Modifiers of Intestinal Tumor Progression

肠肿瘤进展的调节因素

基本信息

批准号：
8230472
负责人：
Linda D Siracusa
金额：
$ 20.23万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8230472
关键词：
Adenocarcinoma Adenomatous Polyposis Coli Age Age-Years Aging Alleles Backcrossings Benign Biological Assay Biological Models Candidate Disease Gene Chromosomes Colon Colonoscopy Colorectal Cancer Columbidae Complex Development Disease Duodenum Environment Female Gene Expression Profile Generations Genes Genetic Genome Goals Human Hybrids Inborn Genetic Diseases Inbred Strain Incidence Individual Intestinal Cancer Intestinal Neoplasms Intestinal Polyps Intestines Knowledge Lead Life Location Longevity Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Mammary Neoplasms MicroRNAs Modeling Mus Mutate Mutation Normal tissue morphology Pathway interactions Patients Phenotype Point Mutation Prevention Preventive Process Protein Truncation Proteins Radiation Research Resistance Risk Factors Role Screening procedure Small Intestines Staging Study models Survival Rate Therapeutic Transcript Translations Tumor Suppressor Genes Variant Work adenoma cancer diagnosis congenic consomic design gene function genetic variant high throughput screening human disease male malignant small intestine tumor mouse model novel prevent public health relevance research study trait tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Cancers of the gastrointestinal tract comprise more than 10% of all cancers diagnosed in the U.S. (www.cancer.org). Disease incidence and phenotype are influenced by genetics and the environment. Although the number of people having colonoscopy screenings is increasing, the incidence of colorectal cancer has not decreased. Cancers of the small intestine total less than 5% of colorectal cancers, but the five year survival rate is very low. The adenomatous polyposis coli (APC) tumor suppressor gene is mutated in Familial Adenomatous Polyposis (FAP), a dominant inherited disorder that predisposes individuals to developing colorectal cancer (Groden et al. 1991). Having FAP is also a risk factor for small intestinal cancer, as tumors tend to form at or near the duodenum in FAP patients. Mouse models of small intestine and colorectal cancers are invaluable for understanding the process of tumorigenesis and discovering mechanisms that interfere with progression to malignancy. The ApcMin/+ mouse contains a point mutation in the Apc gene that results in a truncated protein (Moser et al. 1990; Su et al. 1992). Genetic background has a significant role in determining the phenotypes of ApcMin/+ mice (reviewed in Siracusa et al. 2004) and complex trait analyses have identified several Modifier of Min (Mom) loci that alter intestinal tumor phenotypes (reviewed in Kwong and Dove 2008). This exploratory R21 is focused on using the ApcMin/+ mouse model to identify genes that influence tumor progression. The idea for this study arose when we had an exciting finding, namely that hybrid progeny from an intercross between inbred strains had a long lifespan and were highly resistant to tumor progression, even though they carried the ApcMin mutation. The few tumors that develop in these exceptional mice remain almost exclusively low grade adenomas and do not progress to more advanced stages. This model challenges the existing paradigm that tumor progression is a function of age. We, therefore, have a unique model system that mimics human disease in several ways: 1) the genome of these hybrid mice is heterozygous at virtually every locus (as is the case in humans), 2) the lifespan of these mice is comparable to humans 50 years of age and beyond (a risk factor for intestinal cancers), and 3) tumors develop without losing the entire chromosome carrying the Apc+ allele (a mechanism similar to human tumors). The factor responsible for resistance to progression appears limited to a single chromosome; our research is designed to define this modifier gene and pathways that protect against tumor progression. Translation of this work to human cancers could ultimately lead to better prevention and treatment options for intestinal cancers. PUBLIC HEALTH RELEVANCE: Many steps and changes along the way are responsible for turning a benign tumor growth into a life-threatening cancer. This research is designed to uncover genes that function during the intermediate steps of this process. The goal is to identify genes that can prevent the progression of tumors into cancers in the small intestine and colon. With this knowledge, we can move towards developing novel preventive and therapeutic options for patients.

描述（由申请人提供）：胃肠道的癌症占美国被诊断的所有癌症的10％以上（www.cancer.org）。疾病的发生率和表型受遗传学和环境的影响。尽管进行结肠镜检查的人数有所增加，但结直肠癌的发生率尚未减少。小肠的癌症总数不到结直肠癌的5％，但五年的生存率非常低。腺瘤性息肉病（APC）肿瘤抑制基因在家族性腺瘤性息肉病（FAP）中被突变，这是一种主导的遗传疾病，使个体容易发生结直肠癌（Groden等，1991）。 FAP也是小肠癌的危险因素，因为在FAP患者中，肿瘤倾向于在十二指肠或附近形成。小肠和结直肠癌的小鼠模型对于理解肿瘤发生的过程和发现干扰恶性肿瘤发展的机制是无价的。 APCMIN/+小鼠在APC基因中包含一个点突变，从而导致截短的蛋白质（Moser等，1990； Su等，1992）。遗传背景在确定APCMIN/+小鼠的表型中具有重要作用（在Siracusa等，2004年进行了综述），并且复杂的性状分析已经确定了几个改变肠道肿瘤表型的Min（MOM）基因座的修饰剂（在Kwong和Dove 2008中进行了综述）。该探索性R21的重点是使用APCMIN/+小鼠模型来识别影响肿瘤进展的基因。当我们有一个令人兴奋的发现时，就出现了这项研究的想法，即，近交菌株之间的杂交后代的寿命很长，并且对肿瘤进展具有很高的抵抗力，即使它们带有APCMIN突变。在这些特殊小鼠中出现的几种肿瘤几乎保留几乎完全低级腺瘤，并且不会发展到更高级的阶段。该模型挑战了现有的范式，即肿瘤进展是年龄的函数。 We, therefore, have a unique model system that mimics human disease in several ways: 1) the genome of these hybrid mice is heterozygous at virtually every locus (as is the case in humans), 2) the lifespan of these mice is comparable to humans 50 years of age and beyond (a risk factor for intestinal cancers), and 3) tumors develop without losing the entire chromosome carrying the Apc+ allele (a mechanism similar to人类肿瘤）。负责进展的抗性的因素似乎仅限于单个染色体。我们的研究旨在定义这种修饰基因和防止肿瘤进展的途径。将这项工作翻译给人类癌症最终可能会导致肠癌的更好的预防和治疗选择。公共卫生相关性：途中的许多步骤和变化负责将良性肿瘤的生长变成威胁生命的癌症。这项研究旨在发现在此过程的中间步骤中起作用的基因。目的是确定可以防止肿瘤进展为小肠和结肠中癌症的基因。有了这些知识，我们可以为患者开发新颖的预防和治疗选择。