(PQ1) Mechanisms for Early Onset Colorectal Cancer

(PQ1) 早发性结直肠癌的机制

基本信息

批准号：
10178968
负责人：
Daniel William Rosenberg
金额：
$ 24.36万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10178968
关键词：
Aberrant crypt foci Advanced Malignant Neoplasm Age Age-Years Aneuploidy Appearance Architecture Automobile Driving BRAF gene Biopsy Biopsy Specimen Cancerous Cell division Cells Coculture Techniques CpG Island Methylator Phenotype Custom Cytometry DNA Development Diagnosis Disease Disease Progression Distal Endothelium Epithelial Epithelial Cells Event Extracellular Matrix Fibroblasts Fresh Tissue Genetic Transcription Genotype Hand Hyperactivity Image Immune Immune response Incidence Individual Inflammation Inflammatory Injury Interphase Cell Lesion Longitudinal Studies Malignant Neoplasms Mass Spectrum Analysis Molecular Mucinous Mucous Membrane Mus Mutation Mutation Analysis Myofibroblast Neoplasms Normal tissue morphology Organoids Pathogenesis Patients Phenotype Play Population Prevention Process Reagent Resected Rest Risk Sampling Space Perception Tissues Tumor Angiogenesis adenoma angiogenesis cancer diagnosis cancer risk cell growth cell motility cell type chemokine crypt cell cytokine early onset colorectal cancer experimental study healing immunoregulation interest laser capture microdissection lifestyle factors mutational status neoplastic older patient rectal repository response screening senescence study population tumor tumor growth tumor progression wound

项目摘要

PROJECT SUMMARY The rate of early onset colorectal cancer (EOCRC; <50 years of age at diagnosis) continues to increase, even as CRC rates for individuals over 50 have been declining, largely as a result of prevention by enhanced colonoscopic screening. Cancers diagnosed in younger patients tend to be more distal/rectal, mucinous, poorly differentiated and diagnosed at an advanced stage, suggesting a rapid disease progression. Although sporadic EOCRCs are less likely to show aneuploidy, BRAF mutations or CIMP, they are otherwise similar at a molecular level to cancers in individuals greater than 50 years of age. Given the early formation and rapid progression of EOCRC, it is likely that strong promotional factors are at play. Fibroblasts are a key cell type in establishing a microenvironment conducive to cancer progression as they coordinate the activities of epithelial, endothelial and immune cells in the tissue. Fibroblasts can exist in a number of distinct states with dramatically different activities. Resident fibroblast in healthy tissue are non-dividing cells that help establish tissue architecture and crypt cell dynamics. However, when adjacent to cancerous cells, fibroblasts can become persistently activated as cancer-associated fibroblasts (CAFs) that promote tumor growth and angiogenesis, while suppressing immune responses. CAFs can also become senescent and acquire an irreversible senescence associated secretory phenotype (SASP) that establishes a “permanent” cancer promoting microenvironment. We hypothesize that the underlying stroma advances rapidly in EOCRC to drive early disease pathogenesis. Specifically, we propose that environmental and/or life-style factors cause aberrant fibroblast activation that negatively impacts the normal function of immunoregulatory cells within the stroma, while promoting epithelial cell division. The exploratory experiments proposed here will assess fibroblast proliferation, activation and senescence at different stages of cancer development in young patients. Understanding fibroblast dysregulation in individuals at risk of EOCRC could provide important information for understanding the factors responsible for the increasing incidence of EOCRC and ultimately point to approaches that reduce this risk. We will study fibroblast populations in colonic lesions from patients under 45 and over 60 years old. Using a combination of laser-capture microdissection combined with targeted RNA expression analysis and Imaging Mass CytometryTM, we will define the distinguishing set of molecular alterations characterize define EOCRC cases. Our study population will include normal mucosa, preneoplastic tissue with activated fibroblasts, advanced adenomas and CRCs. Overall, these studies will determine how a hyper-responsive “hot” stromal microenvironment established by activated and/or senescent fibroblasts relates to other stromal events that contribute to the rapid advancement of EOCRC. Once details of the activated fibroblast populations present in these tissues is determined, long term studies would aim to determine how personal factors relate to their appearance and how their activity might be mitigated to suppress CRC risk.

项目摘要早期结直肠癌（EOCRC；诊断时年龄 <50 岁）的发病率尽管 50 岁以上人群的 CRC 发病率一直在下降（主要是由于通过加强结肠镜筛查来预防癌症往往更多地发生在年轻患者中。远端/直肠，粘液性，分化差，诊断时已处于晚期，提示疾病进展迅速尽管散发性 EOCRC 不太可能表现出非整倍体、BRAF 突变或 CIMP，但它们其他方面在分子水平上与 50 岁以上个体的癌症相似。 EOCRC 的形成和快速进展，很可能是强大的促进因素在起作用。建立有利于癌症进展的微环境的关键细胞类型，因为它们协调具有上皮细胞、内皮细胞和免疫细胞活性的组织中可以存在许多不同的成纤维细胞。健康组织中的常驻成纤维细胞是具有显着不同活性的非分裂细胞。建立组织结构和隐窝细胞动力学然而，当邻近癌细胞、成纤维细胞时。可以作为癌症相关成纤维细胞 (CAF) 持续激活，促进肿瘤生长和血管生成，同时抑制免疫反应，CAF 也会衰老并获得免疫反应。不可逆衰老相关分泌表型（SASP），形成“永久性”癌症我们努力让底层基质在 EOCRC 中快速发展以驱动。具体来说，我们认为环境和/或生活方式因素导致异常。成纤维细胞活化，对基质内免疫调节细胞的正常功能产生负面影响，同时促进上皮细胞分裂。这里提出的探索性实验将评估成纤维细胞。年轻患者癌症发展不同阶段的增殖、激活和衰老。了解有 EOCRC 风险的个体中成纤维细胞失调可以为以下方面提供重要信息：了解造成 EOCRC 发病率增加的因素并最终指出解决方法我们将研究 45 岁以下和 60 岁以上患者结肠病变中的成纤维细胞群。结合使用激光捕获显微切割和靶向 RNA 表达。分析和成像质量细胞计数TM，我们将定义一组独特的分子改变，表征定义 EOCRC 病例，我们的研究人群将包括正常粘膜、活化的癌前组织。总体而言，这些研究将确定高反应性“热”如何。由活化和/或衰老成纤维细胞建立的基质微环境与其他基质事件相关一旦出现激活的成纤维细胞群的详细信息，将有助于 EOCRC 的快速发展。在这些组织中已确定，长期研究的目的是确定个人因素如何与其相关的出现以及如何减轻其活动以抑制 CRC 风险。