Quantitative assessment of the role of collagen alterations in ovarian cancer

 描述（由申请人提供）：卵巢癌最常在疾病已经转移时被诊断，而病变仍低于常规成像模式的分辨率。细胞外基质（ECM）中胶原结构的改变已在卵巢癌中观察到，并被认为是许多上皮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，以研究胶原蛋白改变在疾病发展和进展中的作用。这些模型将来自胶原结构的二次谐波产生（SHG）图像，并通过多光子激发（MPE）光化学制造。这种制造方法提供了直接从胶原蛋白以高保真度产生亚微米纤维，其中所得结构是生物相容性和仿生的。我们已经表明，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成像提供了理解卵巢肿瘤微环境（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信息。癌细胞迁移和增殖以及基因表达将在体外和体内进行研究。 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接种在体内，将细胞表型和胶原改变的各自作用分离。活体成像将通过将肿瘤生长与肿瘤细胞的生长之间的关系， 胶原蛋白随着新陈代谢的变化而改变。我们假设这些研究将导致更好的诊断和上级治疗。为了实现这些目标，我们将推进SHG成像和MPE制造技术，其中每一个都将通知对方，并导致更好地了解卵巢癌。我们提出以下目标：目标1。开发基于SHG图像数据的卵巢肿瘤精细模型。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。

 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.