Stromal Myofibroblasts in Gastric Carcinogenesis
基质肌成纤维细胞在胃癌发生中的作用
基本信息
- 批准号:7684700
- 负责人:
- 金额:$ 38.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AMD3100AblationBioluminescenceBody of uterusBone MarrowBone Marrow Stem CellBone Marrow TransplantationCancer EtiologyCancer ModelCellsChronicChronic GastritisCollagenConditionDataDevelopmentDysplasiaDysplastic Epithelial CellEngraftmentEnvironmentEpithelialEpithelial CellsFibroblastsGastric GlandsGastric mucosaGastritisGene ExpressionGene MutationGeneticGoalsGreen Fluorescent ProteinsHelicobacterHelicobacter InfectionsHelicobacter pyloriHematopoietic stem cellsHumanImageIn VitroInfectionInflammationInflammatoryInjection of therapeutic agentLaboratoriesLesionLinkLuciferasesMagnetic Resonance ImagingMalignant NeoplasmsMesenchymalMesenchymal Stem CellsMetaplasiaMetaplasticModalityModelingMusMyofibroblastNatureNeoplastic Epithelial CellNormal tissue morphologyOpticsOrganPatientsPatternPopulationPropertyProtein OverexpressionProteomeProteomicsRecruitment ActivityReporter GenesRoleSignal TransductionSourceStagingStem cellsStimulusStomachStromal Cell-Derived Factor 1Stromal CellsTestingTissuesTransforming Growth Factor betaTransgenesWorkcancer cellcarcinogenesischemokinecytokinein vivomalignant stomach neoplasmmortalitymouse modelneoplasticnovelpathogenprogenitorreceptorresponsesmall moleculetumor
项目摘要
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.
癌症相关的肌纤维细胞与正常成纤维细胞不同,似乎直接有助于
许多癌症的进展,但造成这些差异的原因尚未澄清。胃癌是
全球癌症死亡率的第二大原因,与感染与感染密切相关
幽门螺杆菌,一种诱导慢性胃炎的病原体。我们的实验室使用鼠的工作
依赖性胃癌的模型表明,循环的骨髓源性茎
通过慢性炎症将细胞(BMDC)募集到胃中,然后进行到
化生,发育不良和癌症。我们假设这种异常进展是由于“改变了
利基“在各种小鼠模型中,激活的肌纤维细胞早期且明显增加。
我们实验室的工作表明,发炎的胃中激活的肌纤维细胞可能是骨头
骨髓衍生和间充质干细胞(MSC)可以引起肌纤维细胞和煤气
上皮祖细胞。我们的假设是,与癌症相关的肌纤维细胞的独特特性是
部分原因是它们来自骨髓衍生的间充质干细胞的起源。为了调查这个
关于肿瘤基质的新假设,我们提出了四个特定目标。 (1)在第一个目标中,我们将
利用跨齿报告基因小鼠(Alpha-SMA-RFP和胶原蛋白EGFP/Luciferase)来表征变化
在慢性旋转杆菌感染期间发生的基质中,并探索骨髓的性质
肌纤维细胞。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,我们将表征来自正常和肿瘤的人类胃肌纤维细胞
组织并检查其基因表达/蛋白质组,并研究其与正常和肿瘤的相互作用
上皮细胞,(3)然后我们将检验以下假设:BMDC(主要是MSC)可以引起两者
肌纤维细胞和发育异常上皮细胞,慢性炎症和TGF-β信号是
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
招募BMDC并发展为胃癌。总体而言,这些研究将阐明
依赖炎症的干细胞募集在异常基质环境的发展中
表征胃癌发生的最早阶段。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Timothy Cragin Wang其他文献
Timothy Cragin Wang的其他文献
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{{ truncateString('Timothy Cragin Wang', 18)}}的其他基金
Gastrin Regulation of Gastric Antral Stem and Corpus Progenitor Cells
胃窦干细胞和胃体祖细胞的胃泌素调节
- 批准号:
10490463 - 财政年份:2021
- 资助金额:
$ 38.26万 - 项目类别:
Gastrin Regulation of Gastric Antral Stem and Corpus Progenitor Cells
胃窦干细胞和胃体祖细胞的胃泌素调节
- 批准号:
10686228 - 财政年份:2021
- 资助金额:
$ 38.26万 - 项目类别:
Gastrin Regulation of Gastric Antral Stem and Corpus Progenitor Cells
胃窦干细胞和胃体祖细胞的胃泌素调节
- 批准号:
10367556 - 财政年份:2021
- 资助金额:
$ 38.26万 - 项目类别:
The Role of Stem Cells and the Microenvironment in Gastrointestinal Cancers
干细胞和微环境在胃肠道癌症中的作用
- 批准号:
10532704 - 财政年份:2016
- 资助金额:
$ 38.26万 - 项目类别:
The role of stem cells and the microenvironment in gastrointestinal cancers
干细胞和微环境在胃肠道癌症中的作用
- 批准号:
10737925 - 财政年份:2016
- 资助金额:
$ 38.26万 - 项目类别:
The Role of Stem Cells and the Microenvironment in Gastrointestinal Cancers
干细胞和微环境在胃肠道癌症中的作用
- 批准号:
9186833 - 财政年份:2016
- 资助金额:
$ 38.26万 - 项目类别:
The Role of Stem Cells and the Microenvironment in Gastrointestinal Cancers
干细胞和微环境在胃肠道癌症中的作用
- 批准号:
10307622 - 财政年份:2016
- 资助金额:
$ 38.26万 - 项目类别:
The Role of Stem Cells and the Microenvironment in Gastrointestinal Cancers
干细胞和微环境在胃肠道癌症中的作用
- 批准号:
10059178 - 财政年份:2016
- 资助金额:
$ 38.26万 - 项目类别:
Quiescent Dclk1+ stem cells in the mouse intestine
小鼠肠道中的静态 Dclk1 干细胞
- 批准号:
8865612 - 财政年份:2013
- 资助金额:
$ 38.26万 - 项目类别:
Quiescent Dclk1+ stem cells in the mouse intestine
小鼠肠道中的静态 Dclk1 干细胞
- 批准号:
8577370 - 财政年份:2013
- 资助金额:
$ 38.26万 - 项目类别:
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