(PQ1) Mechanisms for Early Onset Colorectal Cancer

项目摘要：早发性结直肠癌的发病率(确诊时为50岁) 继续上升，尽管50岁以上的人的CRC比率一直在下降，这主要是由于 通过加强结肠镜筛查进行预防。年轻患者诊断出的癌症往往更多 远端/直肠，粘液，分化低，诊断为晚期，提示疾病进展迅速。 进步。尽管零星的EOCR不太可能表现出非整倍体、BRAF突变或CIMP，但它们 在其他方面，在分子水平上与50岁以上个体的癌症相似。考虑到这么早 EOCRC的形成和快速发展，很可能是强大的促进因素在起作用。成纤维细胞是 在建立有利于癌症进展的微环境中的一种关键细胞类型，因为它们协调 组织中上皮细胞、内皮细胞和免疫细胞的活动。成纤维细胞可以存在于许多不同的 有着截然不同活动的国家。健康组织中的常驻成纤维细胞是帮助 建立组织结构和隐窝细胞动力学。然而，当与癌细胞相邻时，成纤维细胞 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也可能变得衰老并获得 不可逆衰老相关的分泌表型(SASP)，可建立一种“永久性”癌症 提升微环境。我们假设在EOCRC中潜在的间质快速推进以驱动 早期疾病发病机制。具体地说，我们认为环境和/或生活方式因素导致异常 成纤维细胞的激活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EOCRC高危个体中成纤维细胞的调控异常可以为 了解导致EOCRC发病率增加的因素，并最终提出解决办法 从而降低了这种风险。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。 很多年了。利用激光捕获显微切割结合靶向RNA表达 分析和成像质量CytometryTM，我们将定义一组与众不同的分子变化特征 定义EOCRC案例。我们的研究人群将包括正常粘膜、癌前组织和激活的 成纤维细胞、晚期腺瘤和癌。总体而言，这些研究将确定一个反应强烈的“热” 活化和/或衰老的成纤维细胞建立的间质微环境与其他间质事件有关 这有助于EOCRC的快速发展。一旦激活的成纤维细胞群体的细节出现 在这些组织中，长期研究的目的是确定个人因素如何与他们的 以及如何减轻他们的活动以抑制结直肠癌风险。

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.