Translational Science of Gastrointestinal Cancer Initiation and Progression

胃肠癌发生和进展的转化科学

• 批准号: 10734003
• 负责人: Ming Yu
• 金额: $ 34.6万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734003
• 关键词: Aberrant DNA Methylation; Acceleration; Atlases; Automobile Driving; Award; Barrett Esophagus; Basic Science; Biological Markers; Biological Models; Cancer Etiology; Carcinoma; Cells; Cessation of life; Clinical; Clonal Expansion; Colon; Colon Carcinoma; Colorectal Cancer; DNA Methylation; Early Detection Research Network; Early Diagnosis; Ensure; Epigenetic Process; Epithelial Cells; Esophageal Adenocarcinoma; Fibroblasts; Funding; Gastrointestinal tract structure; Gene Mutation; High grade dysplasia; Lesion; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mediating; Molecular; Molecular Carcinogenesis; Patients; Polyps; Prevention; Prevention therapy; Process; Prognosis; Public Health; Reproducibility; Research; Risk; Risk Marker; Role; Sampling; Scientist; Specialist; Tissues; Translational Research; Translations; Tumor Promotion; adenoma; biomarker development; cancer initiation; cancer prevention; carcinogenesis; colorectal cancer risk; colorectal cancer screening; improved; in vivo Model; insight; methylation pattern; novel; premalignant; programs; progression marker; senescence; tissue biomarkers; translational cancer research; tumor; tumor progression; tumorigenic

SUMMARY: Gastrointestinal tract cancers (GI cancers) account for >70,000 deaths per year. Among GI cancers, colorectal cancer (CRC) is the third most common cancer in the US. Esophageal adenocarcinoma (EAC) is another GI cancer of large concern to US public health and has risen alarmingly with a poor prognosis (20% 5- year survival). There is an unmet need for effective cancer prevention and early detection of CRC and EAC. CRC & EAC arise from precancer lesions: CRC arises from adenomas and EAC from Barrett’s esophagus (BE), which progress to high-grade dysplasia (HGD) and then cancer. This normal precancer lesioncarcinoma sequence of GI tract epithelial cells has been the established paradigm of the cancer initiation and progression process in the GI tract. The polyp-to-cancer paradigm suggests that progression is driven solely by the accumulation of gene mutations and epigenetic alterations in cancer initiating cells. However, emerging evidence suggests that these molecular alterations are insufficient to drive cancer formation and that multiple tumor promoting mechanisms come from surrounding tissue. For example, our previous studies have shown that increased senescent fibroblasts present in the normal colon of advanced adenoma patients can create a pro-tumorigenic microenvironment. Further, molecular changes in the normal colon of patients with advanced lesions may predispose tissue to tumor formation and mediate the carcinogenesis process, such as presence of aberrant DNA methylation pattern, high gene mutation loads and microinflammation. Based on our previous studies, we hypothesize that cancer initiation and progression require both cell-autonomous (e.g., cancer driver gene mutations) and non-autonomous mechanisms from the tissue microenvironment. Discovery of the factors mediating adenoma initiation & progression, and the translation of these findings into novel risk biomarkers or prevention therapy would have a major impact on clinical prevention and management of GI cancers. To overcome technical barriers in prior studies and ensure scientific rigor and reproducibility, the Research Specialist, Dr. Ming Yu, has developed a research plan to achieve the following objectives within the next five years: Objective 1: Determine the role of senescent fibroblasts to promote the survival and clonal expansion of colon cancer initiating cells in ex-vivo & in-vivo model system; Objective 2: Create a precancer atlas of molecular alterations potentially associated with driving adenoma progression in primary clinical samples; Objective 3: Identify and evaluate DNA methylation-based tissue biomarkers as CRC risk markers and BE progression markers. This research plan is an integral part of the NCI-funded research programs led by Unit Director, Dr. William Grady, including the Early Detection Research Network Biomarker Characterization Center and the Translational & Basic Science of Early Lesion Center. Successful completion of this research plan will provide critical support to these research programs and lead to novel insight on the molecular carcinogenesis of GI cancer. Findings will provide a new direction for discovering biomarkers to improve GI cancer management.

摘要：胃肠道癌症（GI癌症）每年造成超过70，000人死亡。在胃肠道癌症中， 结肠直肠癌（CRC）是美国第三常见的癌症。食管腺癌（EAC）是 另一种胃肠道癌症，是美国公共卫生的一大关注点，并且以惊人的速度上升，预后不良（20%，5- 年生存）。对于有效的癌症预防和CRC和EAC的早期检测存在未满足的需求。 CRC和EAC来自癌前病变：CRC来自腺瘤，EAC来自巴雷特食管 (BE)进展为高度异型增生（HGD），然后是癌症。这种正常的乳腺癌前病变 胃肠道上皮细胞的病变-癌序列已成为癌症起始的既定范例 和胃肠道的进展过程。从息肉到癌症的模式表明， 基因突变和表观遗传学改变在癌症起始细胞中的积累。但新兴 有证据表明，这些分子改变不足以驱动癌症形成， 肿瘤促进机制来自周围组织。例如，我们之前的研究表明， 在晚期腺瘤患者的正常结肠中存在的衰老成纤维细胞的增加可以产生 促肿瘤微环境此外，晚期结肠癌患者的正常结肠中的分子变化， 病变可能使组织易于形成肿瘤，并介导致癌过程，例如存在 异常的DNA甲基化模式、高基因突变负荷和微炎症。基于我们之前 研究中，我们假设癌症的发生和发展需要细胞自主（例如，癌症驱动 基因突变）和来自组织微环境的非自主机制。发现因素 介导腺瘤的发生和进展，并将这些发现转化为新的风险生物标志物， 预防治疗将对GI癌症的临床预防和管理产生重大影响。 为了克服先前研究中的技术障碍，并确保科学的严谨性和可重复性， 专家余明博士制定了一项研究计划，在未来五年内实现以下目标 目的1：确定衰老成纤维细胞在促进细胞存活和克隆扩增中的作用。 结肠癌前病变细胞的体外和体内模型系统;目的2：建立结肠癌前病变细胞的分子图谱 在主要临床样本中可能与驱动腺瘤进展相关的改变;目的 3：鉴定和评估基于DNA甲基化的组织生物标志物作为CRC风险标志物和BE进展 标记。该研究计划是由美国国家癌症研究所资助的研究项目的一个组成部分，该项目由该研究所所长， 威廉·格雷迪，包括早期检测研究网络生物标志物表征中心和 早期病变转化与基础科学中心。成功完成这项研究计划将提供 关键支持这些研究计划，并导致新的见解的分子致癌的GI 癌这些发现将为发现生物标志物以改善GI癌症管理提供新的方向。