Functional Imaging of Twist induced breast cancer

了解肿瘤的侵袭和转移提供与癌症有关的重要信息 进步。为了实现这一目标，我们已经确定了一个中胚层基因Twist，它在 促进乳腺癌的形成。这个实验室的早期结果表明，过度表达 一种基本螺旋-环-螺旋转录因子Twist在MCF-7乳腺癌细胞中的表达促进肿瘤发生 并增加了异种移植瘤微环境内的血管生成和通透性。初步 有数据表明，该转录因子的过表达可促进细胞因子的表达。 胆碱激酶，一种与恶性转化和转移有关的标志物。此外，该组织的活动 从磷胆碱和总胆碱水平的升高可以明显看出胆碱激酶水平的升高。 在这些转基因细胞中含有化合物。 目前的建议旨在了解Twist在促进乳腺癌方面的作用 乳房上皮细胞生理生化改变对侵袭转移的影响 功能成像技术。三个具体目标是：1)鉴定生化和生理 利用功能磁学技术高表达Twist乳腺癌细胞对原位肿瘤的影响 共振成像和光谱学，2)从功能上表征和成像羽绒- 在乳腺癌异种移植模型中调节Twist，以及3)在Twist中识别新的转移标志物 过度表达细胞并在乳腺癌患者样本中验证它们。在这项研究中，我们将使用 功能磁共振成像以确定影响表型的分子变化 乳腺肿瘤的特征，如含有胆碱的化合物水平，乳酸水平， 细胞外Phe、血管体积和通透性表面积乘积在Twist中也过表达 扭转下调调节的细胞。此外，我们将使用非侵入性光学成像来识别不同阶段的 利用转入光学报告基因(TdTomato)的MCF-7/Twist细胞的癌症进展。最后， 使用临床前模型确定的基因签名模式将按顺序应用于患者样本 以确定乳腺癌进展的潜在标记物。从长远来看，这些研究将有助于 为乳腺癌的病理诊断提供了新的见解，将有助于 乳腺癌的影像标志物和化疗药物。

Understanding tumor invasion and metastasis provides crucial information with respect to carcinoma progression. Towards this goal, we have identified a mesodermal gene, Twist, which has a crucial role in promoting breast cancer formation. Earlier results from this laboratory have indicated that over-expression of Twist, a basic helix-loop-helix transcription factor, in MCF-7 breast cancer cells promotes tumorigenesis and increased vasculature and permeability within the tumor microenvironment of xenografts. Preliminary data have indicated that over-expression of this transcription factor can promote the expression of the choline kinase, a marker related to malignant transformation and metastasis. In addition, the activity of the increased levels of choline kinase is evident from the elevated levels of phosphocholine and total choline containing compounds in these transgenic cells. The present proposal is designed to understand the role of Twist in promoting breast cancer invasion and metastasis by altering the cellular physiology and biochemistry of breast epithelium by using functional imaging techniques. The three specific aims are: 1) To identify biochemical and physiological alterations in orthotopic tumors using Twist over-expressing breast cancer cells by functional magnetic resonance imaging and spectroscopy, 2) To functionally characterize and image the effects of down- regulating Twist in breast cancer xenograft models, and 3) To identify novel metastatic markers in Twist over-expressing cells and to validate them in breast cancer patient samples. In this study, we will use functional magnetic resonance imaging to identify the molecular changes that influence the phenotypic characteristics of breast tumors, such as, changes in choline containing compound levels, lactate levels, extracellular pHe, vascular volume and permeability surface area product in Twist over-expressing as well in Twist down-regulated cells. Also, we will use non-invasive optical imaging to identify various stages of cancer progression using MCF-7/Twist cells transfected with an optical reporter gene (tdTomato). Finally, the gene signature patterns identified using the preclinical model will be applied to patient samples in order to identify potential markers of breast cancer progression. In the long term, these studies will help in the pathological diagnosis of breast cancer and provide insights that will contribute to the development of novel imaging markers and chemotherapeutic drugs for breast cancer.