结直肠癌发生和具核梭杆菌：致癌微生物、致癌代谢物和肿瘤免疫学-猫眼课题宝

结直肠癌发生和具核梭杆菌：致癌微生物、致癌代谢物和肿瘤免疫学

批准号：

10665786

负责人：

Wendy S. Garrett

金额：

$37.88万

依托单位：

HARVARD SCHOOL OF PUBLIC HEALTH

依托单位国家：

美国

项目类别：

财政年份：

2011

资助国家：

美国

项目状态：

未结题

起止时间：

2011-03-18 至 2027-07-31

来源：

https://reporter.nih.gov/project-details/10665786

关键词：

Acetates Adenosine Monophosphate Amino Acids Bacteria Bacterial Adhesins Bioenergetics Biology CDX2 gene Cancer Model Cell Proliferation Cell physiology Cells Chemoresistance Chemosensitization Colon Colon Carcinoma Colonic Neoplasms Colorectal Adenoma Colorectal Cancer Cysteine Data Detection Epithelium Feces Fusobacteria Fusobacterium nucleatum Genes Genomics Gnotobiotic Gram-Negative Anaerobic Bacteria Human Hydrogen Sulfide Immune Immunology Immunooncology In Vitro Individual Lipid A Lipids LoxP-flanked allele Malignant Neoplasms Mediating Meta-Analysis Metabolism Modeling Modification Mus Myeloid Cells NF-kappa B Neoadjuvant Therapy Organoids Patients Phosphotransferases Polysaccharides Population Post-Translational Protein Processing Pre-Clinical Model Predisposition Production Progression-Free Survivals Protein S Proteins Proteome Rectal Cancer Rectum Relapse Risk Factors Role Serine Side Spermidine Synthase T-Lymphocyte Technology Testing Therapeutic Threonine Tissues Tryptophanase Tyrosine United States Virulence Volatile Fatty Acids Work adenoma chemoradiation colon carcinogenesis colon tumorigenesis colorectal cancer risk gut microbiome gut microbiota hydroxyl group in vivo insight lactate dehydrogenase A microbial microbiome research microbiota microorganism mouse model mutant neoplastic cell oral microbiome pre-clinical protein profiling rectal rho GTP-Binding Proteins sulfhydration treatment response tumor tumor microenvironment tumor-immune system interactions

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PROJECT SUMMARY Configurations of the gut microbiome and specific bacterial species are associated with CRC, and such data provide fresh perspectives and insights into CRC susceptibility, response to therapy, and therapeutics. A central challenge of cancer gut microbiome studies is to define the bioactive features of micro-organisms that influence CRC susceptibility and progression. Fusobacterium nucleatum, a Gram-negative anaerobic bacterium, is a normal constituent of the human oral microbiome. However, numerous studies now demonstrate that F. nucleatum (Fn) is enriched in human colorectal adenomas and CRC compared to healthy colonic tissues, as well as in stool from individuals with CRC, and that tumoral Fn-enrichment correlates with worse overall-survival, progress-free survival and chemoresistance. My lab has been involved in studies detecting Fn in adenomas and CRC, correlating fusobacterial presence with various CRC risk factors, and determining how Fn may contribute to CRC using preclinical CRC models with a focus on its interactions with immune cells. Yet, much remains to discover about the mechanisms by which Fn contributes to CRC. To date, the bulk of studies on Fn virulence mechanisms in CRC have focused on its adhesins and its lipid polysaccharide. While such studies have revealed important biology about Fn, there are additional mechanisms that may underlie Fn's contribution to CRC. In this renewal proposal, we build upon our expertise with Fn, microbial metabolism, and immunology to further understanding of how Fn contributes to CRC. Specifically, we will investigate the effects of three bioactivities, Fn hydrogen sulfide production, short-chain fatty acids and Fic proteins, on the colonic epithelium and immune cells in the evolving tumor microenvironment. In considering broader mechanisms used by but not exclusive to Fn, we hope to extend the applicability of our findings to Fn-negative CRC and other malignancies.

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