tumor microenvironment; tumor progression

 DESCRIPTION (provided by applicant): Colon cancer is the third leading cause of cancer deaths in men and women in the United States. It is defined by the transformation of the colon epithelium from regulated crypt growth to uncontrolled proliferation and invasion into the surrounding mucosa. The primary mutations that drive this transformation target the canonical Wnt signaling pathway by stabilizing ß-catenin to force overexpression of Wnt target genes and Wnt activity. Despite this chronic Wnt activation, the level of signaling activity within the tumoris heterogeneous, with regions of high and low Wnt activity, suggesting environmental signals crosstalk with the pathway. As one in five colon cancer patients are first identified with metastatic disease, and the typical survival for these patients post-diagnosis is five years, there is a pressing need to understand fluctuations in Wnt activity and how the tumor microenvironment can influence colon cancer progression and invasion. This project focuses on how heterogeneity of Wnt signaling in colon cancer is established through its modulation both by autocrine signaling and crosstalk signaling from stromal cells. Our lab and others have recently discovered that decreasing autocrine Wnt signaling in colon cancer cells through inhibition of Wnt ligand secretion leads to increased cell migration and invasion. Based upon published research and my preliminary findings, my overarching hypothesis is that Wnt signaling activity in colon cancer is down regulated during cancer invasion and metastasis. I will address this hypothesis in three specific aims. The first specific aim will identify the Wnt signaling pathway involved in inhibiting mobility. Scratch assays, three-dimensional tumor spheroid assays, and novel microfluidic devices developed here at UC Irvine will be used to measure changes in cancer cell phenotype when various Wnt pathways are perturbed. In the second aim, I will identify the receptors expressed by colon cancer cells that participate in the activation of the pathway. Lastly, I will specifically define the ligand: receptor interaction(s) tat are involved in inhibiting cell migration. Identifying this mechanism has potential therapeutic benefits in understanding how colon cancer metastasizes to distant organs.

 描述（由适用提供）：结肠癌是美国男性和女性癌症死亡的第三主要原因。它是由结肠上皮从受调节的隐窝生长转变为不受控制的增殖和入侵向周围粘膜的转化所定义的。通过稳定β-catenin迫使Wnt靶基因和Wnt活性的过表达，驱动该转化的主要突变靶向了规范Wnt信号通路。尽管存在这种慢性Wnt激活，但在Tuberis异质性的信号活性水平，具有高WNT和低Wnt活性的区域，表明环境信号与途径串扰。由于首先鉴定出五分之一的结肠癌患者患有转移性疾病，诊断后这些患者的典型生存率为五年，因此 迫切需要了解Wnt活性的波动，以及肿瘤微环境如何影响结肠癌的进展和侵袭。该项目的重点是如何通过自分泌信号传导和基质细胞的串扰信号传导来确定结肠癌中Wnt信号的异质性。我们的实验室和其他实验室最近发现，通过抑制Wnt配体秘密会导致细胞迁移和侵袭增加结肠癌细胞中的自分泌Wnt信号传导。根据已发表的研究和我的初步发现，我的总体假设是，在癌症侵袭和转移期间，结肠癌的Wnt信号传导活性受到调节。我将以三个具体目标解决这一假设。第一个特定目标将确定涉及抑制迁移率的WNT信号通路。刮擦测定，三维肿瘤球形测定以及在UC Irvine上开发的新型微流体设备将用于测量癌细胞表型的变化时，当各种Wnt途径受到干扰。在第二个目标中，我将确定参与途径激活的结肠癌细胞表达的受体。最后，我将专门定义配体：受体相互作用（S）参与抑制细胞迁移。确定这种机制在理解结肠癌如何转移到遥远的器官方面具有潜在的治疗益处。