Stromal Myofibroblasts in Gastric Carcinogenesis

基质肌成纤维细胞在胃癌发生中的作用

• 批准号: 7684700
• 负责人: Timothy Cragin Wang
• 金额: $ 38.26万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7684700
• 关键词: AMD3100; Ablation; Bioluminescence; Body of uterus; Bone Marrow; Bone Marrow Stem Cell; Bone Marrow Transplantation; Cancer Etiology; Cancer Model; Cells; Chronic; Chronic Gastritis; Collagen; Condition; Data; Development; Dysplasia; Dysplastic Epithelial Cell; Engraftment; Environment; Epithelial; Epithelial Cells; Fibroblasts; Gastric Glands; Gastric mucosa; Gastritis; Gene Expression; Gene Mutation; Genetic; Goals; Green Fluorescent Proteins; Helicobacter; Helicobacter Infections; Helicobacter pylori; Hematopoietic stem cells; Human; Image; In Vitro; Infection; Inflammation; Inflammatory; Injection of therapeutic agent; Laboratories; Lesion; Link; Luciferases; Magnetic Resonance Imaging; Malignant Neoplasms; Mesenchymal; Mesenchymal Stem Cells; Metaplasia; Metaplastic; Modality; Modeling; Mus; Myofibroblast; Nature; Neoplastic Epithelial Cell; Normal tissue morphology; Optics; Organ; Patients; Pattern; Population; Property; Protein Overexpression; Proteome; Proteomics; Recruitment Activity; Reporter Genes; Role; Signal Transduction; Source; Staging; Stem cells; Stimulus; Stomach; Stromal Cell-Derived Factor 1; Stromal Cells; Testing; Tissues; Transforming Growth Factor beta; Transgenes; Work; cancer cell; carcinogenesis; chemokine; cytokine; in vivo; malignant stomach neoplasm; mortality; mouse model; neoplastic; novel; pathogen; progenitor; receptor; response; small molecule; tumor

Cancer-associated myofibroblasts are distinct from normal fibroblasts and appear to contribute directly to the progression of many cancers, but the reason for these differences has not been clarified. Gastric cancer is the 2nd leading cause of cancer mortality worldwide, and has been strongly linked to infection with Helicobacter pylori, a pathogen that induces chronic gastritis. Work from our laboratory employing a murine model of Helicobacter-dependent gastric cancer has revealed that circulating bone marrow-derived stem cells (BMDCs) are recruited to the stomach by chronic inflammation, and then undergo progression to metaplasia, dysplasia and cancer. We have postulated that this abnormal progression is due to an "alterred niche" and in a variety of mouse models there is an early and marked increase in activated myofibroblasts. Work from our laboratory has shown that activated myofibroblasts in the inflamed stomach can be bone marrow-derived, and that mesenchymal stem cells (MSCs) can give rise to both myofibroblasts and gasric epithelial progenitors. It is our hypothesis that the unique properties of cancer-associated myofibroblasts is due in part to their origin from bone marrow-derived mesenchymal stem cells. In order to investigate this novel hypothesis regarding tumor stroma, we are proposing four specific aims. (1) In the first aim, we will utilize trangenic reporter gene mice (alpha-SMA-RFP and collagen-EGFP/luciferase) to characterize the changes in stroma that occur during chronic Helicobacter infection, and explore the nature of bone marrow -derived myofibroblasts. These studies will include both microarrays and imaging (bioluminescence, optical and MRI). (2) In the second aim, we will characterize human gastric myofibroblasts from both normal and neoplastic tissues and examine their gene expression/proteome and study their interactions with normal and neoplastic epithelial cells, (3) We will then test the hypothesis that BMDCs (primarily MSCs) can give rise to both myofibroblasts and dysplastic epithelial cells, and that chronic inflammation and TGF-beta signaling are critical to these lineage decisions. (4) Finally, we will examine the role of a key chemokine (SDF-1) in the recruitment of BMDCs and progression to gastric cancer. Overall, these studies will clarify the role of inflammation-dependent stem cell recruitment in the development of the abnormal stromal environment that characterizes the earliest stages of gastric carcinogenesis.

癌症相关肌成纤维细胞与正常成纤维细胞不同，似乎直接促成 许多癌症的进展，但这些差异的原因尚未阐明。胃癌是 全世界癌症死亡的第二大原因，并且与感染密切相关 幽门螺杆菌，一种诱发慢性胃炎的病原体。我们的实验室使用小鼠进行工作 螺杆菌依赖性胃癌模型揭示了循环骨髓来源的干细胞 细胞（BMDC）通过慢性炎症被招募到胃，然后进展为 化生、不典型增生和癌症。我们假设这种异常进展是由于“改变 利基”，并且在多种小鼠模型中，活化的肌成纤维细胞早期显着增加。 我们实验室的工作表明，发炎的胃中激活的肌成纤维细胞可以成为骨骼 骨髓来源的，间充质干细胞（MSC）可以产生肌成纤维细胞和胃细胞 上皮祖细胞。我们的假设是癌症相关肌成纤维细胞的独特特性是 部分原因是它们起源于骨髓间充质干细胞。为了调查此事 关于肿瘤基质的新假设，我们提出了四个具体目标。 (1) 在第一个目标中，我们将 利用转基因报告基因小鼠（α-SMA-RFP 和胶原蛋白-EGFP/荧光素酶）来表征变化 在慢性螺杆菌感染期间发生的基质中，探索骨髓来源的性质 肌成纤维细胞。这些研究将包括微阵列和成像（生物发光、光学和 MRI）。 (2) 在第二个目标中，我们将表征正常和肿瘤性的人胃肌成纤维细胞 组织并检查其基因表达/蛋白质组并研究它们与正常和肿瘤的相互作用 上皮细胞，(3) 然后我们将检验 BMDC（主要是 MSC）可以产生这两种细胞的假设 肌成纤维细胞和发育不良的上皮细胞，以及慢性炎症和 TGF-β 信号传导 对于这些血统决定至关重要。 (4) 最后，我们将研究关键趋化因子（SDF-1）在 BMDC 的募集和进展为胃癌。总的来说，这些研究将阐明 炎症依赖性干细胞募集在异常基质环境的发展中 是胃癌发生最早阶段的特征。