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（由申请人提供）：卵巢癌最常在疾病已经转移、而病变仍低于传统成像方式的分辨率时被诊断出来。在卵巢癌中观察到细胞外基质（ECM）中胶原蛋白结构的改变，并被认为是许多上皮癌发生和进展的关键步骤，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，我们将开发卵巢癌基质的 3D 模型，以研究胶原蛋白改变在疾病发生和进展中的作用。这些模型将源自胶原蛋白结构的二次谐波生成 (SHG) 图像，并通过多光子激发 (MPE) 光化学来制作。这种制造方法可以直接用胶原蛋白高保真度地制造亚微米纤维，所得结构既具有生物相容性又具有仿生性。我们已经证明 SHG 可以区分卵巢癌亚型，这些亚型代表具有不同病因的不同疾病。 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，从而为创建与胶原蛋白改变和肿瘤生长相关的仿生模型提供了信息。将在体外和体内研究癌细胞迁移和增殖以及基因表达 通过在代表正常和卵巢肿瘤的支架上接种代表不同疾病的癌细胞来在体内进行研究，并将解耦细胞表型和胶原蛋白改变各自的作用。活体成像将通过关联肿瘤生长和 胶原蛋白随着新陈代谢的变化而变化。我们假设这些研究将带来更好的诊断和更好的治疗。为了实现这些目标，我们将推进 SHG 成像和 MPE 制造技术，这两种技术将相互告知并更好地了解卵巢癌。我们提出以下目标： 目标 1. 基于 SHG 图像数据开发卵巢肿瘤的精细模型。目标 2. 使用体外和体内模型来了解癌细胞-基质相互作用。目标3.开发具有完整离体功能的体内SHG成像系统。