Alcohol-sensitized macrophages enhance colorectal carcinoma metastasis in the liver
酒精敏感性巨噬细胞增强结直肠癌肝转移
基本信息
- 批准号:10265327
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-01-01 至 2022-12-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAlcohol abuseAlcohol consumptionAlcoholic Liver DiseasesAlcoholsAlkaline PhosphataseAnimalsAttenuatedCarcinoembryonic AntigenCell AdhesionCell Culture TechniquesCellsCessation of lifeClinicalClinical TreatmentColorectalColorectal CancerCombined Modality TherapyDevelopmentDiseaseDisseminated Malignant NeoplasmEffectivenessEndotoxinsEnvironmentEvaluationEventFutureGeneral PopulationGlycoproteinsGoalsGrowthHealthHealthcareHepaticHepatocyteImmune systemImmunocompetentInflammationInflammatoryInflammatory ResponseInjuryInterventionIntervention TrialIntestinesKupffer CellsLarge Intestine CarcinomaLinkLiverLiver diseasesLiver neoplasmsMalignant NeoplasmsMalignant neoplasm of liverMediatingMetastatic Neoplasm to the LiverMusNeoplasm MetastasisOrganPathway interactionsPatientsPeritonealPhenotypePre-Clinical ModelProductionResearchRisk FactorsRoleServicesSeveritiesSignal TransductionSiteStressSupplementationT cell therapyTestingTherapeuticTissuesTraumaTumor AntigensVeteransWorkalcohol riskalcohol use disordercancer cellcell growthchemokinechimeric antigen receptorclinically relevantclinically significantcolorectal cancer metastasiscomorbiditycytokineexperienceexperimental studyhigh riskhuman diseasein vivoinnovationinsightliver injurymacrophagemetastatic colorectalmilitary veteranmonocytenoveloverexpressionpathogenpost-traumatic stresspre-clinicalproblem drinkerresponsetherapeutic targettumor
项目摘要
The liver is the terminal site of metastatic disease of colorectal cancer (CRC), that without intervention usually
heralds death. The liver is also the main organ affected by alcohol consumption. Interestingly, alcohol use has
been identified as a significant risk factor for colorectal liver metastasis (CRLM), yet contributing mechanisms
remain undefined. Although alcohol-related CRLM is a serious health concern for the general population, the
Veteran population is especially vulnerable because of service-connected trauma and injuries that significantly
contribute to alcohol use disorders and liver disease. Considering this, it is clinically important to determine
mechanisms and potential therapeutic targets for colorectal metastasis in the alcohol-affected liver. The goal of
this work is to determine how the alcoholic liver facilitates the colonization of metastatic CRC cells that express
carcinoembryonic antigen (CEA). The CEA tumor glycoprotein is overexpressed in metastatic cancer cells and
correlates with the development of CRLM. It is believed that CEA stimulates cells of the host microenvironment
to produce inflammatory responses and factors that promote metastatic disease. Specifically, it is hypothesized
that alcohol sensitizes hepatic macrophages to the effects of CEA resulting in the accelerated growth of CRC
tumors in the liver. To investigate this, three specific aims are proposed to determine the role of alcohol-
sensitized macrophages (Kupffer cells, infiltrating monocytes, and peritoneal cells) in CEA signaling and
development of CRLM. In the first studies, the role of CEA as a key factor in the promotion of metastases will
be established using a recently developed preclinical model of alcoholic liver injury and CRLM. In the second
aim, the critical role of macrophage phenotype, activation, and related production of prometastatic factors will be
determined in response to CEA-expressing cancer cells. In the last aim, key experiments will define the
effectiveness of targeting CEA-mediated events to reduce the burden of colorectal liver metastasis. Macrophage
inactivation and anti-CEA therapy will be tested alone or in combination with intestinal alkaline phosphatase
supplementation to inhibit alcohol-related effects of gut-derived endotoxin. The successful completion of these
studies will contribute to the field by defining targetable mechanisms involved in the alcohol-mediated
exacerbation of CEA signaling and the associated development of CRLM. Moreover, this work will provide useful
information for future therapeutic strategies aimed at reducing or eliminating liver metastases of colorectal
cancer. This is a clinically relevant topic which has the potential to significantly impact healthcare for Veterans,
especially those who are at a high risk for alcohol use disorders and the associated development colorectal liver
tumors.
肝脏是结直肠癌转移的终末部位,如果不进行干预,
预示着死亡肝脏也是受酒精消耗影响的主要器官。有趣的是,酒精的使用
已被确定为结直肠肝转移(CRLM)的重要危险因素,但其作用机制
仍然未定义。尽管酒精相关的CRLM是普通人群的严重健康问题,
退伍军人群体特别脆弱,因为与服务有关的创伤和伤害,
导致酒精使用障碍和肝脏疾病。考虑到这一点,临床上重要的是确定
机制和潜在的治疗靶点的结直肠转移在酒精影响的肝脏。的目标
这项工作是为了确定酒精肝如何促进转移性CRC细胞的定植,
癌胚抗原(CEA)。CEA肿瘤糖蛋白在转移性癌细胞中过表达,
与CRLM的发展相关。据信CEA刺激宿主微环境的细胞,
产生炎症反应和促进转移性疾病的因子。具体来说,假设
酒精使肝巨噬细胞对CEA的作用敏感,导致CRC的加速生长
肝脏肿瘤为了调查这一点,提出了三个具体的目标,以确定酒精的作用-
致敏的巨噬细胞(枯否细胞,浸润单核细胞和腹膜细胞)在CEA信号传导和
CRLM的发展。在第一项研究中,CEA作为促进转移的关键因素的作用将被证实。
使用最近开发的酒精性肝损伤和CRLM的临床前模型建立。在第二
目的是,巨噬细胞表型、激活和相关促转移因子产生的关键作用将被
在响应于CEA表达癌细胞的情况下测定。在最后一个目标中,关键实验将定义
靶向CEA介导的事件以减少结直肠肝转移负担的有效性。巨噬
灭活和抗CEA治疗将单独或与肠碱性磷酸酶联合进行试验
补充以抑制肠源性内毒素的酒精相关作用。成功完成这些
研究将通过定义参与酒精介导的
CEA信号传导的恶化和CRLM的相关发展。此外,这项工作将提供有用的
旨在减少或消除结直肠癌肝转移的未来治疗策略的信息
癌这是一个临床相关的话题,有可能对退伍军人的医疗保健产生重大影响,
特别是那些有酒精使用障碍和相关发展的高风险的人,
肿瘤的
项目成果
期刊论文数量(0)
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{{ truncateString('BENITA L. MCVICKER', 18)}}的其他基金
Alcohol-sensitized macrophages enhance colorectal carcinoma metastasis in the liver
酒精敏感性巨噬细胞增强结直肠癌肝转移
- 批准号:
10427229 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Development of delivery methods for combination microRNA treatment of alcohol-associated liver disease
开发联合 microRNA 治疗酒精相关性肝病的递送方法
- 批准号:
10442687 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Development of delivery methods for combination microRNA treatment of alcohol-associated liver disease
开发联合 microRNA 治疗酒精相关性肝病的递送方法
- 批准号:
10676945 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Alcohol Alters Hepatic Immune Function: Role of the Asialoglycoprotein Receptor
酒精改变肝脏免疫功能:去唾液酸糖蛋白受体的作用
- 批准号:
8391632 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Alcohol Alters Hepatic Immune Function: Role of the Asialoglycoprotein Receptor
酒精改变肝脏免疫功能:去唾液酸糖蛋白受体的作用
- 批准号:
8598019 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Alcohol Alters Hepatic Immune Function: Role of the Asialoglycoprotein Receptor
酒精改变肝脏免疫功能:去唾液酸糖蛋白受体的作用
- 批准号:
8244030 - 财政年份:2011
- 资助金额:
-- - 项目类别:
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