Abstract
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.
Highlights
Despite the currently available treatment options for patients with advanced Head and Neck Squamous Cell Carcinoma (HNSCC), the disease outcome remains poor, mostly due to locoregional tumor recurrence
Since it has been reported that TGF-β1 is one of the main promoters of epithelial-to-mesenchymal transition (EMT) [31], we investigated levels of TGF-β1 in the cargo of total exosomes obtained from pre- and post photodynamic therapy (PDT) plasma of all the patients
We found that exosomes isolated from pre-PDT plasma contained high levels of TGF-β1, and that following PDT, these levels significantly decreased to reach the lowest levels in exosomes harvested at t4 (4-6 weeks after PDT) as shown in Figure 2C and 2D
Summary
Despite the currently available treatment options for patients with advanced Head and Neck Squamous Cell Carcinoma (HNSCC), the disease outcome remains poor, mostly due to locoregional tumor recurrence. We show for the first time that exosomes isolated from plasma of patients with HNSCC treated with and responding to PDT recapitulate molecular characteristics www.impactjournals.com/oncoscience of the parent tumors, serving as markers of PDT-induced molecular changes in the parent tumor These exosomes upon co-incubation with carcinoma cells can reverse the EMT phenotype of recipient cells and suppress their migration as well as invasiveness. Exosomes obtained at t3 and t4 after PDT induced strong expression of EpCAM and down-regulated Vimentin in both recipient cells (Figure 4) These experiments show that plasma-derived exosomes of the HNSCC patients undergoing PDT when co-incubated with tumor cells induced transcriptional and translational alterations in the key components of the EMT pathway in the recipient cells. Co-incubation with t3 and t4 exosomes did not enhance tumor cell invasiveness, remaining at the level of invasion mediated by exosomes from plasma of normal controls
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