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

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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BENITA L. MCVICKER其他文献

BENITA L. MCVICKER的其他文献

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{{ truncateString('BENITA L. MCVICKER', 18)}}的其他基金

ACORN: BioCore
橡子:生物核心
  • 批准号:
    10526255
  • 财政年份:
    2023
  • 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:
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:
Alcohol & FAS-Mediated Apoptosis in Polarized Liver Cell
酒精
  • 批准号:
    7045785
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
Alcohol & FAS-Mediated Apoptosis in Polarized Liver Cell
酒精
  • 批准号:
    7564111
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
Alcohol & FAS-Mediated Apoptosis in Polarized Liver Cell
酒精
  • 批准号:
    7337638
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:

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Insula-amygdala circuits in alcohol abuse
酒精滥用中的岛杏仁核回路
  • 批准号:
    10735851
  • 财政年份:
    2023
  • 资助金额:
    --
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A novel animal model to study the association between alcohol abuse during late adolescence with common conditions observed in combat Veterans
一种新的动物模型,用于研究青春期后期酗酒与退伍军人中观察到的常见状况之间的关联
  • 批准号:
    10644999
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Reinforcement as a Prospective Predictor of Real-time Alcohol Abuse Following Bariatric Surgery
强化作为减肥手术后实时酒精滥用的前瞻性预测因子
  • 批准号:
    10370120
  • 财政年份:
    2022
  • 资助金额:
    --
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ACSS2 inhibition in treating Alcohol Abuse
ACSS2 抑制治疗酒精滥用
  • 批准号:
    10546942
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
A novel animal model to study the association between alcohol abuse during late adolescence with common conditions observed in combat Veterans
一种新的动物模型,用于研究青春期后期酗酒与退伍军人中观察到的常见状况之间的关联
  • 批准号:
    10368295
  • 财政年份:
    2022
  • 资助金额:
    --
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Reinforcement as a Prospective Predictor of Real-time Alcohol Abuse Following Bariatric Surgery
强化作为减肥手术后实时酒精滥用的前瞻性预测因子
  • 批准号:
    10705563
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
The Functional Implications of Astrocytic GPCR-signaling on Alcohol Abuse
星形胶质细胞 GPCR 信号传导对酒精滥用的功能影响
  • 批准号:
    10472456
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Trauma and Neurobiological Threat Reactivity as Risk Factors for Alcohol Abuse in Youth
创伤和神经生物学威胁反应作为青少年酗酒的危险因素
  • 批准号:
    10582520
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Trauma and Neurobiological Threat Reactivity as Risk Factors for Alcohol Abuse in Youth
创伤和神经生物学威胁反应作为青少年酗酒的危险因素
  • 批准号:
    10368089
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
The Functional Implications of Astrocytic GPCR-signaling on Alcohol Abuse
星形胶质细胞 GPCR 信号传导对酒精滥用的功能影响
  • 批准号:
    10089613
  • 财政年份:
    2021
  • 资助金额:
    --
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