In the past several years, the importance of microRNA (miRNA) in cancer cells has been recognized. Proper control of miRNA expression is essential for maintaining a steady state of the cellular ...machinery. Recently, it was discovered that extracellular miRNAs circulate in the blood of both healthy and diseased patients, although ribonuclease is present in both plasma and serum. Most of the circulating miRNAs are included in lipid or lipoprotein complexes, such as apoptotic bodies, microvesicles, or exosomes, and are, therefore, highly stable. The existence of circulating miRNAs in the blood of cancer patients has raised the possibility that miRNAs may serve as a novel diagnostic marker. However, the secretory mechanism and biological function, as well as the meaning of the existence of extracellular miRNAs, remain largely unclear. In this review, we summarize the usefulness of circulating miRNA for cancer diagnosis, prognosis, and therapeutics. Furthermore, we propose a mechanism for the secretion and incorporation of miRNA into the cells. (Cancer Sci 2010)
Since comprehensive analysis of the mammalian genome revealed that the majority of genomic products are transcribed in long non‐coding RNA (lncRNA), increasing attention has been paid to these ...transcripts. The applied next‐generation sequencing technologies have provided accumulating evidence of dysregulated lncRNA in cancer. The implication of this finding can be seen in many forms and at multiple levels. With impacts ranging from integrating chromatin remodeling complexes to regulating transcription and post‐transcriptional processes, aberrant expression of lncRNA may have repercussions in cell proliferation, tumor progression or metastasis. lncRNA may act as enhancers, scaffolds or decoys by physically interacting with other RNA species or proteins, resulting in a direct impact on cell signaling cascades. Even though their functional classification is well‐established in the context of cancer, clearer characterization in terms of their phenotypic outputs is needed to optimize and identify suitable candidates that enable the development of new therapeutic strategies and the design of novel diagnostic approaches. The present article aims to outline different cancer‐associated lncRNA according to their contribution to tumor suppression or tumor promotion based on their most current functional annotations.
lncRNAs involved in tumor plasticity. Aberrantly expressed lncRNAs may have an important impact in the EMT‐MET processes by interacting with diverse signaling cascades.
Extracellular vesicles (EV), known as exosomes and microvesicles, serve as versatile intercellular communication vehicles. Increasing evidence has shown that cancer cell‐derived EV carry pathogenic ...components, such as proteins, messenger RNA (mRNA), microRNA (miRNA), DNA, lipids and transcriptional factors, that can mediate paracrine signaling in the tumor microenvironment. These data suggest that EV transfer of cancer pathogenic components enable long‐distance crosstalk between cancer cells and distant organs, resulting in the promotion of the initial steps for pre‐metastatic niche formation. Understanding the metastatic mechanisms through EV transfer may open up a new avenue for cancer therapeutic strategies. Furthermore, the circulating EV have also been of interest as a source for liquid biopsies. EV in body fluids provide a reliable source of miRNA and proteins for cancer biomarkers. The tumor‐specific components in EV effectively provide various messages on the physiological and pathological status of cancer patients. Although many researchers are searching for EV biomarkers using miRNA microarrays and proteome analyses, the detection technology for circulating EV in body fluids has not yet reached the point of clinical application. In this review, we summarize recent findings regarding EV function, specifically in metastasis through the transfer of cancer pathogenic components. Furthermore, we highlight the potential of using circulating EV for cancer diagnosis.
In this review, we summarize recent findings regarding Extracellular vesicle (EV) function, specifically in metastasis through the transfer of cancer pathogenic components. Furthermore, we also highlight the potential of using circulating EVs for cancer diagnosis.
Extracellular vesicles (EVs) are small lipid membrane vesicles that are secreted from almost all kinds of cells into the extracellular space. EVs are widely accepted to be involved in various ...cellular processes; in particular, EVs derived from cancer cells have been reported to play important roles in modifying the tumor microenvironment and promoting tumor progression. In addition, EVs derived from cancer cells encapsulate various kinds of tumor-specific molecules, such as proteins and RNAs, which contribute to cancer malignancy. Therefore, the unveiling of the precise mechanism of intercellular communication via EVs in cancer patients will provide a novel strategy for cancer treatment. Furthermore, a focus on the contents of EVs could promote the use of EVs in body fluids as clinically useful diagnostic and prognostic biomarkers. In this review, we summarize the current research knowledge on EVs as biomarkers and therapeutic targets and discuss their potential clinical applications.
There is a long-held consensus that several proteins are unique to small extracellular vesicles (EVs), such as exosomes. However, recent studies have shown that several of these markers can also be ...present in other subpopulations of EVs to a similar degree. Furthermore, few markers have been identified as enriched or uniquely present in larger EVs, such as microvesicles. The aim of this study was to address these issues by conducting an in-depth comparison of the proteome of large and small EVs. Large (16,500g) and small EVs (118,000g) were isolated from three cell lines using a combination of differential ultracentrifugation and a density cushion and quantitative mass spectrometry (tandem mass tag–liquid chromatography–tandem mass spectrometry) was used to identify differently enriched proteins in large and small EVs. In total, 6493 proteins were quantified, with 818 and 1567 proteins significantly enriched in small and large EVs, respectively. Tetraspanins, ADAMs and ESCRT proteins, as well as SNAREs and Rab proteins associated with endosomes were enriched in small EVs compared with large EVs, whereas ribosomal, mitochondrial, and nuclear proteins, as well as proteins involved in cytokinesis, were enriched in large EVs compared with small EVs. However, Flotillin-1 was not differently expressed in large and small EVs. In conclusion, our study shows that the proteome of large and small EVs are substantially dissimilar. We validated several proteins previously suggested to be enriched in either small or large EVs (e.g., ADAM10 and Mitofilin, respectively), and we suggest several additional novel protein markers.
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•Quantitative proteomics of small and large extracellular vesicles.•Tetraspanins, ADAMs, and ESCRT proteins are enriched in small EVs.•Ribosomal, mitochondrial, and cytokinesis proteins are enriched in large EVs.•Suggests protein markers for large and small EVs.
The proteome of large and small extracellular vesicles has been determined with quantitative mass spectrometry. Tetraspanins, ADAMs, and ESCRT proteins, as well as SNAREs and Rab proteins associated with endosomes were enriched in small EVs, whereas ribosomal, mitochondrial, and nuclear proteins, as well as proteins involved in cytokinesis, were enriched in large EVs. Several proteins previously suggested to be enriched in either small or large EVs were validated, and several additional novel protein markers were suggested.
Extracellular vesicles (EVs), membrane vesicles that are secreted by a variety of mammalian cell types, have been shown to play an important role in intercellular communication. The contents of EVs, ...including proteins, microRNAs, and mRNAs, vary according to the cell type that secreted them. Accordingly, researchers have demonstrated that EVs derived from various cell types play different roles in biological phenomena. Considering the ubiquitous presence of mesenchymal stem cells (MSCs) in the body, MSC‐derived EVs may take part in a wide range of events. In particular, MSCs have recently attracted much attention due to the therapeutic effects of their secretory factors. MSC‐derived EVs may therefore provide novel therapeutic approaches. In this review, we first summarize the wide range of functions of EVs released from different cell types, emphasizing that EVs echo the phenotype of their parent cell. Then, we describe the various therapeutic effects of MSCs and pay particular attention to the significance of their paracrine effect. We then survey recent reports on MSC‐derived EVs and consider the therapeutic potential of MSC‐derived EVs. Finally, we discuss remaining issues that must be addressed before realizing the practical application of MSC‐derived EVs, and we provide some suggestions for enhancing their therapeutic efficiency.
Over the past few decades, siRNA and miRNA have attracted a great deal of attention from researchers and clinicians. These molecules have been extensively studied from the standpoint of developing ...biopharmaceuticals against various diseases, including heart disease, diabetes and cancers. siRNA suppresses only a single target, whereas each miRNA regulates the expression of multiple target genes. More importantly, because miRNA are also secreted from cancer cells, and their aberrant expression is associated with tumor development and progression, they represent not only therapeutic targets but also promising biomarkers for diagnosis and prognosis. Therefore, miRNA may be more effective tools against cancers, in which multiple signal pathways are dysregulated. In this review, we summarize recent progress in the development of miRNA therapeutics for the treatment of cancer patients, and describe delivery systems for oligonucleotide therapeutics.
This review article summarizes recent progress in the development of miRNA therapeutics for the treatment of cancer patients, and describes delivery systems for oligonucleotide therapeutics.
Circulating non-coding RNAs, including microRNAs and long non-coding RNAs, and the protein components of extracellular vesicles are promising biomarkers for the non-invasive detection of cancer at an ...early stage. This systematic review discusses the increasing number of well-designed cancer biomarker-related studies that have been published worldwide. In many of these studies, high diagnostic accuracy, which is represented as the area under the receiver operating characteristic curve being >0.8, could be achieved using combinations of circulating microRNAs. In addition, similar diagnostic accuracies were reported using long non-coding RNAs or proteins present in extracellular vesicles, although these evidences were based on a limited number of studies.
Drug Resistance Driven by Cancer Stem Cells and Their Niche Prieto-Vila, Marta; Takahashi, Ryou-U; Usuba, Wataru ...
International journal of molecular sciences,
2017-Dec-01, 2017-12-01, 20171201, Letnik:
18, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Drug resistance represents one of the greatest challenges in cancer treatment. Cancer stem cells (CSCs), a subset of cells within the tumor with the potential for self-renewal, differentiation and ...tumorigenicity, are thought to be the major cause of cancer therapy failure due to their considerable chemo- and radioresistance, resulting in tumor recurrence and eventually metastasis. CSCs are situated in a specialized microenvironment termed the niche, mainly composed of fibroblasts and endothelial, mesenchymal and immune cells, which also play pivotal roles in drug resistance. These neighboring cells promote the molecular signaling pathways required for CSC maintenance and survival and also trigger endogenous drug resistance in CSCs. In addition, tumor niche components such as the extracellular matrix also physically shelter CSCs from therapeutic agents. Interestingly, CSCs contribute directly to the niche in a bilateral feedback loop manner. Here, we review the recent advances in the study of CSCs, the niche and especially their collective contribution to resistance, since increasingly studies suggest that this interaction should be considered as a target for therapeutic strategies.
Interleukin-33 (IL-33) was recently shown to be involved in the inflammatory tumour microenvironment and the progression of colorectal cancer (CRC). We report here that the expression level of sST2, ...a soluble form of the IL-33 receptor (ST2L), is inversely associated with the malignant growth of CRC. sST2 is downregulated in high-metastatic cells compared with low-metastatic human and mouse CRC cells. Knockdown of sST2 in low-metastatic cells enhances tumour growth, metastasis and tumour angiogenesis, whereas its overexpression in high-metastatic cells suppresses these processes. Circulating and intratumourally administered sST2-Fc fusion protein reduce tumour growth, metastatic spread and tumour angiogenesis in mice bearing high-metastatic CRC. Mechanistically, sST2 suppresses IL-33-induced angiogenesis, Th1- and Th2-responses, macrophage infiltration and macrophage M2a polarization. In conclusion, we show that sST2 negatively regulates tumour growth and the metastatic spread of CRC through modification of the tumour microenvironment. Thus, the IL-33/ST2L axis may be a potential therapeutic target in CRC.
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