Functional Imaging of Twist induced breast cancer

了解肿瘤的侵袭和转移提供了关于癌症的重要信息 进展为了实现这一目标，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。该实验室的早期结果表明， Twist是一种碱性螺旋-环-螺旋转录因子，在MCF-7乳腺癌细胞中促进肿瘤发生 以及增加异种移植物的肿瘤微环境内的脉管系统和渗透性。初步 数据表明，该转录因子的过表达可以促进 胆碱激酶，与恶性转化和转移相关的标志物。此外， 胆碱激酶水平的增加从磷酸胆碱和总胆碱水平的升高是明显的 含有这些转基因细胞中的化合物。 本提案旨在了解Twist在促进乳腺癌中的作用 通过改变乳腺上皮的细胞生理学和生物化学， 功能成像技术。这三个具体目标是：1）确定生物化学和生理 通过功能性磁共振成像，使用Twist过表达乳腺癌细胞在原位肿瘤中的改变 共振成像和光谱学，2）为了功能性地表征和成像下- 在乳腺癌异种移植模型中调节Twist，和3）鉴定Twist中的新转移标志物 过表达细胞，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，如含胆碱化合物水平，乳酸盐水平， 细胞外pH、血管容积和通透性表面积乘积在Twist过表达中以及在 扭曲下调细胞。此外，我们将使用非侵入性光学成像来识别不同阶段的 使用用光学报告基因（tdTomato）转染的MCF-7/Twist细胞的癌症进展。最后， 将使用临床前模型鉴定的基因标记模式应用于患者样品， 以确定乳腺癌进展的潜在标志物。从长远来看，这些研究将有助于 乳腺癌的病理诊断，并提供见解，将有助于新的发展， 乳腺癌的成像标记物和化疗药物。

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.