(PQ1) Mechanisms for Early Onset Colorectal Cancer

早发性结直肠癌（EOCRC;诊断时年龄<50岁）的发病率 继续增加，即使50岁以上人群的CRC率一直在下降，主要是由于 通过加强结肠镜筛查进行预防。在年轻患者中诊断出的癌症往往更多 远端/直肠，粘液性，分化差，在晚期诊断，提示快速疾病 进展尽管散发性EOCRC不太可能显示非整倍体、BRAF突变或CIMP，但它们是 否则在分子水平上与大于50岁的个体中的癌症相似。鉴于早 在EOCRC的形成和快速进展中，很可能有强烈的促进因素在起作用。成纤维细胞是 一种关键的细胞类型，在建立一个有利于癌症进展的微环境，因为它们协调 组织中上皮细胞、内皮细胞和免疫细胞的活性。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，当邻近癌细胞时，成纤维细胞 可以作为促进肿瘤生长的癌症相关成纤维细胞（CAF）持续活化， 血管生成，同时抑制免疫反应。CAFs也会衰老，并获得 不可逆衰老相关分泌表型（SASP），建立“永久性”癌症 改善微环境。我们假设EOCRC的基础间质快速进展， 早期发病机制。具体来说，我们认为环境和/或生活方式因素会导致异常的 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 在年轻患者癌症发展的不同阶段的增殖、活化和衰老。 了解有EOCRC风险的个体中的成纤维细胞失调可以为 了解导致EOCRC发病率增加的因素，并最终指出方法 降低这种风险。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 岁使用激光捕获显微切割结合靶向RNA表达的组合 分析和成像质量细胞仪TM，我们将定义分子改变的区别集， 定义EOCRC病例。我们的研究人群将包括正常粘膜，癌前组织与活化的 成纤维细胞、晚期腺瘤和CRC。总的来说，这些研究将确定一个反应过度的“热” 由活化的和/或衰老的成纤维细胞建立的基质微环境涉及其它基质事件 这有助于EOCRC的快速发展。一旦激活的成纤维细胞群的细节出现， 长期研究的目的是确定个人因素如何与其 外观以及如何减轻其活性以抑制CRC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.