Induction and Evolution of Metaplasia in the Stomach

人类胃腺癌在幽门螺杆菌环境中发展- 诱发泌酸萎缩和慢性粘液细胞化生。我们最近的血统 绘图研究表明，小鼠胃底的化生确实 不是来自位于上颈部区域的专职祖细胞， 腺体，而是从成熟的主细胞转分化发育成 痉挛性多肽表达化生或SPEM。这些研究导致了 胃肿瘤起源概念的重大范式转变，提示 肿瘤前谱系不是由专业常驻粘膜祖细胞产生 细胞群，而是从成熟的产酶细胞的转分化发展而来 血统此外，现在多项研究表明，SPEM，在影响下， 炎症，可以发展增加的增殖和增加的 使基因表达异常，并在人类中引起肠杯状细胞 化生我们最近的研究表明，巨噬细胞是 负责促进增殖性SPEM进展，但精确的 介导剂，负责SPEM向细胞化的进展， 发育不良仍然未知。因此，我们假设，离散的内在粘膜和 巨噬细胞源性因子不仅调节细胞的进化，而且调节细胞的进展。 SPEM向增殖性、癌前化生转变。为了解决这个问题，我们 我们将追求两个具体目标：首先，我们将研究巨噬细胞在 化生的演变和进展。其次，我们将评估Ras的作用 激活从转分化主细胞的SPEM进化，并进一步 在一种新的诱导分化驱动的化生模型中SPEM谱系的分化 活化的K-Ras在主细胞中的表达。虽然我们之前的调查 专注于建立一种新的途径，通过 主细胞的转分化，目前的研究集中在 可能驱动化生到癌前病变的机制。

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.