Department of Obstetrics and Gynaecology, University of Otago, Christchurch, 2 Riccarton Avenue, Christchurch, 8011, New Zealand.
MacDiarmid Institute of Advanced Materials and Nanotechnology, Christchurch, New Zealand.
Cell Biochem Biophys. 2021 Jun;79(2):375-386. doi: 10.1007/s12013-020-00964-9. Epub 2021 Jan 12.
It has been long known that the oncogenic extracellular environment plays an indispensable role in developing and nurturing cancer cell progression and in resistance to standard treatments. However, by how much the biophysical components of tumour extracellular environment contribute to these processes is uncertain. In particular, the topographic environment is scarcely explored. The biophysical modulation of cell behaviour is primarily facilitated through mechanotransduction-associated mechanisms, including focal adhesion and Rho/ROCK signalling. Dysregulation of these pathways is commonly observed in ovarian cancer and, therefore, biophysical modulation of these mechanisms may be of great importance to ovarian cancer development and progression. In this work, aspects of the biophysical environment were explored using a bioimprinting technique. The study showed that topography-mediated substrate sensing delayed cell attachment, however, cell-cell interactions overrode the effect of topography in some cell lines, such as OVCAR-5. Also, 3D topographical cues were shown to modulate the inhibition of focal adhesion and Rho signalling, which resulted in higher MAPK activity in cells on the bioimprints. It was revealed that c-Src is vital to the biophysical modulation of cell proliferation and inhibition of c-Src could downregulate biophysically modulated MAPK activity. This study provides evidence that the biophysical extracellular environment affects key intracellular mechanisms associated with tumourigenicity in ovarian cancer cells.
长期以来，人们已经知道致癌的细胞外环境在促进癌细胞的发展和培育以及对标准治疗的抵抗方面起着不可或缺的作用。然而，肿瘤细胞外环境的生物物理成分在多大程度上促成了这些过程尚不确定。特别是地形环境几乎没有被探索过。细胞行为的生物物理调节主要通过机械转导相关机制来实现，包括黏着斑和 Rho/ROCK 信号通路。这些途径的失调在卵巢癌中很常见，因此，这些机制的生物物理调节可能对卵巢癌的发展和进展非常重要。在这项工作中，使用生物印迹技术探索了生物物理环境的某些方面。研究表明，形貌介导的底物感应会延迟细胞附着，但在某些细胞系（如 OVCAR-5）中，细胞-细胞相互作用会超过形貌的影响。此外，还显示三维形貌线索可以调节黏着斑和 Rho 信号的抑制，从而导致生物印迹上的细胞中 MAPK 活性更高。研究揭示 c-Src 对细胞增殖的生物物理调节至关重要，抑制 c-Src 可以下调生物物理调节的 MAPK 活性。这项研究提供了证据，表明细胞外生物物理环境会影响卵巢癌细胞中与致瘤性相关的关键细胞内机制。
