Dissecting the roles of ASPM and Clusterin in gastric oxyntic mucosa - from immature stem cells to metaplastic chief cells
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Gastric cancer is the third most common cause of cancer-related mortality worldwide. Increased understanding of initiation of gastric carcinogenesis and development of tools that enable early diagnosis are of critical importance. Knowledge about how gastric glands self-renew is central for understanding gastric carcinogenesis, as gastric tumors may arise through dysregulated differentiation of gastric stem and/or progenitor cells or possibly through de-/transdifferentiation of mature cell types. Disturbances in differentiation could be due to abnormal levels of hormones and local growth factors. Gastrin is important for normal function and maturation of the gastric oxyntic mucosa and hypergastrinemia is associated with several premalignant conditions in the stomach. In paper I, we studied the proliferating cells in the gastric oxyntic mucosa, mainly consisting of stem and progenitor cells, showing that their gene expression profile was associated with cell cycle regulation and was related to stem cell transcriptional networks. Our analyses also revealed that the protein Asp (Abnormal Spindle) Homolog, Microcephaly Associated (Drosophila) (ASPM) could be a novel biomarker for gastric stem and/or progenitor cells. In addition, ASPM and its related transcription factor E2F1, were overexpressed in a subset of human gastric adenocarcinomas. In paper II and III, we focused mainly on how loss of gastric acid secretion and hypergastrinemia affect the gastric carcinogenic cascade, with a special emphasis on the role of the gastrin-regulated and cytoprotective protein clusterin. Clusterin is a stressinduced molecular chaperone associated with a wide array of biological functions. We found that in the normal oxyntic mucosa, neuroendocrine cells express clusterin, and in the absence of clusterin (clusterin knockout mice), the morphology of the gastric mucosa was not significantly altered. When examining the oxyntic mucosa of animal models with perturbed acid secretion and hypergastrinemia, expression of clusterin was increased and its localization shifted to proliferative cells from the mucous neck cellchief cell lineage. Secretory clusterin had an anti-apoptotic effect on gastric cancer cells, and clusterin was overexpressed in a subtype of human gastric adenocarcinomas. This suggested that clusterin was involved in development of metaplasia in the stomach. However, when inducing acute oxyntic atrophy and metaplasia in clusterin knockout mice, we showed that clusterin was not a promoting factor for gastric metaplasia. Instead, clusterin might actually have a subtle protective role against emergence and premalignant progression of gastric metaplastic lesions. In total, the studies in this thesis bring forth new information about gastric stem/progenitor cells and the role of clusterin in the normal and diseased stomach, thereby contributing to our understanding of normal gastric mucosal homeostasis and what mediators and cell types are involved in development of metaplasia as a precursor for gastric cancer.