The influence of biomechanical properties and cannabinoids on tumor invasion

Background: Cannabinoids are known to have an anti-tumorous effect, but the underlying mechanisms are only sparsely understood. Mechanical characteristics of tumor cells represent a promising marker to distinguish between tumor cells and the healthy tissue. We tested the hypothesis whether cannabinoids influence the tumor cell specific mechanical and migratory properties and if these factors are a prognostic marker for the invasiveness of tumor cells. Methods: 3 different glioblastoma cell lines were treated with cannabinoids and changes of mechanical and migratory properties of single cells were measured using atomic force microscopy and time lapse imaging. The invasiveness of cell lines was determined using a co-culture model with organotypic hippocampal slice cultures. Results: We found that cannabinoids are capable of influencing migratory and mechanical properties in a cell line specific manner. A network analysis revealed a correlation between a “generalized stiffness” and the invasiveness for all tumor cell lines after 3 and 4 d of invasion time: <i>r</i>_<i>3d</i> = −<i>0.88 [−0.52;−0.97]; r</i>_<i>4d</i> = −<i>0.90 [−0.59;−0.98]</i>. Conclusions: Here we could show that a “generalized stiffness” is a profound marker for the invasiveness of a tumor cell population in our model and thus might be of high clinical relevance for drug testing. Additionally cannabinoids were shown to be of potential use for therapeutic approaches of glioblastoma.研究背景：大麻素类化合物已被证实具备抗肿瘤效应，但其潜在作用机制目前仍了解甚少。肿瘤细胞的力学特性可作为区分肿瘤细胞与健康组织的潜在生物标志物。本研究旨在验证两项假说：其一，大麻素是否会影响肿瘤细胞特异性的力学与迁移特性；其二，此类特性是否可作为肿瘤细胞侵袭性的预后标志物。 研究方法：本研究选取3种不同的胶质母细胞瘤细胞系，经大麻素处理后，采用原子力显微镜（atomic force microscopy）与延时成像技术，检测单细胞的力学与迁移特性变化。同时通过器官型海马脑片共培养模型，测定各细胞系的侵袭能力。 研究结果：本研究发现，大麻素可通过细胞系特异性的方式调控肿瘤细胞的迁移与力学特性。网络分析结果显示，在侵袭时长为3天与4天时，所有受试肿瘤细胞系的"广义刚度"（generalized stiffness）与侵袭能力均存在相关性：<i>r</i>_<i>3d</i> = −<i>0.88 [−0.52;−0.97]</i>; <i>r</i>_<i>4d</i> = −<i>0.90 [−0.59;−0.98]</i>。 研究结论：本研究证实，在本实验模型中，"广义刚度"可作为肿瘤细胞群体侵袭能力的可靠标志物，因此在药物筛选领域具备较高的临床应用价值。此外，大麻素在胶质母细胞瘤的治疗方案中展现出潜在的应用前景。