シンポジウム
03 理事会企画シンポジウム
03 JSN Symposium
座長：有村 奈利子（東北大学 大学院薬学研究科 薬理学分野）・池中 健介（大阪大学大学院医学系研究科） |
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| 2022年7月3日 9:00～9:24 沖縄コンベンションセンター 劇場棟 第1会場
4S01m-01
エクソソームによるがん・ストレスの診断と治療
Diagnosis and treatment of cancer and stress by extracellular vesicles
*落谷 孝広(1)
1. 東京医科大学
*Takahiro Ochiya(1)
1. Tokyo Medical University
Keyword: extracellular vesicles, autonomic nervous system, cancer
In the tumor microenvironment, it is attracting attention that the autonomic nervous system (ANS) is extremely involved, as is the case with the immune system that has been actively studied so far. Since Dr. Batsakis et al. first reported the presence of large nerves in the vicinity of human epithelial carcinoma in 1985, the widespread involvement of the ANS in malignant tumors and the infiltration of nerve fibers in and around tumors are growing as new areas of research in the tumor microenvironment. For example, sympathetic and parasympathetic fibers from ANS infiltrate human prostate cancer, gastric cancer, breast cancer, etc., and contribute to the early stages of cancer development, infiltration, metastasis, and drug resistance. ANS is also associated with a poor patient prognosis by causing an imbalance in ANS cybernetics due to central nervous system stress through its action of promoting the expression of neurotransmitter receptors on tumor cells. Furthermore, in recent years, extracellular vesicles (EVs) secreted from cancer cells have contributed to the malignant transformation of cancer cells under ANS control, and thus it has been suggested that EV may be a potential target for neuro-antitumor therapy. We also currently have evidence that EV secreted from sympathetic nerves controls the cancer microenvironment. Here we will discuss the novel mechanisms, diagnosis, and treatment of cancer malignancy brought about by the elucidation of ANS-EVs. | | 2022年7月3日 9:24～9:48 沖縄コンベンションセンター 劇場棟 第1会場
4S01m-02
エクソソーム含有タンパク質による病態寄与機構と疾患バイオマーカーの解析
【エクソソームが司る、がん転移の新しいストーリー】
Exosomal proteins for mechanistic insight and biomarker potential ~Exosomes, new players in the field of metastasis~
*星野 歩子(1)
1. 東京工業大学
*Ayuko Hoshino Hoshino(1)
1. Tokyo Institute of Technology
Keyword: Pre-metastatic niche, Proteomics, Biomarker, Organotropic metastasis
For over 130 years, metastatic organotropism remained as one of the greatest mysteries in cancer biology. Experimental evidence indicates that tumor-derived microvesicles, referred to as exosomes, released by lung-, liver- and brain-tropic tumor cells fuse with cells at their future metastatic sites preparing the pre-metastatic niche. Proteomic profiling of exosomes revealed integrin expression patterns associated with lung and liver metastasis, whereas CEMIP in brain tropic exosomes enhanced metastasis in the brain. To gain a more comprehensive understanding of the exosomal protein cargo and tumor progression, we investigated the proteomic profile of exosomes in 426 human samples from tissue explants, plasma and other bodily fluids. Machine learning classification of plasma-derived exosome (n=120) proteomes revealed 95% sensitivity/90% specificity in identifying cancer-associated exosomes. We found that the protein signatures that determine cancer types were derived from a variety of sources, including tumor tissue, distant organs, as well as the immune system, emphasizing the importance of using non-cancer cell-derived exosomal signatures to identify cancer-associated alterations and define tumor-associated biomarkers. Finally, we defined a panel of tumor-type specific exosomal proteins in plasma, which may help classify tumors of unknown primary origin. These data suggest that tumor-associated exosomal proteins could be used as biomarkers for early-stage cancer detection and potentially for diagnosing tumors of unknown primary origin. In the last part of the talk, I will also briefly introduce our new findings on potential role of exosomes in other pathophysiological conditions as well as biomarker potential. | | 2022年7月3日 9:48～10:12 沖縄コンベンションセンター 劇場棟 第1会場
4S01m-03
エクソソームと疲労、うつ
Identification of protein barcode in circulating extracellular vesicles from fatigue and depression
*江口 暁子(1)、福田 早苗(2)
1. 三重大学大学院医学系研究科、2. 関西福祉科学大学
*Akiko Eguchi(1), Sanae Fukuda(2)
1. Grad Sch med, Mie University, Mie, Japan, 2. Kansai University of Welfare Sciences
Keyword: Extracellular vesicles, chronic fatigue syndrome
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, debilitating disorder with a wide spectrum of symptoms, including pain, depression, and neurocognitive deterioration. Over 17 million people around the world have ME/CFS, predominantly women with peak onset at 30–50 years. Given the wide spectrum of symptoms and unclear etiology, specific biomarkers for diagnosis and stratification of ME/CFS are lacking. In addition, the distinguishment of ME/CFS from other diseases with fatigue, such as idiopathic chronic fatigue (ICF) and depression, is significant important for accurate diagnosis. Furthermore, objective biomarkers have been developing for depression, but the biomarkers are not enough for diagnosis use. Extracellular vesicles (EVs) are released from damaged or stressed cells with cellular content, such as proteins, and circulate in the bloodstream. EVs are thus recognized as noninvasive biomarkers for a variety of diseases. To investigate the specific noninvasive biomarkers for ME/CFS and depression, we measured circulating EV number and identified EV composition in ME/CFS, ICF, depression patients, and healthy individuals. We found that circulating EVs were significantly increased in ME/CFS patients correlating to C-reactive protein, as well as biological antioxidant potential. Area under the receiver operating characteristic curve for circulating EVs was 0.80, allowing correct diagnosis in 90–94% of ME/CFS cases. From two independent proteomic analyses using circulating EVs from ME/CFS and healthy controls or ME/CFS, ICF, and depression, proteins identified from ME/CFS patients were involved in focal adhesion, actin skeletal regulation, PI3K-Akt signaling pathway, and Epstein-Barr virus infection. In particular, talin-1, filamin-A, and 14-3-3 family proteins were the most abundant proteins, representing highly specific ME/CFS biomarkers. When we compared the protein profile of circulating EVs between depression and ICF patients, we found that 13 proteins were significantly changed including corticosteroid-binding globulin and CD36 in depression patient. Our results identified circulating EV number and EV-specific proteins as novel biomarkers for diagnosing ME/CFS and depression. | | 2022年7月3日 10:12～10:36 沖縄コンベンションセンター 劇場棟 第1会場
4S01m-04
神経由来エクソソーム分離への挑戦
Challenge to separation of nerve-derived exosomes
*工藤 喬(1,2)、赤嶺 祥真(1,2)
1. 大阪大学キャンパスライフ健康支援・相談センター、2. 大阪大学大学院医学系研究科精神健康医学
*Takashi Kudo(1,2), Shoshin Akamine(1,2)
1. Osaka University Health and Counseling Center, 2. Osaka University, Graduate School of Medicine, Department of Mental Health Promotion
Keyword: exosome, iPS, digital ELISA, proteinase K
Exosomes are vesicles composed of lipid bilayers with a diameter of 50-150 nm secreted from various cells. Therefore, their contents are conserved from proteinase, DNase, or RNase and reach the periphery. That is, nerve-derived exosomes (NDEs) are considered to contain proteins, RNA, or DNA in central nerve cells. Based on the characteristics of exosomes, the contents of exosomes secreted from cancer cells into plasma are being established as liquid biopsy in the field of cancer medicine as markers for various cancers. We are applying this concept to the central nervous system and aim to establish "Brain Liquid Biopsy". Is NDE present in plasma? We performed a protection assay with proteinase K in plasma. As a result, tau, a neural protein contained in exosomes, was detected by digital ELISA, indicating that NDE is certainly present in plasma. The lipid bilayer of exosomes reflects the cell membrane of the parent cell. That is, since NDE contains a nerve cell membrane-specific molecule, it can be assumed that NDE can be separated from plasma by using an immunoprecipitation method targeting this molecule. The idea of separating NDE by targeting nerve cell membrane-specific molecules has already been reported by the group of Kapogiannis et al. They have reported in recent years that L1CAM isolates NDE and becomes a plasma biomarker for dementia, including AD. They have used L1CAM to isolate NDE and have reported that it becomes a plasma biomarker for dementia, including AD, over the last few years. However, in 2021, a negative paper was published that L1CAM was not related to NDE (Nat Methods. 2021 Jun; 18 (6): 631-634.). Therefore, a new nerve cell membrane-specific molecular target is needed. All exosomes contained in the medium of nerve cells differentiated from iPS are NDE. We analyzed the exosome membrane molecules obtained from this medium and identified the neural cell membrane-specific molecule APLP1. Immunoprecipitation was performed on APLP1 as a target in iPS medium and plasma, and it was proved that exosome markers such as CD63 and Flotillin-1 coexist. I will introduce our established NDE separation method (already filed with PCT) and describe our prospects. | | 2022年7月3日 10:36～11:00 沖縄コンベンションセンター 劇場棟 第1会場
4S01m-05
エクソソームと認知症
Exosome and Dementia
*池津 庸哉(1)
1. メイヨークリニックフロリダ校
*Tsuneya Ikezu(1)
1. Mayo Clinic Florida
Keyword: exosome, Alzheimer's disease, extracellular vesicles, proteomics
Extracellular vesicles (EVs) are universal secretory vesicles from eukaryotes. EVs are consisted with exosome, microvesicles, apoptotic bodies as major categories, and mitovesicles, lysovesicles, and exomeres as minor categories EVs contain molecular signatures of cell types, cellular conditions, signaling molecules including miRNAs, immunogenic/immunotolerant factors, regenerative factors, and pathogenic molecules such as prion protein, tau and alpha-synuclein. EVs have been studied for multiple applications, including biomarkers, regenerative agents, drug delivery vehicles, and disease-disseminating vehicles. Biological characterization of EVs in the central nervous system is still on the horizon, and our laboratory and others are establishing the methods for the isolation and characterization of EVs from brains, plasma, cerebrospinal fluids and induced pluripotent stem cell-derived neuronal cells. Using the state-of-the-art proteomics and bioinformatics, we have identified disease-specific protein markers for Alzheimer's disease and chronic traumatic encephalopathy using EV samples isolated from frozen brain tissues, cerebrospinal fluid and plasma samples, and cell type specific EV markers for human neuronal cells, using isolated EVs from induced neurons, astrocytes, microglia-like cells and oligodendrocytes. Integration of these dataset led to identification of the enrichment of unique cell type and its activation status in the Alzheimer’s disease brain derived EVs. Functional validation of the enriched molecules shows their role on intercellular trafficking of EVs among neuronal cell types. These studies deepen our understanding of cell type-specific EV delivery and their role in disease progression. | | | |
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