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Visualizing cancer-originating acetate uptake through monocarboxylate transporter 1 in reactive astrocytes in the glioblastoma tumor microenvironment

 Dongwoo Kim 1  ;  Hae Young Ko 1  ;  Jee-In Chung 1  ;  Yongmin Mason Park 2 3  ;  Sangwon Lee 1  ;  Seon Yoo Kim  ;  Jisu Kim  ;  Joong-Hyun Chun  ;  Kyung-Seok Han  ;  Misu Lee  ;  Yeon Ha Ju  ;  Sun Jun Park  ;  Ki Duk Park  ;  Min-Ho Nam  ;  Se Hoon Kim  ;  Jin-Kyoung Shim  ;  Youngjoo Park  ;  Hyunkeong Lim  ;  Jaekyung Park  ;  Gwan-Ho Lee  ;  Hyunjin Kim  ;  Suhyun Kim  ;  Uiyeol Park  ;  Hoon Ryu  ;  So Yun Lee  ;  Sunghyouk Park  ;  Seok-Gu Kang  ;  Jong Hee Chang  ;  C Justin Lee  ;  Mijin Yun 
 NEURO-ONCOLOGY, Vol.26(5) : 843-857, 2024-05 
Journal Title
Issue Date
Acetates* / metabolism ; Animals ; Astrocytes* / metabolism ; Astrocytes* / pathology ; Brain Neoplasms* / diagnostic imaging ; Brain Neoplasms* / metabolism ; Brain Neoplasms* / pathology ; Glioblastoma* / diagnostic imaging ; Glioblastoma* / metabolism ; Glioblastoma* / pathology ; Gliosis / metabolism ; Gliosis / pathology ; Humans ; Male ; Mice ; Monocarboxylic Acid Transporters* / metabolism ; Positron-Emission Tomography* / methods ; Prognosis ; Symporters* / metabolism ; Tumor Microenvironment*
PET imaging ; acetate ; glioblastoma ; monocarboxylate transporter 1 ; reactive astrogliosis
Background : Reactive astrogliosis is a hallmark of various brain pathologies, including neurodegenerative diseases and glioblastomas. However, the specific intermediate metabolites contributing to reactive astrogliosis remain unknown. This study investigated how glioblastomas induce reactive astrogliosis in the neighboring microenvironment and explores 11C-acetate PET as an imaging technique for detecting reactive astrogliosis.

Methods : Through in vitro, mouse models, and human tissue experiments, we examined the association between elevated 11C-acetate uptake and reactive astrogliosis in gliomas. We explored acetate from glioblastoma cells, which triggers reactive astrogliosis in neighboring astrocytes by upregulating MAO-B and MCT1 expression. We evaluated the presence of cancer stem cells in the reactive astrogliosis region of glioblastomas and assessed the correlation between the volume of 11C-acetate uptake beyond MRI and prognosis.

Results : Elevated 11C-acetate uptake is associated with reactive astrogliosis and astrocytic MCT1 in the periphery of glioblastomas in human tissues and mouse models. Glioblastoma cells exhibit increased acetate production as a result of glucose metabolism, with subsequent secretion of acetate. Acetate derived from glioblastoma cells induces reactive astrogliosis in neighboring astrocytes by increasing the expression of MAO-B and MCT1. We found cancer stem cells within the reactive astrogliosis at the tumor periphery. Consequently, a larger volume of 11C-acetate uptake beyond contrast-enhanced MRI was associated with worse prognosis.

Conclusion : Our results highlight the role of acetate derived from glioblastoma cells in inducing reactive astrogliosis and underscore the potential value of 11C-acetate PET as an imaging technique for detecting reactive astrogliosis, offering important implications for the diagnosis and treatment of glioblastomas.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Urology (비뇨의학교실) > 1. Journal Papers
Yonsei Authors
Kang, Seok Gu(강석구) ORCID logo https://orcid.org/0000-0001-5676-2037
Kim, Se Hoon(김세훈) ORCID logo https://orcid.org/0000-0001-7516-7372
Kim, Ji Su(김지수)
Yun, Mijin(윤미진) ORCID logo https://orcid.org/0000-0002-1712-163X
Chang, Jong Hee(장종희) ORCID logo https://orcid.org/0000-0003-1509-9800
Chun, Joong-Hyun(전중현) ORCID logo https://orcid.org/0000-0002-9665-7829
Han, Kyung Seok(한경석)
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