Induction and Evolution of Metaplasia in the Stomach

人类胃腺癌是在幽门螺杆菌感染的背景下发展起来的。 引起氧合萎缩和慢性粘液细胞化生。我们最近的血统 地形图研究表明，小鼠胃底的化生 而不是来自位于上颈区的专业祖细胞。 腺体，而不是从成熟的主细胞转分化为 表达化生的解痉性多肽，或SPEM。这些研究导致了一项 胃肿瘤起源的概念发生了显著的范式转变，表明 癌前谱系不是来自专业的常驻粘膜祖细胞 细胞群体，而不是从成熟的产酶细胞的转分化发展而来 血统。此外，多项研究现在表明，在SPEM的影响下， 炎症，可发展为增殖增加和水平增加的 肠化基因表达，并在人类中产生杯状细胞肠道 化生。我们最近的研究表明，巨噬细胞是 负责促进增生性SPEM进展，但准确的 在SPEM向肠化和肠化的过程中起作用的介质 不典型增生仍未可知。因此，我们假设离散的固有粘膜和 巨噬细胞衍生因子不仅调节细胞的进化，而且还调节肿瘤的进展。 SPEM多为增生性、癌前化生。为了解决这一假设，我们 将追求两个具体目标：第一，我们将研究巨噬细胞在 化生的演变和进展。第二，我们将评估RAS的作用 转分化主细胞在SPEM进化中的激活及进一步研究 诱导物驱动的新的化生模型中SPEM谱系的肠化 激活的K-RAS在主细胞中的表达虽然我们之前的调查已经 致力于建立一种新的化生途径，通过 主细胞的转分化，目前的研究主要集中在 可能推动再生障碍物转化为创业型的机制。

Adenocarcinoma in the human stomach evolves in the setting of Helicobacter pylori- induced oxyntic atrophy and chronic mucous cell metaplasia. Our recent lineage mapping studies have demonstrated that metaplasia in the gastric fundus in mice does not arise from the professional progenitor cells located in the upper neck region of the glands, but rather develops from transdifferentiation of mature chief cells into Spasmolytic Polypeptide Expressing Metaplasia, or SPEM. These studies have led to a significant paradigm shift in the concepts for the origin of gastric neoplasia, suggesting that pre-neoplastic lineages do not arise from professional resident mucosal progenitor cell populations, but rather develop from transdifferentiation of mature zymogenic cell lineages. Furthermore, multiple studies now indicate that SPEM, under the influence of inflammation, can develop both increased proliferation and increasing levels of intestinalizing gene expression, and in humans gives rise to goblet cell intestinal metaplasia. Our recent investigations have demonstrated that macrophages are responsible for the promotion of proliferative SPEM progression, but the precise mediators that are responsible for the progression of SPEM towards intestinalization and dysplasia remain unknown. We therefore hypothesize that discrete intrinsic mucosal and macrophage-derived factors regulate not only the evolution, but also the progression of SPEM to more proliferative, preneoplastic metaplasia. To address this hypothesis, we will pursue two specific aims: First, we will examine the role of macrophages in the evolution and progression of metaplasia. Second, we will evaluate the role of Ras activation in evolution of SPEM from transdifferentiating chief cells and the further intestinalization of SPEM lineages in a novel model of metaplasia driven by inducible expression of activated K-Ras in chief cells. While our previous investigations have focused on the establishment of a novel pathway for generation of metaplasia through transdifferentiation of chief cells, the present investigations now focus on the mechanisms that might drive metaplasias to preneoplasia.