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 (E_VLCM/E_emb > 1), the emboli were constrained to grow within the channel, and when the elastic modulus of the matrix was less than the emboli (0 < E_VLCM/E_emb < 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.

中文翻译：

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血管模型内肿瘤栓子的生长表明依赖于机械约束的大小

肿瘤栓子——血管内肿瘤细胞的聚集体——构成临床挑战，因为它们与增加的转移和肿瘤复发有关。当在血管内生长时，肿瘤栓子受到血管管状几何形状提供的独特机械约束。当前的肿瘤栓塞模型使用不受约束的多细胞肿瘤球体，忽略了这种机械相互作用。在这里，我们在坚硬或柔软的生物惰性琼脂糖基质中将淋巴管建模为直径为 200 μm 的通道，以创建血管样约束模型 (VLCM)，并使用 HCT116 或SUM149PT 细胞，分别。刚性基质 VLCM 将肿瘤栓子限制在圆柱形通道内，导致栓子持续生长，与不受约束的球体表现出的增长率降低形成对比。然而，软基质 VLCM 中的栓子形态取决于基质和细胞聚集体之间的机械失配程度。一般来说，当 VLCM 基质的弹性模量大于栓子时（E _VLCM / E _emb  > 1)，栓子被约束在通道内生长，当基质的弹性模量小于栓子时（0 <  E _VLCM / E _emb < 1)，栓子凸入基质。由于细胞系之间肌球蛋白 II 表达的巨大差异，我们假设肿瘤细胞聚集体刚度是细胞力产生能力的指标。肌球蛋白相关力产生的抑制剂降低了弹性模量和/或增加了肿瘤细胞聚集体的应力松弛，有效地增加了机械错配。药物治疗后增加的机械错配与肿瘤栓子沿通道生长的限制增加相关，这可能转化为肿瘤负荷增加，因为在营养物质和氧气的扩散距离内肿瘤体积增加。