Department of Oral and Craniofacial Sciences, Level 9, Postgraduate and Research Tower, Faculty of Dentistry, University of Malaya, 50603, Kuala Lumpur, Malaysia.
Centre for Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Sci Rep. 2021 Jan 12;11(1):584. doi: 10.1038/s41598-020-79789-8.
Many of the characteristics ascribed to cancer-associated fibroblasts (CAFs) are shared by activated, autophagic and senescent fibroblasts. Whilst most oral squamous cell carcinomas (OSCCs) are genetically unstable (GU-OSCC), genetically stable variants (GS-OSCC) have been described and, notably, CAF activation (myofibroblast differentiation) and senescence are characteristics particularly associated with GU-OSCCs. However, it is not known whether autophagy is disrupted in these cells or whether autophagy regulates the development of the myofibroblast and senescent phenotypes. In this study, we show that senescent CAFs from GU-OSCCs contained more autophagosomes than normal human oral fibroblasts (NHOFs) and CAFs from GS-OSCCs possibly due to autophagic impairment. Further, we show that deregulation of autophagy in normal fibroblasts, either by inhibition with autophagy inhibitor, SAR405, or activation with TGF-β1, induced fibroblast activation and senescence: In response to TGF-β1, autophagy was induced prior to the development of the activated and senescent phenotypes. Lastly, we show that both SAR405- and TGF-β1-treated NHOFs enhance OSCC cell migration but only TGF-β1-treated cells increase OSCC invasion through Matrigel, indicating that TGF-β1 has additional effects that are independent of fibroblast activation/senescence. These results suggest a functional role for autophagy in the development of myofibroblast and CAF phenotypes.
许多被归因于癌症相关成纤维细胞（CAF）的特征与激活的、自噬的和衰老的成纤维细胞共享。虽然大多数口腔鳞状细胞癌（OSCC）具有遗传不稳定性（GU-OSCC），但已经描述了遗传稳定的变体（GS-OSCC），值得注意的是，CAF 激活（肌成纤维细胞分化）和衰老与 GU-OSCC 特别相关。然而，目前尚不清楚这些细胞中的自噬是否受到破坏，或者自噬是否调节肌成纤维细胞和衰老表型的发展。在这项研究中，我们表明，GU-OSCC 中的衰老 CAF 比正常人类口腔成纤维细胞（NHOF）和 GS-OSCC 中的 CAF 含有更多的自噬体，可能是由于自噬受损。此外，我们表明，正常成纤维细胞中的自噬失调，无论是通过自噬抑制剂 SAR405 抑制还是通过 TGF-β1 激活，都会诱导成纤维细胞激活和衰老：响应 TGF-β1，自噬在激活和衰老表型发展之前被诱导。最后，我们表明，SAR405 和 TGF-β1 处理的 NHOF 均增强了 OSCC 细胞的迁移，但只有 TGF-β1 处理的细胞通过 Matrigel 增加了 OSCC 的侵袭，表明 TGF-β1 具有独立于成纤维细胞激活/衰老的其他作用。这些结果表明自噬在肌成纤维细胞和 CAF 表型的发展中具有功能作用。
