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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：
BENITA L. MCVICKER
金额：
--
依托单位：
OMAHA VA MEDICAL CENTER
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：
https://reporter.nih.gov/project-details/10427229
关键词：
Affect Alcohol abuse Alcohol consumption Alcoholic Liver Diseases Alcohols Alkaline Phosphatase Animals Attenuated Carcinoembryonic Antigen Cell Adhesion Cell Culture Techniques Cells Cessation of life Clinical Clinical Treatment Colorectal Colorectal Cancer Combined Modality Therapy Development Disease Disseminated Malignant Neoplasm Effectiveness Endotoxins Environment Evaluation Event Future General Population Glycoproteins Goals Growth Health Healthcare Hepatic Hepatocyte Immune system Immunocompetent Inflammation Inflammatory Inflammatory Response Injury Intervention Intervention Trial Intestines Kupffer Cells Large Intestine Carcinoma Link Liver Liver diseases Liver neoplasms Malignant Neoplasms Malignant neoplasm of liver Mediating Metastatic Neoplasm to the Liver Mus Neoplasm Metastasis Organ Pathway interactions Patients Peritoneal Phenotype Pre-Clinical Model Production Research Risk Factors Role Services Severities Signal Transduction Site Stress Supplementation T cell therapy Testing Therapeutic Tissues Trauma Tumor Antigens Veterans Work alcohol risk alcohol use disorder cancer cell cell growth chemokine chimeric antigen receptor T cells clinically relevant clinically significant colorectal cancer metastasis comorbidity cytokine experience experimental study high risk human disease in vivo innovation insight liver injury macrophage metastatic colorectal military veteran monocyte novel overexpression pathogen post-traumatic stress pre-clinical problem drinker response therapeutic target tumor

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：
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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。