Early detection and pathogenesis during the progression of Barrett's esophagus to esophageal adenocarcinoma

Abstract

As more studies are needed to gain detailed insight in the pathologic processes during the transition from SQ epithelium to BE and EAC, the first aim of this thesis is to address the functional effect of aberrantly expressed proteins and non-coding RNA molecules and to explore if there are differences in circulating miRNAs between groups of patients with BE (Part 1). In addition, to optimize current surveillance and treatment strategies, the second aim of this thesis is to evaluate in detail the risk of malignant progression in different histological groups of BE patients (Part 2). Part 1 In Chapter 2 we address the effect of aberrant BMP4 signaling in the pathogenesis of EAC using in vitro cell culture experiments. Chapter 3 summarizes current knowledge of the function of differently expressed miRNAs in esophageal cancer. MiRNAs play important regulatory roles in cancer development and we describe various ways for developing new treatment modalities. In Chapter 4 we focus on miRNA-203. MiRNA-203 is known to be downregulated in BE and EAC compared to SQ and we therefore evaluate the role of miRNA-203 in the development of BE. In Chapter 5, the focus shifts from tissue specific miRNAs to circulating miRNAs. We explore if there are differences in circulating miRNAs between healthy controls, patients with BE and EAC, which is the first step in order to evaluate if circulating miRNAs could be used as biomarker. In Chapter 6 we explore if circulating miRNAs can be used to identify patients at risk for malignant progression. We describe miRNA expression profiles in patients with long- and short- segment BE, as patients with long-segment BE are known to be at a higher risk for malignant progression. Part 2 In Chapter 7, we describe the risk of malignant progression in BE patients diagnosed with IND in order to tailor surveillance protocols as current available progression rates for IND are only based on small (sub)cohort analyses. In Chapter 8, we evaluate the interobserver variability in the diagnosis of IND in BE as interobser variability is a wellknown problem in other histological categories of BE. In addition, we evaluate the use of P53 immunohistochemistry in patients with IND to identify patients at risk of malignant progression. In Chapter 9 we shift from IND to LGD and report on the effect of persistent LGD (LGD in repeated biopsy samples) on the risk of malignant progression, in order to Introduction 15 1 identify a subgroup of LGD patients that could benefit from endoscopic treatment or intensified endoscopic follow-up. Part 3 Last, the significance of the results of this thesis are discussed in Chapter 10, and, in addition, the main findings are summarized in Chapter 11.