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

用于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: 10545054
• 负责人: Luiz Eduardo Bertassoni
• 金额: $ 17.64万
• 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/10545054
• 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; Calcium; 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; Invaded; Literature; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mesenchymal; Metastatic Neoplasm to the Bone; Methods; Microfluidic Microchips; Modeling; Neoplasm Metastasis; Organ; Osteoblasts; Osteoclasts; Paracrine Communication; Patients; Pericytes; Physiologic calcification; Physiological; Play; Process; Proliferating; Research; Role; Site; Soil; System; Testing; Time; Tissue Embedding; Tissues; Tumor Angiogenesis; Tumor Cell Invasion; Vascularization; Visualization; biomineralization; bone; bone cell; calcification; cancer cell; cell type; effective therapy; extracellular; inorganic phosphate; metastatic process; microfluidic technology; migration; 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.

项目摘要 基于“种子和土壤”理论，某些肿瘤表现出转移到特定器官的偏好。为 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。 前列腺癌晚期癌症转移的器官芯片模型已经成为一种强大的 癌症进展的预测因子。然而，尽管用于体外移植的器官芯片平台的发展， 尽管骨转移的研究在很大程度上还不发达， 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，这是研究骨重建的基本要素。在这里，（目标1）我们 将使用一种新型的器官芯片平台，该平台具有高度矿化和钙化的细胞负载水凝胶，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之而来的骨吸收。一个潜在 转移形成中的限速步骤是外渗过程，其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。它有 已经确定EC毛细血管的周细胞支持是形成非渗漏血管所必需的， 因此，EC-hMSC连接的扰动导致血管渗漏。周细胞在肿瘤转移中的作用 主要集中在肿瘤血管生成和研究这种细胞类型对癌症的作用 外渗仍然不发达。在这里，（目标2）我们将使用骨转移芯片平台 为了测试包埋在矿化骨基质中的脉管系统中的周细胞在抑制人前列腺 癌症渗出以及癌细胞释放的因子对血管完整性的影响。我们认为 这种多管齐下的策略将使体外骨转移芯片模型系统的工程化成为可能， 了解前列腺癌向骨的优先转移以及骨破坏的作用， 前列腺癌的周细胞通过脉管系统外渗。最终，该项目将导致模型 该系统可用于研究癌症骨转移和开发新的治疗方法。