Translational Science of Gastrointestinal Cancer Initiation and Progression

摘要：胃肠道癌症(GI癌症)每年造成70000人死亡。在胃肠道癌症中， 结直肠癌(CRC)是美国第三常见的癌症。食管腺癌(EAC) 另一种严重影响美国公众健康的胃肠道癌症，发病率上升惊人，预后差(20%-5%) 年存活率)。对有效预防癌症和及早发现结直肠癌和结直肠癌的需求尚未得到满足。 CRC和EAC起源于癌前病变：CRC起源于腺瘤，EAC起源于Barrett‘s食道 (BE)，发展为高度异型增生(HGD)，然后发展为癌症。这种正常的癌前病变 胃肠道上皮细胞的病变癌序列已成为肿瘤发生的既定范式 和胃肠道的进展过程。息肉到癌症的范例表明，进展完全是由 通过癌症启动细胞中基因突变和表观遗传变化的积累。然而，新兴的 有证据表明，这些分子变化不足以推动癌症的形成，而且 肿瘤的促进机制来自周围组织。例如，我们之前的研究表明， 晚期腺瘤患者正常结肠中衰老的成纤维细胞增加可产生 有利于肿瘤发生的微环境。此外，晚期结肠炎患者正常结肠的分子变化 病变可能使组织易于形成肿瘤，并介导致癌过程，如存在 DNA甲基化模式异常，高基因突变负荷和微炎症。基于我们之前的 研究表明，我们假设癌症的发生和发展都需要细胞自主(例如，癌症驱动因素 基因突变)和来自组织微环境的非自主机制。因素的发现 介导腺瘤的发生和发展，并将这些发现转化为新的风险生物标记物或 预防治疗将对胃肠道癌症的临床预防和治疗产生重大影响。 为了克服先前研究中的技术障碍，确保科学的严谨性和重复性，该研究 专家于明博士制定了一项研究计划，以在未来五年内实现以下目标 年：目标1：确定衰老成纤维细胞在促进卵巢癌存活和克隆性扩增中的作用 结肠癌起始细胞的体内外模型系统；目的2：建立癌前病变分子图谱 在初级临床样本中可能与推动腺瘤进展相关的改变；目的 3：确定和评估基于DNA甲基化的组织生物标记物作为结直肠癌风险标记物和BE进展 记号笔。这项研究计划是NCI资助的研究计划的组成部分，由单位主任Dr。 威廉·格雷迪，包括早期检测研究网络生物标记物表征中心和 早期病变中心的翻译与基础科学。成功完成这项研究计划将提供 对这些研究项目的关键支持，并导致对GI分子致癌的新见解 癌症。这些发现将为发现生物标记物以改善胃肠道癌症管理提供新的方向。

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.