UCL Division of Surgery and Interventional Science, London, U.K.
Unit of Preclinical Models and New Therapeutic Agents, IRCCS, Regina Elena National Cancer Institute, Rome, Italy.
Clin Sci (Lond). 2024 Nov 20;138(22):1441-1450. doi: 10.1042/CS20240371.
High-grade serous ovarian cancer (HG-SOC), accounting for 70-80% of ovarian cancer deaths, is characterized by a widespread and rapid metastatic nature, influenced by diverse cell types, cell-cell interactions, and acellular components of the tumour microenvironment (TME). Within this tumour type, autocrine and paracrine activation of the endothelin-1 receptors (ET-1R), expressed in tumour cells and stromal elements, drives metastatic progression. The lack of three-dimensional models that faithfully recapitulate the unique HG-SOC TME has been the bottleneck in performing drug screening for personalized medicine. Herein, we developed HG-SOC tumouroids by engineering a dense central artificial cancer mass (ACM) containing HG-SOC cells, nested within a compressed hydrogel recapitulating the stromal compartment comprising type I collagen, laminin, fibronectin, and stromal cells (fibroblasts and endothelial cells). ET-1-stimulated HG-SOC cells in the tumouroids showed an altered migration pattern and formed cellular aggregates, mimicking micrometastases that invaded the stroma. Compared with control cells, ET-1-stimulated tumouroids showed a higher number of invasive bodies, which were reduced by treatment with the dual ET-1 receptor (ET-1R) antagonist macitentan. In addition, ET-1 increased the size of the invading aggregates compared with control cells. This study establishes an experimental 3D multicellular model eligible for mechanical research, investigating the impact of matrix stiffness and TME interactions, which will aid drug screening to guide therapeutic decisions in HG-SOC patients.
高级别浆液性卵巢癌（HG-SOC）占卵巢癌死亡人数的 70-80%，其特征是广泛且快速的转移性，受多种细胞类型、细胞间相互作用以及肿瘤微环境（TME）的无细胞成分影响。在这种肿瘤类型中，肿瘤细胞和基质成分中表达的内皮素-1 受体（ET-1R）的自分泌和旁分泌激活，驱动转移进展。缺乏真实再现独特 HG-SOC TME 的三维模型一直是进行个性化药物药物筛选的瓶颈。在此，我们通过工程化一个包含 HG-SOC 细胞的密集中央人工癌块（ACM），嵌套在压缩水凝胶中，再现包含 I 型胶原、层粘连蛋白、纤连蛋白和基质细胞（成纤维细胞和内皮细胞）的基质区室，从而开发了 HG-SOC tumouroids。在 tumouroids 中，ET-1 刺激的 HG-SOC 细胞显示出改变的迁移模式并形成细胞聚集体，模拟了侵袭基质的微转移。与对照细胞相比，ET-1 刺激的 tumouroids 形成了更多的侵袭体，用双重内皮素-1 受体（ET-1R）拮抗剂 macitentan 处理可减少侵袭体。此外，与对照细胞相比，ET-1 增加了侵袭聚集物的大小。这项研究建立了一种适用于机械研究的实验性 3D 多细胞模型，研究基质刚度和 TME 相互作用的影响，这将有助于药物筛选，以指导 HG-SOC 患者的治疗决策。
