Mouse model of invasive colon cancer

侵袭性结肠癌小鼠模型

• 批准号: 8878756
• 负责人: JAMES Richard GOLDENRING
• 金额: $ 20.49万
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8878756
• 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; 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; RNA Sequences; 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; public health relevance; 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（由申请人提供）：结肠癌和直肠癌（结直肠癌）仍然是发病和死亡的主要原因。由于转移性结直肠癌对于手术不可切除的患者来说在很大程度上仍然无法治愈，因此转移性结直肠癌模型的开发仍然是一个优先事项。表现出侵袭和/或转移且与人类结直肠癌具有显着相似性的小鼠肿瘤模型的可用性将为识别导致恶性肿瘤的遗传和分子改变以及评估治疗和预防策略提供强大的工具。我们最近在 Smad3+/-;Rab25-/- 小鼠中开发了一种新的侵袭性结直肠癌模型，该模型在 8-10 个月大时发展为侵袭性结肠癌，可通过非侵入性 PET 和 MRI 成像识别，并表达高水平的 Src 和 Src 活性。因此，Smad3+/-;Rab25-/- 小鼠代表了人类结直肠癌的独特模型，并且作为评估治疗效果的临床前工具可能具有相当大的价值。我们假设 Smad3+/-;Rab25-/- 小鼠提供了与人类疾病高度相关的稳健的结肠癌小鼠模型。目前的提案旨在开发该模型以实现两个具体目标：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，这可能是侵袭特征增加的原因。肿瘤的 RNA 测序结果将与其他小鼠模型和人类结直肠癌进行比较，以确定该模型的相关特征。常见的生物标志物将通过免疫化学和定量 PCR 进行验证，以更好地了解侵袭性癌症表型。其次，我们将利用 Smad3+/-;Rab25-/- 小鼠结直肠肿瘤的 PET 和 MRI 成像来评估结直肠癌的治疗策略。我们将使用影像学和病理学标准评估 AZD-0530（一种 Src 激酶家族抑制剂）在 Smad3+/-;Rab25-/- 小鼠模型中调节侵袭性结直肠癌进展的功效。这些研究将促进结肠癌 Smad3+/-;Rab25-/- 小鼠模型的开发，作为评估侵袭性结直肠癌临床前治疗干预的关键场所。