Kulwatno Jonathan, Gearhart Jamie, Gong Xiangyu, Herzog Nora, Getzin Matthew, Skobe Mihaela, Mills Kristen L
Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA.
Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA.
Integr Biol (Camb). 2021 Feb 3;13(1):1-16. doi: 10.1093/intbio/zyaa024.
Tumor emboli-aggregates of tumor cells within vessels-pose a clinical challenge as they are associated with increased metastasis and tumor recurrence. When growing within a vessel, tumor emboli are subject to a unique mechanical constraint provided by the tubular geometry of the vessel. Current models of tumor emboli use unconstrained multicellular tumor spheroids, which neglect this mechanical interplay. Here, we modeled a lymphatic vessel as a 200 μm-diameter channel in either a stiff or soft, bioinert agarose matrix to create a vessel-like constraint model (VLCM), and we modeled colon or breast cancer tumor emboli with aggregates of HCT116 or SUM149PT cells, respectively. The stiff matrix VLCM constrained the tumor emboli to the cylindrical channel, which led to continuous growth of the emboli, in contrast to the growth rate reduction that unconstrained spheroids exhibit. Emboli morphology in the soft matrix VLCM, however, was dependent on the magnitude of mechanical mismatch between the matrix and the cell aggregates. In general, when the elastic modulus of the matrix of the VLCM was greater than the emboli (EVLCM/Eemb > 1), the emboli were constrained to grow within the channel, and when the elastic modulus of the matrix was less than the emboli (0 < EVLCM/Eemb < 1), the emboli bulged into the matrix. Due to a large difference in myosin II expression between the cell lines, we hypothesized that tumor cell aggregate stiffness is an indicator of cellular force-generating capability. Inhibitors of myosin-related force generation decreased the elastic modulus and/or increased the stress relaxation of the tumor cell aggregates, effectively increasing the mechanical mismatch. The increased mechanical mismatch after drug treatment was correlated with increased confinement of tumor emboli growth along the channel, which may translate to increased tumor burden due to the increased tumor volume within the diffusion distance of nutrients and oxygen.
肿瘤栓子——血管内肿瘤细胞的聚集体——构成了一项临床挑战，因为它们与转移增加和肿瘤复发相关。当在血管内生长时，肿瘤栓子会受到血管管状结构所提供的独特机械约束。当前的肿瘤栓子模型使用无约束的多细胞肿瘤球体，而忽略了这种机械相互作用。在这里，我们将淋巴管模拟为直径200μm的通道，置于坚硬或柔软的生物惰性琼脂糖基质中，以创建一种类似血管的约束模型（VLCM），并且我们分别用HCT116或SUM149PT细胞聚集体模拟结肠癌或乳腺癌肿瘤栓子。坚硬基质VLCM将肿瘤栓子限制在圆柱形通道内，这导致栓子持续生长，这与无约束球体所表现出的生长速率降低形成对比。然而，柔软基质VLCM中的栓子形态取决于基质与细胞聚集体之间机械失配的程度。一般来说，当VLCM基质的弹性模量大于栓子（EVLCM/Eemb > 1）时，栓子被限制在通道内生长，而当基质的弹性模量小于栓子（0 < EVLCM/Eemb < 1）时，栓子会向基质中凸起。由于细胞系之间肌球蛋白II表达存在很大差异，我们假设肿瘤细胞聚集体的硬度是细胞产生力能力的一个指标。肌球蛋白相关力产生的抑制剂降低了肿瘤细胞聚集体的弹性模量和/或增加了其应力松弛，有效地增加了机械失配。药物治疗后机械失配的增加与肿瘤栓子沿通道生长的受限增加相关，这可能由于营养物质和氧气扩散距离内肿瘤体积增加而导致肿瘤负担增加。
