細胞外小胞による生体バリアの制御に関する研究

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 古川 洋一, 東京大学教授 水島 昇, 東京大学准教授 佐々木 毅, 東京大学教授 井上 純一郎, 東京大学教授 齋藤 延人University of Tokyo(東京大学

ホスピス トクシマ ニオケル マッキ ガン カンジャ ノ ボウシュヨウセイ シンケイ ショウコウグン ノ ハッショウ ヒンド ト ソノ リンショウテキ イギ

Neurological complications in advanced cancer occur frequently and therefore an adequate neurological assessment must always be part of patient evaluation in hospice palliative care. Paraneoplastic neurological syndromes are rare, probably affecting less than 1 per cent of patients with cancer, even if the most commonly associated neoplasms, such as small-cell lung cancer and ovarian cancer are considered. Neurological complications were studied in 127 inpatients with advanced cancers. Neurological complications were seen in up to 40 per cent of the patients. The most frequent symptom was derilium, followed in order to lethargy, paraplegia, depression, dementia, hemiplegia, restlessness, aphasia, stupor, facial palsy, recurrent laryngeal nerve palsy, convulsion, and myastenia. Those symptoms were seen in patients in hepatic encephalitis（12）, metastatic brain tumor（9）, metastatic spinal cord injury（8）, depression（4）, paraneoplastic syndrome（4）, hypercalcemia（2）, senile dementia（2）, peripheral neuritis（2）, and cerebral infarction（2）. Of the four patients with paraneoplastic syndrome, one patient had both anti-Hu antibody and anti-VGCC antibody and two patients had anti-neuronal nuclear antibodies. These results indicate that paraneoplastic neurological syndromes are associated more than 1 per cent of patients with advanced cancer

Anti-Cancer Role and Therapeutic Potential of Extracellular Vesicles

Cell–cell communication is an important mechanism in biological processes. Extracellular vesicles (EVs), also referred to as exosomes, microvesicles, and prostasomes, are microvesicles secreted by a variety of cells. EVs are nanometer-scale vesicles composed of a lipid bilayer and contain biological functional molecules, such as microRNAs (miRNAs), mRNAs, and proteins. In this review, “EVs” is used as a comprehensive term for vesicles that are secreted from cells. EV research has been developing over the last four decades. Many studies have suggested that EVs play a crucial role in cell–cell communication. Importantly, EVs contribute to cancer malignancy mechanisms such as carcinogenesis, proliferation, angiogenesis, metastasis, and escape from the immune system. EVs derived from cancer cells and their microenvironments are diverse, change in nature depending on the condition. As EVs are thought to be secreted into body fluids, they have the potential to serve as diagnostic markers for liquid biopsy. In addition, cells can encapsulate functional molecules in EVs. Hence, the characteristics of EVs make them suitable for use in drug delivery systems and novel cancer treatments. In this review, the potential of EVs as anti-cancer therapeutics is discussed

Altered biodistribution of deglycosylated extracellular vesicles through enhanced cellular uptake

Extracellular vesicles (EVs) from cancer are delivered both proximal and distal organs. EVs are highly glycosylated at the surface where EVs interact with cells and therefore has an impact on their properties and biological functions. Aberrant glycosylation in cancer is associated with cancer progression and metastasis. However, the biological function of glycosylation on the surface of EV is uncovered. We first demonstrated differential glycosylation profiles of EVs and their originated cells, and distinct glycosylation profiles in a brain-metastatic subline BMD2a from its parental human breast cancer cell line, MDA-MB-231-luc-D3H2LN by lectin blot. We then investigated the roles of surface glycoconjugates on EV uptake. N- and/or O-glycosylation removal of fluorescent-labelled BMD2a EVs enhanced cellular uptake to endothelial cells, suggesting that surface glycosylation has inhibitory effects on cellular uptake. Biodistribution of glycosylation-deprived BMD2a EVs administrated intravenously into mice was further analysed ex vivo using near-infrared lipophilic dye. EVs treated with O-deglycosylation enzymes enhanced the accumulation of EVs to the lungs after 24 h from the injection, while N-deglycosylation did not markedly alter biodistribution. As the lungs are first organs in which intravenous blood flows, we suggest that surface glycosylation of cancer-derived EVs avoid promiscuous adhesion to proximal tissues to be delivered to distant organs