Theodoraki Marie-Nicole, Yerneni Saigopalakrishna S, Brunner Cornelia, Theodorakis Joannis, Hoffmann Thomas K, Whiteside Theresa L
Department of Pathology, University of Pittsburgh School of Medicine and UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.
Department of Otorhinolaryngology, Head and Neck Surgery, University of Ulm, Germany.
Oncoscience. 2018 Apr 29;5(3-4):75-87. doi: 10.18632/oncoscience.410. eCollection 2018 Mar.
Photodynamic therapy (PDT) is a palliative treatment option for head and neck squamous cell carcinoma (HNSCC) patients which induces local inflammation and alters tumor cell morphology. We show that exosomes in plasma of HNSCC patients undergoing PDT reprogram tumor cells towards an epithelial phenotype. Nine HNSCC patients were treated with PDT and plasma was collected prior to and at three timepoints after therapy. Exosome levels of E-Cadherin, N-Cadherin and TGF-β1 were tested by flow cytometry. Exosomes were co-incubated with cancer cells, and changes in expression of EMT markers were evaluated as were proliferation, migration, chemotaxis and invasiveness of tumor cells. Exosomes harvested pre- and 24h after PDT were enriched in N-Cadherin and TGF-β1. They induced the mesenchymal phenotype and up-regulated Vimentin and transcripts for Snail, Twist, α-SMA, Slug and ZEB1 in epithelial tumor cells. These exosomes also enhanced tumor proliferation, migration and invasion. In contrast, exosomes obtained on day 7 or 4-6 weeks after PDT carried E-cadherin, restored epithelial morphology and EpCAM expression in tumor cells, down-regulated expression of mesenchymal genes and inhibited proliferation, migration and invasion. The PDT-mediated conversion from the mesenchymal to epithelial tumor phenotype was mediated by exosomes, which also served as non-invasive biomarkers of this transition.
光动力疗法（PDT）是头颈部鳞状细胞癌（HNSCC）患者的一种姑息治疗选择，可诱导局部炎症并改变肿瘤细胞形态。我们发现，接受PDT治疗的HNSCC患者血浆中的外泌体可将肿瘤细胞重编程为上皮表型。9例HNSCC患者接受了PDT治疗，并在治疗前及治疗后的三个时间点采集了血浆。通过流式细胞术检测E-钙黏蛋白、N-钙黏蛋白和转化生长因子-β1的外泌体水平。将外泌体与癌细胞共同孵育，评估上皮-间质转化（EMT）标志物表达的变化以及肿瘤细胞的增殖、迁移、趋化性和侵袭性。PDT治疗前及治疗后24小时收集的外泌体富含N-钙黏蛋白和转化生长因子-β1。它们诱导上皮肿瘤细胞的间质表型，并上调波形蛋白以及Snail、Twist、α-平滑肌肌动蛋白、Slug和锌指蛋白E盒结合因子1（ZEB1）的转录本。这些外泌体还增强了肿瘤的增殖、迁移和侵袭。相比之下，PDT治疗后第7天或4 - 6周获得的外泌体携带E-钙黏蛋白，恢复了肿瘤细胞的上皮形态和上皮细胞黏附分子（EpCAM）表达，下调了间质基因的表达，并抑制了增殖、迁移和侵袭。PDT介导的肿瘤表型从间质向上皮的转变是由外泌体介导的，外泌体也是这种转变的非侵入性生物标志物。
