Junseong Park1,2,3, Seung Jae Oh4, Jin-Kyoung Shim1,2, Young Bin Ji4,5, Ju Hyung Moon1, Eui Hyun Kim1,2, Yong-Min Huh4,6, Jin-Suck Suh4,6, Jong Hee Chang1, Su-Jae Lee7,8, Seok-Gu Kang9,10,11. 1. Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. 2. Brain Tumor Translational Research Laboratory, Severance Biomedical Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea. 3. Precision Medicine Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. 4. YUHS-KRIBB Medical Convergence Research Institute, Yonsei University, Seoul, Republic of Korea. 5. Gimhae Biomedical Center, Gimhae Biomedical Industry Promotion Agency, Gimhae, Republic of Korea. 6. Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea. 7. Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of Korea. 8. Fibrosis and Cancer Targeting Biotechnology, FNCT Biotech, Seoul, Republic of Korea. 9. Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. seokgu9@gmail.com. 10. Brain Tumor Translational Research Laboratory, Severance Biomedical Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea. seokgu9@gmail.com. 11. Department of Medical Science, Yonsei University Graduate School, Seoul, Republic of Korea. seokgu9@gmail.com.
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 C5α, 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 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. CONCLUSIONS: 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.
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 C5α, 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 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. CONCLUSIONS: 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.
Authors: Brenda Auffinger; Drew Spencer; Peter Pytel; Atique U Ahmed; Maciej S Lesniak Journal: Expert Rev Neurother Date: 2015-05-31 Impact factor: 4.618