Oxyntic Atrophy and Novel Gastric Lineages

 描述(由申请人提供)： 胃腺癌仍然是全球癌症相关死亡的第二大常见原因。绝大多数胃癌发生在慢性萎缩性胃炎的胃部，通常与幽门螺杆菌感染有关。虽然幽门螺杆菌作为胃癌发生的直接原因已被证实，但导致癌前化生和进展为癌症的谱系变化的细胞学基础仍不清楚。正常的胃底粘膜是由一组负责正常分泌粘蛋白、胃蛋白酶原和盐酸的异质上皮细胞组成的。与幽门螺杆菌感染相关的慢性损伤导致胃上皮细胞成分的显著变化，壁细胞丢失(氧合萎缩)，表面细胞扩张 (小凹增生)和粘液细胞化生。在人类氧化性萎缩的背景下，目前公认有两种化生谱系：肠化生(特征是胃粘膜中存在肠杯状细胞)和痉挛多肽表达化生(SPEM；特征是胃体中存在胃窦型粘液细胞)。然而，小鼠体内的幽门螺杆菌感染只会导致SPEM。在过去的15年里，我们研究了在氧合萎缩的情况下导致SPEM发展的因素。利用小鼠的谱系图谱研究，我们已经证明，SPEM不是来自专业的祖细胞，而是来自表达Mist1的成熟主细胞向粘液细胞化生的转分化。所有这些结果都支持胃底黏膜壁细胞的丧失导致主细胞转分化形成SPEM的假说。由于SPEM似乎是含氧酸萎缩的癌前化生反应，了解主细胞的转分化如何导致SPEM的出现是至关重要的，因为它是胃不典型增生和肿瘤发展所必需的中心初始事件。因此，我们将通过以下三个具体目标继续研究化生的起源：第一，我们将检查主细胞转分化为化生的可塑性。由于我们目前的研究表明，转分化能力可能是主细胞的一种普遍特性，我们将评估氧合萎缩诱导的转分化是否是一个多克隆过程。由于SPEM的诱导在急性氧合萎缩中是可逆的，我们将使用谱系图谱研究来评估SPEM转分化是否直接可逆地返回主细胞。其次，我们将评估CD44变异体在SPEM发生中的作用。由于我们已经发现CD44变体的上调标志着转分化过程中最早被发现的点，我们将试图确定伴随着CD44变体上调的主要细胞中关键的基因转录变化。此外，我们将研究抑制XCT半胱氨酸-谷氨酸反向转运体是否可以改变SPEM的诱导或进展。第三，我们将研究miRNAs在化生表型诱导中的作用，方法是确定主要细胞中DICER表达的靶向性缺失是否改变了SPEM的诱导。所有这些研究都将有助于确定主要细胞转分化的基本机制，并可能导致对如何预防或逆转肿瘤前化生谱系变化的见解。

 DESCRIPTION (provided by applicant): Gastric adenocarcinoma remains the second most common cause of cancer-related death worldwide. The vast majority of gastric cancer evolves in the stomach in the setting of chronic atrophic gastritis usually in association with Helicobacter pylori infection. While the role of H. pylori as the proximate cause of gastric carcinogenesis is well established, the cellular basis of lineage changes that lead to development of preneoplastic metaplasia and progression to cancer remain unclear. The normal gastric fundic mucosa is assembled from a heterogeneous group of epithelial lineages responsible for the normal secretion of mucins, pepsinogen and HCl. Chronic injury associated with H. pylori infection leads to prominent changes in the composition of the gastric epithelia, with loss of parietal cells (oxyntic atrophy), expansion of surface cells (foveolar hyperplasia) and mucous cell metaplasia. Two metaplastic lineages are now acknowledged in the setting of oxyntic atrophy in humans: intestinal metaplasia (characterized by the presence of intestinal goblet cells in the gastric mucosa) and Spasmolytic Polypeptide Expressing Metaplasia (SPEM; characterized by presence of antral type mucous cells in the body of the stomach). However, Helicobacter infection in mice leads only to SPEM. Over the past 15 years, we have investigated the factors that lead to the development of SPEM in the face of oxyntic atrophy. Using lineage-mapping studies in mice, we have demonstrated that SPEM arises, not from professional progenitor cells, but from transdifferentiation of mature Mist1-expressing chief cells into mucous cell metaplasia. All of these results support the hypotheses that loss of parietal cells from the gastric fundic mucosa induces the development of SPEM from transdifferentiation of chief cells. Since SPEM appears to be the initial pre-cancerous metaplastic response to oxyntic atrophy, it is critical to understand how transdifferentiation of chief cells leads to the emergence of SPEM as the central initial event required for the development of dysplasia and neoplasia in the stomach. We will therefore continue our studies of the origin of metaplasia through the prosecution of three specific aims: First, we will examine the plasticity of chief cell transdifferentiation into metaplasia. Sice our present studies suggest that the ability to transdifferentiate may be a general property of chief cells, we will evaluate whether transdifferentiation induced by oxyntic atrophy is a polyclonal process. Because induction of SPEM is reversible in acute oxyntic atrophy, we will use lineage-mapping studies to evaluate whether SPEM transdifferentiation is directly reversible back into chief cells. Second, we will evaluate the role of CD44variant in the initiation of SPEM. Since we have found that up-regulation of CD44variant marks the earliest point yet identified in the process of transdifferentiation, we will seek to identify critical gene transcription changes attendant with CD44variant up- regulation in chief cells. Further, we will examine whether inhibition of the xCT cystine-glutamate antiporter, a target for activation by CD44variant, can alter the induction or progression of SPEM. Third, we will examine the role of miRNAs in the induction of metaplastic phenotypes by determining whether targeted loss of Dicer expression in chief cells alters the induction of SPEM. All of these studies will help identify fundamental mechanisms involved in chief cell transdifferentiation and may lead to insights in how pre-neoplastic metaplastic lineage changes can be prevented or reversed.