Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy.
Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy.
Biomed Res Int. 2020 Mar 16;2020:1726309. doi: 10.1155/2020/1726309. eCollection 2020.
The development of colorectal cancer (CRC) is a multistep process initiated by a benign polyp that has the potential to evolve into carcinoma through the interactions between environmental and genetic factors. CRC incidence rates are constantly increased for young adult patients presenting an advanced tumor stage. The majority of CRCs arise from colonic adenomas originating from aberrant cell proliferation of colon epithelium. Endoscopic polypectomy represents a tool for early detection and removal of polyps, although the occurrence of cancers after negative colonoscopy shows a significant incidence. It has long been recognized that the aberrant regulation of Wingless/It (Wnt)/-Catenin signaling in the pathogenesis of colorectal cancer is supported by its critical role in the differentiation of stem cells in intestinal crypts and in the maintenance of intestinal homeostasis. For this review, we will focus on the development of adenomatous polyps through the interplay between renewal signaling in the colon epithelium and reactive oxygen species (ROS) production. The current knowledge of molecular pathology allows us to deepen the relationships between oxidative stress and other risk factors as lifestyle, microbiota, and predisposition. We underline that the chronic inflammation and ROS production in the colon epithelium can impair the Wnt/-catenin and/or base excision repair (BER) pathways and predispose to polyp development. In fact, the coexistence of oxidative DNA damage and errors in DNA polymerase can foster C>T transitions in various types of cancer and adenomas, leading to a hypermutated phenotype of tumor cells. Moreover, the function of Adenomatous Polyposis Coli () protein in regulating DNA repair is very important as therapeutic implication making DNA damaging chemotherapeutic agents more effective in CRC cells that tend to accumulate mutations. Additional studies will determine whether approaches based on Wnt inhibition would provide long-term therapeutic value in CRC, but it is clear that disruption plays a central role in driving and maintaining tumorigenesis.
结直肠癌（CRC）的发展是一个多步骤的过程，由具有发展为癌潜能的良性息肉起始，其通过环境和遗传因素之间的相互作用而发生。CRC 的发病率在呈现晚期肿瘤分期的年轻成年患者中不断增加。大多数 CRC 起源于结肠腺瘤，这些腺瘤源自结肠上皮细胞的异常细胞增殖。内镜息肉切除术是早期发现和切除息肉的工具，尽管阴性结肠镜检查后的癌症发生具有显著的发生率。长期以来，人们已经认识到，Wingless/It（Wnt）/-Catenin 信号通路的异常调节在结直肠癌的发病机制中起关键作用，这是因为它在肠隐窝干细胞的分化和维持肠道内稳态中起关键作用。在这篇综述中，我们将重点讨论通过结肠上皮细胞更新信号与活性氧（ROS）产生之间的相互作用来发展腺瘤性息肉。目前的分子病理学知识使我们能够深入了解氧化应激与其他风险因素（如生活方式、微生物群和易感性）之间的关系。我们强调，结肠上皮细胞中的慢性炎症和 ROS 产生会损害 Wnt/-Catenin 和/或碱基切除修复（BER）途径，并导致息肉的发生。事实上，氧化 DNA 损伤和 DNA 聚合酶错误的共存可以促进各种类型的癌症和腺瘤中的 C>T 转换，导致肿瘤细胞的超突变表型。此外，腺瘤性息肉病基因（APC）蛋白在调节 DNA 修复中的功能非常重要，因为它具有治疗意义，使 DNA 损伤化学疗法在倾向于积累突变的 CRC 细胞中更有效。进一步的研究将确定基于 Wnt 抑制的方法是否会为 CRC 提供长期的治疗价值，但很明显，APC 失活在驱动和维持肿瘤发生中起着核心作用。
