Extracellular protonation modulates cell-cell interaction mechanics and tissue invasion in human melanoma cells
Extracellular protonation modulates cell-cell interaction mechanics and tissue invasion in human melanoma cells
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DOI：
10.1038/srep42369
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发表时间：
2017-02-13
影响因子：
4.6
通讯作者：
Schwab, Albrecht
中科院分区：
文献类型：
--
作者：
Hofschroeer, Verena;Koch, Kevin Alexander;Schwab, Albrecht
通过促进细胞释放到组织中，细胞从原发性肿瘤的脱离先于转移进展。实体瘤表现出细胞外酸化改变的pH稳态。在人类黑色素瘤中，Na +/H+交换器NHE1是肿瘤纳米环境的重要调节剂。在这里，我们测试了细胞外pH和NHE1对细胞-细胞粘附的调节。MV3肿瘤球状体包埋在胶原蛋白基质中揭示了细胞-细胞接触松动和3D迁移到模拟生理限制的环境中的功效。使用原子力显微镜定量单个MV3细胞之间的粘附相互作用强度，并通过多细胞聚集试验进行验证。从pH（e）7.4至6.4的细胞外酸化降低了细胞迁移和侵袭，但增加了单细胞从球状体的脱离。酸化和NHE1过表达均降低细胞-细胞粘附强度，其通过降低的最大拉力和粘附能来表示。酸化或NHE1过表达会严重损害多细胞聚集和球状体形成。我们显示了一个明确的依赖黑色素瘤细胞-细胞粘附pHe和NHE1作为调制器。这些效应与通过NHE1挤出的质子加强的细胞-基质相互作用相反。我们的结论是，这些相反的作用NHE1的协同作用，在转移级联。
Detachment of cells from the primary tumour precedes metastatic progression by facilitating cell release into the tissue. Solid tumours exhibit altered pH homeostasis with extracellular acidification. In human melanoma, the Na+/H+ exchanger NHE1 is an important modifier of the tumour nanoenvironment. Here we tested the modulation of cell-cell-adhesion by extracellular pH and NHE1. MV3 tumour spheroids embedded in a collagen matrix unravelled the efficacy of cell-cell contact loosening and 3D emigration into an environment mimicking physiological confinement. Adhesive interaction strength between individual MV3 cells was quantified using atomic force microscopy and validated by multicellular aggregation assays. Extracellular acidification from pH(e) 7.4 to 6.4 decreases cell migration and invasion but increases single cell detachment from the spheroids. Acidification and NHE1 overexpression both reduce cell-cell adhesion strength, indicated by reduced maximum pulling forces and adhesion energies. Multicellular aggregation and spheroid formation are strongly impaired under acidification or NHE1 overexpression. We show a clear dependence of melanoma cell-cell adhesion on pHe and NHE1 as a modulator. These effects are opposite to cell-matrix interactions that are strengthened by protons extruded via NHE1. We conclude that these opposite effects of NHE1 act synergistically during the metastatic cascade.