Impact of aging on intestinal tumorigenesis

衰老对肠道肿瘤发生的影响

• 批准号: 9203123
• 负责人: David M. Sabatini
• 金额: $ 7.5万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9203123
• 关键词: 3-Dimensional; Address; Age; Aging; Animal Model; Biological Assay; Cancer Model; Carcinoma; Cell Aging; Cell Count; Cell physiology; Cells; Colon; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Data; Disease; Elderly; Engineering; Epithelial Cells; Fluorouracil; Genetic Engineering; Human; In Vitro; Incidence; Intestinal Cancer; Intestinal Neoplasms; Intestines; Isogenic transplantation; Laboratory Animals; Malignant Neoplasms; Mediating; Modeling; Mus; Neoplasm Metastasis; Organoids; Pathologic; Pelvis; Primary Neoplasm; Radiation; Risk Factors; Rodent Model; S-Phase Fraction; Small Intestines; Staging; Stem cells; System; Techniques; Testing; Transplantation; Tumor Promotion; Tumor Suppressor Genes; Tumorigenicity; Work; adenoma; age related; aged; base; cancer therapy; cell age; chemotherapeutic agent; chemotherapy; human subject; in vivo; irradiation; juvenile animal; mouse model; neoplastic cell; novel; novel therapeutics; oxaliplatin; preclinical study; research study; response; stem; tissue regeneration; treatment response; tumor; tumor growth; tumor heterogeneity; tumor initiation; tumor progression; tumorigenesis; tumorigenic

Aging has a profound impact on tissue regeneration and cancer incidence. However, the mechanisms of how aging reduces the function of stem cells, alters the transformability of stem cells to beget tumors, or influences tumor progression are poorly understood. Although aging is the single biggest risk factor for cancer in humans and laboratory animals, cancer has been modeled and interrogated solely in young rodent models. Our system for addressing these questions is the mammalian intestine where a majority of intestinal stem cells (ISCs) in the small intestine and colon express Lgr5. Our preliminary studies suggest that ISC numbers are diminished and less proliferative in old mice and humans and that elderly ISCs are less functional in an in vitro organoid (3-D mini-intestinal) assay of stem cell function, indicating that cell autonomous mechanisms contribute to intestinal stem cell aging. Finally, we find that aged mice, like aged humans, develop spontaneous intestinal adenomas and carcinoma; however, the mechanisms of how aging reduces the function of stem cells, alters the transformability of stem cells to give rise to tumors, or influences tumor progression/metastasis are poorly understood. In this proposal, we will study how aging influences the genesis, progression, and treatment response of intestinal adenomas and carcinomas in inducible, genetically defined mouse models of intestinal tumors. Specifically, we will establish aging mouse colonies to interrogate how age- related changes in the tumorigenic potential of intestinal stem and progenitor cells contribute to enhanced tumor incidence in old age (Aim 1); that aging has autonomous and non-autonomous effects on tumor progression (Aim 2), and that aging alters the treatment response of intestinal tumors to chemotherapy or radiation (Aim 3).

衰老对组织再生和癌症发病率有着深远的影响。然而，机制