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C5 alpha secreted by tumor mesenchymal stem-like cells mediates resistance to 5-aminolevulinic acid-based photodynamic therapy against glioblastoma tumorspheres

Authors
 Junseong Park  ;  Seung Jae Oh  ;  Jin-Kyoung Shim  ;  Young Bin Ji  ;  Ju Hyung Moon  ;  Eui Hyun Kim  ;  Yong-Min Huh  ;  Jin-Suck Suh  ;  Jong Hee Chang  ;  Su-Jae Lee  ;  Seok-Gu Kang 
Citation
 JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY, Vol.149(8) : 4391-4402, 2023-07 
Journal Title
JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
ISSN
 0171-5216 
Issue Date
2023-07
MeSH
Aminolevulinic Acid / pharmacology ; Aminolevulinic Acid / therapeutic use ; Animals ; Cell Line, Tumor ; Glioblastoma* / drug therapy ; Glioblastoma* / genetics ; Glioblastoma* / pathology ; Humans ; Mice ; Photochemotherapy* / methods ; Photosensitizing Agents / pharmacology ; Photosensitizing Agents / therapeutic use ; Protoporphyrins / metabolism ; Protoporphyrins / pharmacology
Keywords
5-Aminolevulilic acid ; Acquired PDT resistance ; Glioblastoma ; Photodynamic diagnosis ; Photodynamic therapy ; Tumor mesenchymal stem-like cells
Abstract
Purpose 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. Methods PDT was performed using a 635 nm light-emitting diode (LED). Transcriptome profiles were obtained from microarray data. For knockdown of C5 alpha, siRNA was transfected into tumor mesenchymal stem-like cells (tMSLCs). The invasiveness of TSs was quantified using collagen-based 3D invasion assays. Results 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 C5 alpha, and their correlations with the expression of stemness- or mesenchymal transition-associated genes. By adding or inhibiting C5 alpha, we confirmed that acquired resistance to PDT was induced via tMSLC-secreted C5 alpha. Conclusions Our results show substantial therapeutic effects of 5-ALA-based PDT on GBM TSs, suggesting C5 alpha as a key molecule responsible for PDT resistance. These findings could trigger PDT as a standard clinical modality for the treatment of GBM.
Full Text
https://link.springer.com/article/10.1007/s00432-022-04347-w
DOI
10.1007/s00432-022-04347-w
Appears in Collections:
1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
Yonsei Authors
Kang, Seok Gu(강석구) ORCID logo https://orcid.org/0000-0001-5676-2037
Kim, Eui Hyun(김의현) ORCID logo https://orcid.org/0000-0002-2523-7122
Moon, Ju Hyung(문주형)
Park, Junseong(박준성)
Suh, Jin Suck(서진석) ORCID logo https://orcid.org/0000-0001-9455-9240
Oh, Seung Jae(오승재)
Chang, Jong Hee(장종희) ORCID logo https://orcid.org/0000-0003-1509-9800
Ji, Young Bin(지영빈)
Huh, Yong Min(허용민) ORCID logo https://orcid.org/0000-0002-9831-4475
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/199502
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