Vectorization of biomacromolecules into cells using extracellular vesicles with enhanced internalization induced by macropinocytosis

Nakase, Ikuhiko; Noguchi, Kosuke; Fujii, Ikuo; Futaki, Shiroh

doi:10.1038/srep34937

Cited by 76 publications

(97 citation statements)

References 33 publications

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“…Detailed examinations of the physiological effects of miR-107 are needed for its safe clinical utilization. Moreover, further studies are needed on the cellular uptake or secretion systems of tumor suppressor miRNAs, leading to the development of miRNA delivery systems for future therapeutic and diagnostic applications [93][94][95][96] . These studies are currently under evaluation.…”

Section: Discussionmentioning

confidence: 99%

Depleted Tumor Suppressor miR-107 in Plasma Relates to Tumor Progression and Is a Novel Therapeutic Target in Pancreatic Cancer

Imamura

Komatsu

Ichikawa

et al. 2017

Journal of the American College of Surgeons

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This study explored decreased tumor suppressor microRNA (miRNA) plasma levels in pancreatic cancer (PCa) patients to clarify their potential as novel biomarkers and therapeutic targets. We used the microRNA array-based approach to select candidates by comparing plasma levels between PCa patients and healthy volunteers. Six down-regulated miRNAs (miR-107, miR-126, miR-451, miR-145, miR-491-5p, and miR-146b-5p) were selected. Small-and large-scale analyses using samples from 100 PCa patients and 80 healthy volunteers revealed that miR-107 was the most down-regulated miRNA in PCa patients compared with healthy volunteers (P < 0.0001; area under the receiver-operating characteristic curve, 0.851). A low miR-107 plasma level was significantly associated with advanced T stage, N stage, and liver metastasis and was an independent factor predicting poor prognosis in PCa patients (P = 0.0424; hazard ratio, 2.95). miR-107 overexpression in PCa cells induced G1/S arrest with the production of p21 and inhibited cell proliferation through the transcriptional regulation of Notch2. In vivo, the restoration and maintenance of the miR-107 plasma level significantly inhibited tumor progression in mice. Depletion of the tumor suppressor miR-107 in plasma relates to tumor progression and poor outcomes. The restoration of the plasma miR-107 level might be a novel anticancer treatment strategy for PCa.Pancreatic cancer (PCa) is the fourth leading cause of cancer-related death in Japan and the United States 1 and the seventh worldwide 2 . PCa is one of the most aggressive cancer types and constitutes a global health problem, with more than 330,000 cancer-related deaths annually 2 . Although perioperative chemo-and/or radiotherapy regimens, surgical techniques and perioperative management have greatly progressed, PCa continues to present an extremely poor prognosis. Even now, the median survival time of PCa patients is 5 to 8 months, and their 5-year survival rate is less than 10%. This is because PCa develops with no symptoms, local invasiveness, or metastases to distant organs in the early stage of its clinical course [3][4][5] . Therefore, novel early diagnostic tools and effective treatment strategies are urgently needed to improve the survival rate of PCa patients.Because understanding the molecular mechanisms of tumorigenesis and identifying clinical biomarkers and molecular targets for PCa contribute to improving the management of this lethal disease, several studies have attempted to detect the biological factors involved in the malignant potential of PCa 6, 7 . Nevertheless, in clinical settings, no molecule has been used as an early diagnostic biomarker, and only a few molecules have been

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Section: Discussionmentioning

confidence: 99%

Depleted Tumor Suppressor miR-107 in Plasma Relates to Tumor Progression and Is a Novel Therapeutic Target in Pancreatic Cancer

Imamura

Komatsu

Ichikawa

et al. 2017

Journal of the American College of Surgeons

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“…Another promising therapy would be to utilize the biological functions of exosomes to deliver cancer drugs and therapies (2,(35)(36)(37)(38). For example, nanoparticle drug delivery is a rapidly burgeoning area of inquiry that capitalizes on the endogenous functions of extracellular particles by applying these to manufactured vesicles (39)(40)(41). Each of these potential therapies relies on a clear understanding of exosome internalization by recipient cells.…”

Section: Introductionmentioning

confidence: 99%

“…Macropinocytosis is not selective in which molecules are internalized from the extracellular environment, and so uptake may be dictated simply by proximity to the cells and not targeted by the exosome specifically. However, it has been shown that some exosomes naturally induce macropinocytosis internalization (64) and others, through manipulation of exosomal content, can selectively activate this mechanism increase uptake (40). Phagocytosis is a much more common method of taking up exosomes, especially with phagocytic cells of the immune system.…”

Section: Introductionmentioning

confidence: 99%

Internalization of Exosomes through Receptor-Mediated Endocytosis

Gonda

Kabagwira

Senthil

et al. 2019

Molecular Cancer Research

213

157

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The tumor microenvironment is replete with factors secreted and internalized by surrounding cells. Exosomes are nanosized, protein-embedded, membrane-bound vesicles that are released in greater quantities from cancer than normal cells and taken up by a variety of cell types. These vesicles contain proteins and genetic material from the cell of origin and in the case of tumor-derived exosomes, oncoproteins and oncogenes. With increasing understanding of the role exosomes play in basic biology, a more clear view of the potential exosomes are seen to have in cancer therapeutics emerges. However, certain essential aspects of exosome function, such as the uptake mechanisms, are still unknown. Various methods of cell-exosome interaction have been proposed, but this review focuses on the protein-protein interactions that facilitate receptor-mediated endocytosis, a broadly used mechanism by a variety of cells.

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“…Macropinocytosis is not selective in which molecules are internalized from the extracellular environment, and so uptake may be dictated simply by proximity to the cells and not targeted by the exosome specifically [121]. However, it has been shown that some exosomes naturally induce macropinocytosis internalization [90] and others, through manipulation of exosomal content, can selectively activate this mechanism in order to increase uptake [122]. Phagocytosis is a much more common method of taking up exosomes, especially with phagocytic cells of the immune system.…”

Section: Resultsmentioning

confidence: 99%

Cellular-Defined Microenvironmental Internalization of Exosomes

Gonda¹,

Moyron²,

Kabagwira³

et al. 2020

Extracellular Vesicles and Their Importance in Human Health

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The extracellular environment exhibits a potent effect on cellular growth and development. Exosomes secreted into this milieu carry functional proteins and nucleic acids from the cell of origin to recipient cells, facilitating intercellular communication. This interaction is particularly influential in the tumor microenvironment, transporting oncogenes and oncoproteins within a tumor and to distant sites. The mechanisms by which cells internalize exosomes vary greatly and the factors dictating this process are still unknown. Most cancers show evidence of exosomal transfer of material, but differences in cell type can dictate the effectiveness and extent of the process. Improving therapeutics requires addressing specific cellular functions, illustrating the need to better understand the forces involved in exosome-cell interactions. This review summarizes what is known about the different types of cells that play a role in exosome internalization.

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Vectorization of biomacromolecules into cells using extracellular vesicles with enhanced internalization induced by macropinocytosis

Cited by 76 publications

References 33 publications

Depleted Tumor Suppressor miR-107 in Plasma Relates to Tumor Progression and Is a Novel Therapeutic Target in Pancreatic Cancer

Depleted Tumor Suppressor miR-107 in Plasma Relates to Tumor Progression and Is a Novel Therapeutic Target in Pancreatic Cancer

Internalization of Exosomes through Receptor-Mediated Endocytosis

Cellular-Defined Microenvironmental Internalization of Exosomes

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