Quantitative assessment of the role of collagen alterations in ovarian cancer

胶原蛋白改变在卵巢癌中作用的定量评估

• 批准号: 9114715
• 负责人: Paul J Campagnola
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9114715
• 关键词: 3-Dimensional; Algorithms; Animals; Architecture; Benign; Biocompatible; Biological; Biological Markers; Biology; Biomimetics; Carcinoma; Cell Proliferation; Cells; Clinical; Collagen; Collagen Fiber; Data; Data Analyses; Detection; Development; Diagnosis; Diagnostic; Disease; Disease remission; Epithelial; Etiology; Extracellular Matrix; Fiber; Gene Expression; Generations; Goals; Gold; Image; Image Analysis; In Vitro; Lead; Lesion; Malignant neoplasm of ovary; Measures; Metabolism; Methods; Microfabrication; Microscope; Microscopy; Modality; Modeling; Modification; Molecular; Monitor; Morphology; Neoplasm Metastasis; Normal tissue morphology; Ovarian; Ovarian Serous Tumor; Ovarian Tissue; Phenotype; Photochemistry; Physiological; Protein Isoforms; Protocols documentation; Recurrence; Resolution; Role; Structure; Survival Rate; Techniques; Technology; Testing; Three-Dimensional Imaging; Tissues; Tumor Tissue; Up-Regulation; Validation; base; cancer cell; cancer subtypes; cell motility; cell stroma; chemotherapeutic agent; clinical care; efficacy testing; imaging modality; imaging system; improved; in vitro Model; in vivo; in vivo imaging; insight; instrument; intravital imaging; migration; new technology; novel; ovarian neoplasm; peritoneal cancer; public health relevance; research study; scaffold; second harmonic; submicron; three-dimensional modeling; tool; tumor; tumor growth; tumor microenvironment

 DESCRIPTION (provided by applicant): Ovarian cancer is most often diagnosed when the disease has already metastasized, while lesions are still below the resolution of conventional imaging modalities. Alterations of the collagen architecture in the extracellular matrix (ECM) have been observed in ovarian cancer and are thought to be a critical step in the initiation and progression of many epithelial carcinomas and we suggest these changes are potential quantitative biomarkers. To study this possibility, we will develop 3D models of the stroma in ovarian cancer to study the role of collagen alterations in disease development and progression. These models will be derived from Second Harmonic Generation (SHG) images of the collagen architecture and fabricated through multiphoton excited (MPE) photochemistry. This fabrication method affords the creation of sub-micron fibers directly from collagen with high fidelity, where the resulting structures are both biocompatible and biomimetic. We have shown that SHG can differentiate ovarian cancer subtypes which represent different diseases with different etiologies. We therefore hypothesize that SHG imaging provides the context to understand the biological relevance of collagen remodeling in the ovarian tumor microenvironment (TME) and thereby inform the creation of biomimetic models to relate collagen alterations and tumor growth. Cancer cell migration and proliferation and gene expression will be studied both in in vitro and in vivo by seeding the scaffolds representing normal and ovarian tumors with cancer cells representing different disease and will decouple the respective roles of cell phenotype and collagen alterations. Intravital imaging will further these studies by correlating tumor growth and collagen alterations with changes in metabolism. We hypothesize these studies will lead to better diagnostics and superior therapies. To achieve these goals we will advance both the SHG imaging and MPE fabrication technologies, where each will inform the other and lead to better insight into ovarian cancer. We propose the following Aims: Aim 1. Develop refined models of ovarian tumors based on SHG image data. Aim 2. Use the models in vitro and in vivo to understand cancer cell-stromal interactions. Aim 3. Develop in vivo SHG imaging system with complete ex vivo capabilities.

 描述(申请人提供)：卵巢癌最常见的诊断是当疾病已经转移，而病变仍然低于传统的成像方式的分辨率。在卵巢癌中观察到细胞外基质(ECM)中胶原构筑的改变，被认为是许多上皮性癌发生和发展的关键步骤，我们认为这些变化是潜在的定量生物标志物。为了研究这种可能性，我们将开发卵巢癌间质的3D模型，以研究胶原改变在疾病发展和进展中的作用。这些模型将从胶原结构的二次谐波(SHG)图像中衍生出来，并通过多光子激发(MPE)光化学来制造。这种制造方法可以直接从高保真的胶原蛋白中产生亚微米纤维，所得到的结构既是生物兼容的，又是仿生的。我们已经证明，SHG可以区分卵巢癌亚型，这些亚型代表不同的疾病和不同的病因。 因此，我们假设SHG成像提供了了解卵巢肿瘤微环境(TME)中胶原蛋白重塑的生物学相关性的背景，从而为创建将胶原蛋白改变与肿瘤生长联系起来的仿生模型提供信息。我们将在体外和体外研究癌细胞的迁移、增殖和基因表达。 通过将代表正常和卵巢肿瘤的支架与代表不同疾病的癌细胞种植在体内，将分离细胞表型和胶原蛋白改变的各自作用。活体成像将通过将肿瘤生长和 随着新陈代谢的变化，胶原蛋白也发生了变化。我们假设这些研究将导致更好的诊断和更好的治疗。为了实现这些目标，我们将同时推进SHG成像和MPE制造技术，在这两种技术中，每一项都将相互告知，并导致对卵巢癌的更好了解。我们提出了以下目标：目的1.建立基于SHG图像数据的卵巢肿瘤精细模型。目的2.利用体外和体内模型了解癌细胞与间质的相互作用。目的3.研制具有完整体外功能的在体倍频成像系统。