An organ-on-a-chip model system to study prostate cancer metastasis into vascularized bone

研究前列腺癌转移至血管化骨的器官芯片模型系统

• 批准号: 10373347
• 负责人: Luiz Eduardo Bertassoni
• 金额: $ 21.6万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-31 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373347
• 关键词: Address; Adhesions; Affect; Basement membrane; Behavior; Biocompatible Materials; Biological; Biological Models; Biomedical Engineering; Biomimetics; Blood Vessels; Blood capillaries; Bone Matrix; Bone Resorption; Bone Tissue; Bone remodeling; Bone structure; Cancer Model; Capillary Endothelial Cell; Cell Communication; Cells; Chemicals; Complement; Complex; Development; Elements; Endothelial Cells; Endothelium; Engineering; Event; Exhibits; Extracellular Matrix; Extravasation; Growth; Homeostasis; Human; Human Characteristics; Hydrogels; In Vitro; Infiltration; Literature; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mesenchymal; Metastatic Neoplasm to the Bone; Methods; Microfluidic Microchips; Minerals; Modeling; Neoplasm Metastasis; Organ; Osteoblasts; Osteoclasts; Paracrine Communication; Patients; Pericytes; Physiologic calcification; Physiological; Play; Process; Research; Role; Seeds; Site; Soil; System; Testing; Time; Tissue Embedding; Tissues; Tumor Angiogenesis; Tumor Cell Invasion; Visualization; base; biomineralization; bone; bone cell; calcification; calcium phosphate; cancer cell; cell type; effective therapy; extracellular; metastatic process; microfluidic technology; mineralization; monolayer; nanoscale; neoplastic cell; novel; organ on a chip; osteoprogenitor cell; prostate cancer cell; prostate cancer metastasis; release factor; scaffold; success; theories; tumor; tumor progression

PROJECT SUMMARY Based on “seed and soil” theory, certain tumors exhibit a predilection for metastasis to particular organs. For example, bone is the most common site of metastasis for prostate cancer, happening in ~90% of patients with advanced stages of prostate cancer. Organ-on-a-chip models of cancer metastasis have emerged as a powerful predictor of cancer progression. However, despite the development in organ-on-a-chip platforms for in-vitro studies in metastasis, research in bone metastasis on-a-chip remains largely underdeveloped, and the only few available models in the literature lack the complex mineralization and the inclusion of bone cells, especially osteoclasts into the system, which are essential elements in order to study bone remodeling. Here, (aim 1) we will use a novel organ-on-a-chip platform with a highly mineralized and calcified cell-laden hydrogel including osteoclasts to determine the influence of mineralization and the cross-talk of prostate cancer cells and bone cells on the process of preferential prostate cancer growth in bone and the consequent bone resorption. A potentially rate-limiting step in metastasis formation is the extravasation process that involves adhesion of tumor cells to endothelial cells and their transmigration through the endothelial cell monolayer and basement membrane. It has been well-established that pericyte-support of EC capillaries is required for formation of non-leaky vessels and perturbation of the EC-hMSC linkage, therefore results in leaky vessels. The role of pericytes in tumor metastasis has been mostly focused on tumor angiogenesis and the research on the role of this cell type on cancer extravasation has remained underdeveloped. Here, (aim 2) we will use the bone metastasis-on-a-chip platform to test the role of pericytes in a vasculature embedded in a mineralized bone matrix in inhibiting human prostate cancer extravasation as well as the effects of factors released by cancer cells on vasculature integrity. We argue that this multi-pronged strategy will enable the engineering of in-vitro bone metastasis-on-a-chip model system to understand the preferential metastasis of prostate cancer to the bone and bone destruction as well as the role of pericytes in prostate cancer extravasation through the vasculature. Ultimately, this project will lead to model systems that can be used for studying cancer metastasis to bone and developing new treatments.

项目概要 根据“种子和土壤”理论，某些肿瘤表现出向特定器官转移的倾向。 例如，骨是前列腺癌最常见的转移部位，约 90% 的前列腺癌患者发生骨转移 前列腺癌晚期的癌症转移器官芯片模型已成为一种强大的方法。 然而，尽管体外器官芯片平台得到了发展。 转移方面的研究，芯片上骨转移的研究在很大程度上仍然不发达，并且仅有少数 文献中可用的模型缺乏复杂的矿化和骨细胞的包含，特别是 破骨细胞进入系统，这是研究骨重塑的基本要素，（目标 1）我们。 将使用一种新型的芯片器官平台，该平台具有高度矿化和钙化的充满细胞的水凝胶，包括 破骨细胞以确定矿化的影响以及前列腺癌细胞和骨细胞的串扰 前列腺癌在骨中优先生长的过程以及随后的骨吸收。 转移形成的限速步骤是外渗过​​程，涉及肿瘤细胞粘附到 内皮细胞及其通过内皮细胞单层和基底膜的迁移。 已经确定 EC 毛细血管的周细胞支持是形成无渗漏血管所必需的 EC-hMSC 连接的扰动，因此导致血管渗漏。周细胞在肿瘤转移中的作用。 主要关注肿瘤血管生成以及这种细胞类型对癌症的作用的研究 在这里，（目标 2）我们将使用骨转移芯片平台。 测试嵌入矿化骨基质的脉管系统中周细胞在抑制人类前列腺中的作用 我们认为癌症外渗以及癌细胞释放的因子对脉管系统完整性的影响。 这种多管齐下的策略将使体外骨转移芯片模型系统的设计成为可能 了解前列腺癌向骨的优先转移及骨破坏的作用 最终，该项目将建立模型。 可用于研究癌症骨转移和开发新疗法的系统。