Molecular Aspects of Colorectal Adenomas: The Interplay among Microenvironment, Oxidative Stress, and Predisposition

Abstract

The development of colorectal cancer (CRC) is a multistep process initiated by a benign polyp that has the potential to evolve into in situ 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)/β-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/β-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 (APC) 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 APC disruption plays a central role in driving and maintaining tumorigenesis.

Antioxidant and Chemopreventive Effect of Aliophen® Formulation Based on Malts and Hops

“…If the decrease of ROS is the cause of the consequence of Aliophen ® represents a highly debatable issue, common to other botanical extracts possessing putative antioxidant and anticancer properties. Certainly, it is well known that oxidative damage promotes tumor initiation and progression by increasing mutation rates and activating oncogenic pathways, such as impairing the Wnt/β-catenin and/or base excision repair pathways and predisposing to polyp development [ 67 ]. The oxidative DNA damage and errors in DNA polymerase favor C > T transitions in various types of adenomas and cancer, leading to a hyper-mutated phenotype of tumor cells [ 68 ].…”

Role of Stress-Survival Pathways and Transcriptomic Alterations in Progression of Colorectal Cancer: A Health Disparities Perspective

“…Oxidative stress is an imbalance of oxidants or reactive oxygen species (ROS) and antioxidant defense in the cell. It can be produced both intracellularly or extracellularly [ 175 , 176 ]. Intracellularly, the production of ROS is dependent on almost all enzymes that use molecular oxygen as a substrate like NADPH oxidase, microsomal cytochrome P450, peroxisomes, xanthine oxidase, cytokines, and growth factors.…”

Reflections of an aging free radical

“…Is it because oxidative damage is unimportant in the origin and progression of human disease? Data indicate that this is not so, especially for certain cancers, such as those related to chronic inflammation [ 8 , [65] , [66] , [67] ] and for neurodegenerative diseases such as Alzheimer [ 8 , [68] , [69] , [70] , [71] ] and Parkinson disease [ 8 , [72] , [73] , [74] ]. So why then have high-dose antioxidants failed to deter the development or progression of these conditions?…”