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C5α secreted by tumor mesenchymal stem-like cells mediates resistance to 5-aminolevulinic acid-based photodynamic therapy against glioblastoma tumorspheres

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Advancements in photodynamic diagnosis (PDD) and photodynamic therapy (PDT) as a standard care in cancer therapy have been limited. This study is aimed to investigate the clinical availability of 5-aminolevulinic acid (5-ALA)-based PDD and PDT in glioblastoma (GBM) patient-derived tumorspheres (TSs) and mouse orthotopic xenograft model.


PDT was performed using a 635 nm light-emitting diode (LED). Transcriptome profiles were obtained from microarray data. For knockdown of C5α, siRNA was transfected into tumor mesenchymal stem-like cells (tMSLCs). The invasiveness of TSs was quantified using collagen-based 3D invasion assays.


Treatment with 1 mM 5 ALA induced distinct protoporphyrin IX (PpIX) fluorescence in GBM TSs, but not in non-tumor cells or tissues, including tMSLCs. These observations were negatively correlated with the expression levels of FECH, which catalyzes the conversion of accumulated PpIX to heme. Furthermore, the 5-ALA-treated GBM TSs were sensitive to PDT, thereby significantly decreasing cell viability and invasiveness. Notably, the effects of PDT were abolished by culturing TSs with tMSLC-conditioned media. Transcriptome analysis revealed diverse tMSLC-secreted chemokines, including C5α, and their correlations with the expression of stemness- or mesenchymal transition-associated genes. By adding or inhibiting C5α, we confirmed that acquired resistance to PDT was induced via tMSLC-secreted C5α.


Our results show substantial therapeutic effects of 5-ALA-based PDT on GBM TSs, suggesting C5α as a key molecule responsible for PDT resistance. These findings could trigger PDT as a standard clinical modality for the treatment of GBM.

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Data availability

The data sets supporting the conclusions of this article are available in the Gene Expression Omnibus repository at, GSE159000 (GBM TSs) and GSE131837 (GBM tissues) (Park et al. 2019). Gene expression profiles of other samples, including NHAs, BM–MSCs, and tMSLCs, are available from the corresponding author upon reasonable request.


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This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government Ministry of Science and ICT (NRF-2022R1A2B5B03001199, NRF-2020M2D9A2092372, NRF-2020M3E5E2037960, NRF-2017R1C1B2003686); Ministry of Education (NRF-2021R1I1A1A01048717); Team Science Award of Yonsei University College of Medicine (6-2021-0192).

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Conceptualization: JP and S-GK; methodology: JP, J-KS, SJO, and YBJ; software: JP; validation: JP, J-KS, SJO, and YBJ.; formal analysis: JP and YBJ; investigation: JP and YBJ; resources: SJO, JHM, EHK, JHC, and S-JL; data curation: JP, J-KS, and SJO; writing—original draft: JP; writing—review and editing: S-GK; visualization: JP; project administration: Y-MH, J-SS, and S-GK; funding acquisition: JP and S-GK.

Corresponding author

Correspondence to Seok-Gu Kang.

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The authors declare no competing interests.

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The authors have no relevant financial or non-financial interests to disclose.

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Experiments in this study were conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of Severance Hospital, Yonsei University College of Medicine (4-2012-0212, 4-2014-0649). All in vivo experimental procedures were approved by the Yonsei University College of Medicine Institutional Animal Care and Use Committee (2017-0347) and adheres to the ARRIVE guidelines.

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Park, J., Oh, S.J., Shim, JK. et al. C5α secreted by tumor mesenchymal stem-like cells mediates resistance to 5-aminolevulinic acid-based photodynamic therapy against glioblastoma tumorspheres. J Cancer Res Clin Oncol 149, 4391–4402 (2023).

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