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:10427229
- 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 2023-05-31
- 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 receptor T cellsclinically 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(CRC)转移的终末部位,通常不需要干预
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The Non-Invasive Prediction of Colorectal Neoplasia (NIPCON) Study 1995-2022: A Comparison of Guaiac-Based Fecal Occult Blood Test (FOBT) and an Anti-Adenoma Antibody, Adnab-9.
1995-2022的结直肠肿瘤(NIPCON)研究的无创预测:基于Guaiac的粪便隐匿血液测试(FOBT)和抗腺瘤抗体ADNAB-9的比较。
- DOI:10.3390/ijms242417257
- 发表时间:2023-12-08
- 期刊:
- 影响因子:5.6
- 作者:Tobi, Martin;Antaki, Fadi;Rambus, Mary Ann;Yang, Yu-Xiao;Kaplan, David;Rodriguez, Rebecca;Maliakkal, Benedict;Majumdar, Adhip;Demian, Ereny;Tobi, Yosef Y.;Sochacki, Paula;Ehrinpreis, Murray;Lawson, Michael G.;McVicker, Benita
- 通讯作者:McVicker, Benita
The Celiac Disease Microbiome Depends on the Paneth Cells of the Puzzle.
乳糜泻微生物组取决于谜题的潘氏细胞。
- DOI:10.1053/j.gastro.2021.02.023
- 发表时间:2021
- 期刊:
- 影响因子:29.4
- 作者:Tobi,Martin;Talwar,Harvinder;McVicker,Benita
- 通讯作者:McVicker,Benita
Alcohol Use and the Risk of Colorectal Liver Metastasis: A Systematic Mapping Review.
- DOI:10.3390/biology12020257
- 发表时间:2023-02-06
- 期刊:
- 影响因子:4.2
- 作者:
- 通讯作者:
Role of cell-free network communication in alcohol-associated disorders and liver metastasis.
- DOI:10.3748/wjg.v27.i41.7080
- 发表时间:2021-11-07
- 期刊:
- 影响因子:4.3
- 作者:Kuracha MR;Thomas P;Tobi M;McVicker BL
- 通讯作者:McVicker BL
p38γ Activation and BGP (Biliary Glycoprotein) Induction in Primates at Risk for Inflammatory Bowel Disease and Colorectal Cancer-A Comparative Study with Humans.
- DOI:10.3390/vaccines8040720
- 发表时间:2020-12-02
- 期刊:
- 影响因子:7.8
- 作者:Talwar H;McVicker B;Tobi M
- 通讯作者:Tobi M
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{{ truncateString('BENITA L. MCVICKER', 18)}}的其他基金
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:
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:
10265327 - 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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