Mouse model of invasive colon cancer

 描述（由申请人提供）：结肠和直肠癌（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是不可治愈的患者手术切除的疾病，转移性结直肠癌模型的发展仍然是一个优先事项。一个小鼠肿瘤模型，证明入侵和/或转移，并具有显着的相似性，人类结直肠癌的可用性将提供一个强大的工具，用于识别的遗传和分子的改变，导致恶性肿瘤，以及评估的治疗和预防策略。我们最近在Smad 3 +/-; Rab 25-/-小鼠中开发了一种侵袭性结肠直肠癌的新模型，该模型在8-10月龄时发展为侵袭性结肠癌，其可通过非侵袭性PET和MRI成像识别并表达高水平的Src和Src活性。Smad3+/-;因此，Rab 25-/-小鼠代表了人类结直肠癌的独特模型，并且作为评估治疗功效的临床前工具可能具有相当大的价值。我们假设Smad 3 +/-; Rab 25-/-小鼠提供了与人类疾病高度相关的结肠癌的稳健小鼠模型。目前的建议旨在开发这种模型有两个具体的目标：首先，我们将评估Smad 3 +/-; Rab 25-/-小鼠结直肠肿瘤中RNA表达模式的差异，这可能导致侵袭性增加。肿瘤中的RNA测序结果将与其他小鼠模型和人结直肠癌进行比较，以确定该模型的相关特征。将通过免疫化学和定量PCR验证常见生物标志物，以更好地了解浸润性癌症表型。其次，我们将利用Smad 3 +/-; Rab 25- /-小鼠中结直肠肿瘤的PET和MRI成像来评估结直肠癌的治疗策略。我们将使用成像和病理学标准评估AZD-0530（一种Src激酶家族抑制剂）在Smad 3 +/-; Rab 25-/-小鼠模型中调节浸润性结直肠癌进展的疗效。这些研究将促进Smad 3 +/- ; Rab 25-/-结肠癌小鼠模型的开发，作为评估浸润性结直肠癌临床前治疗干预的关键场所。

 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.