Mouse model of invasive colon cancer

侵袭性结肠癌小鼠模型

• 批准号: 9043831
• 负责人: JAMES Richard GOLDENRING
• 金额: $ 1.42万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2016-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9043831
• 关键词: Accounting; Age-Months; Apoptosis; Biological Markers; Cancer Etiology; Cancer Model; Cell physiology; Cessation of life; Characteristics; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Colorectal Neoplasms; Detection; Development; Disease; Evaluation; Genetic Transcription; Health; Human; Image; Immunochemistry; Inflammation; Lead; Magnetic Resonance Imaging; Malignant Neoplasms; Messenger RNA; Methodology; MicroRNAs; Modeling; Molecular Genetics; Molecular Profiling; Morbidity - disease rate; Mucous Membrane; Mus; Neoplasm Metastasis; Patients; Pattern; Phenotype; Physiological Processes; Physiology; Positron-Emission Tomography; Prevention strategy; RNA; Rectum; Subgroup; Therapeutic; Therapeutic Intervention; Transcript; Treatment Efficacy; Tumor Markers; Up-Regulation; base; human cancer mouse model; human disease; imaging modality; in vivo; inhibitor/antagonist; kinase inhibitor; metastatic colorectal; miRNA expression profiling; model development; molecular imaging; mortality; mouse model; novel; pre-clinical; pre-clinical research; src-Family Kinases; tool; transcriptome sequencing; tumor; tumor growth

 DESCRIPTION (provided by applicant): Cancers of the colon and rectum (colorectal cancer) remain a major cause of morbidity and mortality. Since metastatic colorectal cancer remains largely incurable for patients with surgically non-resectable disease, the development of models of metastatic colorectal cancer remains a priority. The availability of a mouse tumor model that demonstrates invasion and/or metastasis and has prominent similarity to human colorectal cancer would provide a powerful tool for identifying the genetic and molecular alterations that lead to malignancy as well as for assessment of therapeutic and preventive strategies. We have recently developed a novel model of invasive colorectal cancer in Smad3+/-;Rab25-/- mice, which develop invasive colon cancers by 8-10 months of age that are identifiable by non-invasive PET and MRI imaging and express high levels of Src and Src activity. The Smad3+/-;Rab25-/- mouse therefore represents a unique model for colorectal cancer in humans and may be of considerable value as a pre-clinical tool for evaluating therapeutic efficacy. We have hypothesized that the Smad3+/-;Rab25-/- mouse provides a robust mouse model of colon cancer with high correlation to human disease. The present proposal seeks to develop this model in two specific aims: First, we will evaluate the differences in RNA expression patterns in Smad3+/-;Rab25-/- mouse colorectal tumors that could account for increased invasive characteristics. RNA sequencing results in tumors will be compared with both other mouse models and human colorectal cancers to determine the correlative characteristics of this model. Common biomarkers will be validated by immunochemistry and quantitative PCR to obtain a greater understanding of the invasive cancer phenotype. Second, we will utilize PET and MRI imaging of colorectal tumors in the Smad3+/-;Rab25- /- mouse to evaluate therapeutic strategies in colorectal cancer. We will assess the efficacy of AZD-0530, a Src kinase family inhibitor, in modulating the progression of invasive colorectal cancers in the Smad3+/-;Rab25-/- mouse model using both imaging and pathological criteria. These studies will facilitate the development of the Smad3+/- ;Rab25-/- mouse model of colon cancer as a critical venue for the evaluation of pre- clinical therapeutic interventions in invasive colorectal cancer.

 描述(申请人提供)：结肠癌和直肠癌(结直肠癌)仍然是发病率和死亡率的主要原因。由于转移性结直肠癌在很大程度上仍然无法治愈，因此发展转移性结直肠癌模型仍然是当务之急。如果有一种小鼠肿瘤模型能够显示肿瘤的侵袭和/或转移，并且与人类结直肠癌有显著的相似性，这将为识别导致恶性肿瘤的基因和分子改变以及评估治疗和预防策略提供强有力的工具。我们最近在Smad3+/-；Rab25-/-小鼠身上开发了一种新的侵袭性结直肠癌模型，这些小鼠在8-10个月大时发生侵袭性结肠癌，通过非侵入性PET和MRI成像可以识别，并表达高水平的Src和Src活性。因此，SMAD3+/-；Rab25-/-小鼠代表了一种独特的人类结直肠癌模型，并可能作为临床前评估疗效的工具具有相当大的价值。我们假设Smad3+/-；Rab25-/-小鼠提供了一个与人类疾病高度相关的结肠癌小鼠模型。目前的建议试图在两个特定的目标下建立这个模型：首先，我们将评估Smad3+/-；Rab25-/-小鼠结直肠肿瘤中RNA表达模式的差异，这些差异可能解释了侵袭性增加的特征。肿瘤中的RNA测序结果将与其他小鼠模型和人类结直肠癌模型进行比较，以确定该模型的相关特征。常见的生物标记物将通过免疫化学和定量聚合酶链式反应进行验证，以更好地了解浸润性癌症的表型。其次，我们将利用在Smad3+/-；Rab25-/-小鼠中的结直肠癌的PET和MRI成像来评估结直肠癌的治疗策略。在Smad3+/-；Rab25-/-小鼠模型中，我们将使用成像和病理标准来评估SZD-0530，一种Src激酶家族抑制剂，在调节侵袭性结直肠癌进展中的有效性。这些研究将促进Smad3+/-；Rab25-/-小鼠结肠癌模型的发展，作为评估侵袭性结直肠癌临床前治疗干预措施的关键场所。