Extracellular histones are the ligands for the uptake of exosomes and hydroxyapatite‐nanoparticles by tumor cells <i>via</i> syndecan‐4

Ochieng, Josiah; Nangami, Gladys N.; Sakwe, Amos M.; Rana, Tanu; Ingram, Shalonda; Goodwin, J. Shawn; Moye, Cierra; Lammers, Philip E.; Adunyah, Samuel E.

doi:10.1002/1873-3468.13236

Cited by 27 publications

(25 citation statements)

References 50 publications

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“…Several histones were also detected to be increased in dT-EVs. There is evidence showing that EV-associated histones have a pro-inflammatory activity and can mediate the endocytosis/uptake of EVs by tumor cells that express syndecan-4 [50,51]. Although not yet tested in experimental studies, we hypothesize that these upregulated proteins in dT-EVs can promote binding/uptake by specific target cells, which is expected to elicit a biological response.…”

Section: Discussionmentioning

confidence: 90%

SILAC-Based Quantification of TGFBR2-Regulated Protein Expression in Extracellular Vesicles of Microsatellite Unstable Colorectal Cancers

Fricke

Michalak

Warnken

et al. 2019

IJMS

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Microsatellite unstable (MSI) colorectal cancers (CRCs) are characterized by mutational inactivation of Transforming Growth Factor Beta Receptor Type 2 (TGFBR2). TGFBR2-deficient CRCs present altered target gene and protein expression. Such cellular alterations modulate the content of CRC-derived extracellular vesicles (EVs). EVs function as couriers of proteins, nucleic acids, and lipids in intercellular communication. At a qualitative level, we have previously shown that TGFBR2 deficiency causes overall alterations in the EV protein content. To deepen the basic understanding of altered protein dynamics, this work aimed to determine TGFBR2-dependent EV protein signatures in a quantitative manner. Using a stable isotope labeling with amino acids in cell culture (SILAC) approach for mass spectrometry-based quantification, 48 TGFBR2-regulated proteins were identified in MSI CRC-derived EVs. Overall, TGFBR2 deficiency caused upregulation of several EV proteins related to the extracellular matrix and nucleosome as well as downregulation of proteasome-associated proteins. The present study emphasizes the general overlap of proteins between EVs and their parental CRC cells but also highlights the impact of TGFBR2 deficiency on EV protein composition. From a clinical perspective, TGFBR2-regulated quantitative differences of protein expression in EVs might nominate novel biomarkers for liquid biopsy-based MSI typing in the future.

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Section: Discussionmentioning

confidence: 90%

SILAC-Based Quantification of TGFBR2-Regulated Protein Expression in Extracellular Vesicles of Microsatellite Unstable Colorectal Cancers

Fricke

Michalak

Warnken

et al. 2019

IJMS

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“…Some proteins such as syndecan 4, ERK1/2 and Hsp27 have been proposed to be involved in EV uptake [30][31][32] and are also upregulated or activated under hypoxia [33][34][35]. We thus hypothesised that hypoxia could lead to an increased EV uptake.…”

Section: Influence Of Hypoxia On the Ev Uptakementioning

confidence: 98%

Hypoxia-Induced Adaptations of miRNomes and Proteomes in Melanoma Cells and Their Secreted Extracellular Vesicles

Walbrecq

Lecha

Gaigneaux

et al. 2020

Cancers

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Reduced levels of intratumoural oxygen are associated with hypoxia-induced pro-oncogenic events such as invasion, metabolic reprogramming, epithelial–mesenchymal transition, metastasis and resistance to therapy, all favouring cancer progression. Small extracellular vesicles (EV) shuttle various cargos (proteins, miRNAs, DNA and others). Tumour-derived EVs can be taken up by neighbouring or distant cells in the tumour microenvironment, thus facilitating intercellular communication. The quantity of extracellular vesicle secretion and their composition can vary with changing microenvironmental conditions and disease states. Here, we investigated in melanoma cells the influence of hypoxia on the content and number of secreted EVs. Whole miRNome and proteome profiling revealed distinct expression patterns in normoxic or hypoxic growth conditions. Apart from the well-known miR-210, we identified miR-1290 as a novel hypoxia-associated microRNA, which was highly abundant in hypoxic EVs. On the other hand, miR-23a-5p and -23b-5p were consistently downregulated in hypoxic conditions, while the protein levels of the miR-23a/b-5p-predicted target IPO11 were concomitantly upregulated. Furthermore, hypoxic melanoma EVs exhibit a signature consisting of six proteins (AKR7A2, DDX39B, EIF3C, FARSA, PRMT5, VARS), which were significantly associated with a poor prognosis for melanoma patients, indicating that proteins and/or miRNAs secreted by cancer cells may be exploited as biomarkers.

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“…Therefore, exosomes can also interact with the recipient cells via the ligands on the cell surface in a protein–protein interaction, induce internalization, or promote intracellular signaling cascades without being internalized (Figure 1). Exosomes are responsible for a variety of normal physiological processes and abnormal pathological processes, such as the progression of neuronal degeneration [35,36], cancer [37,38], and diabetes.…”

Section: Exosome Uptakementioning

confidence: 99%

Exosomes and Their Noncoding RNA Cargo Are Emerging as New Modulators for Diabetes Mellitus

Chang

Wang

2019

Cells

139

110

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Diabetes belongs to a group of metabolic disorders characterized by long term high blood glucose levels due to either inadequate production of insulin (Type 1 diabetes, T1DM) or poor response of the recipient cell to insulin (Type 2 diabetes, T2DM). Organ dysfunctions are the main causes of morbidity and mortality due to high glucose levels. Understanding the mechanisms of organ crosstalk may help us improve our basic knowledge and find novel strategies to better treat the disease. Exosomes are part of a newly emerged research area and have attracted a great deal of attention for their capacity to regulate communications between cells. In conditions of diabetes, exosomes play important roles in the pathological processes in both T1DM and T2DM, such as connecting the immune cell response to pancreatic tissue injury, as well as adipocyte stimulation to insulin resistance of skeletal muscle or liver. Furthermore, in recent years, nucleic acids containing exosomes—especially microRNAs (miRNAs) and long noncoding RNAs (lncRNAs)—have been shown to mainly regulate communications between organs in pathological processes of diabetes, including influencing metabolic signals and insulin signals in target tissues, affecting cell viability, and modulating inflammatory pancreatic cells. Moreover, exosome miRNAs show promise in their use as biomarkers or in treatments for diabetes and diabetic complications. Thus, this paper summarizes the recent work on exosomes related to diabetes as well as the roles of exosomal miRNAs and lncRNAs in diabetic pathology and diagnosis in order to help us better understand the exact roles of exosomes in diabetes development.

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Extracellular histones are the ligands for the uptake of exosomes and hydroxyapatite‐nanoparticles by tumor cells via syndecan‐4

Cited by 27 publications

References 50 publications

SILAC-Based Quantification of TGFBR2-Regulated Protein Expression in Extracellular Vesicles of Microsatellite Unstable Colorectal Cancers

SILAC-Based Quantification of TGFBR2-Regulated Protein Expression in Extracellular Vesicles of Microsatellite Unstable Colorectal Cancers

Hypoxia-Induced Adaptations of miRNomes and Proteomes in Melanoma Cells and Their Secreted Extracellular Vesicles

Exosomes and Their Noncoding RNA Cargo Are Emerging as New Modulators for Diabetes Mellitus

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