Growth of tumor emboli within a vessel model reveals dependence on the magnitude of mechanical constraint
Growth of tumor emboli within a vessel model reveals dependence on the magnitude of mechanical constraint
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DOI：
10.1093/intbio/zyaa024
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发表时间：
2021-01-14
影响因子：
2.5
通讯作者：
Mills, Kristen L.
中科院分区：
文献类型：
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作者：
Kulwatno, Jonathan;Gearhart, Jamie;Mills, Kristen L.
肿瘤栓塞-肿瘤细胞在血管内的聚集体-构成了临床挑战，因为它们与增加的转移和肿瘤复发相关。当在血管内生长时，肿瘤栓子受到由血管的管状几何形状提供的独特机械约束。目前的肿瘤栓子模型使用无约束的多细胞肿瘤球体，忽略了这种机械相互作用。在这里，我们将淋巴管建模为200 μ m直径的通道，在硬或软的生物惰性琼脂糖基质中创建血管样约束模型（VLCM），并分别用HCT 116或SUM 149 PT细胞聚集体建模结肠癌或乳腺癌肿瘤栓子。刚性基质VLCM将肿瘤栓子限制在圆柱形通道中，这导致栓子的连续生长，与不受约束的球体表现出的生长速率降低相反。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的大小。通常，当VLCM的基质的弹性模量大于栓子（E-VLCM/E-emb > 1）时，栓子被限制在通道内生长，并且当基质的弹性模量小于栓子（0 < E-VLCM/E-emb < 1）时，栓子凸出到基质中。由于肌球蛋白II表达的细胞系之间的差异很大，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，有效地增加了机械失配。药物治疗后机械不匹配的增加与肿瘤栓子沿着通道生长的限制增加相关，这可能会转化为肿瘤负荷的增加，因为营养物质和氧气扩散距离内的肿瘤体积增加。
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 mu m-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.