Mesenchymal stromal/stem cells (MSCs) exist in almost all tissues, possessing the potential to differentiate into specialized cell types and exert immunomodulatory functions. Thus, they have ...attracted much attention as a promising therapeutic candidate. Recent studies have demonstrated that paracrine signaling is mainly responsible for the involvement of MSCs in the modulation of immune responses and the progression of diseases. Through release of secretome consisting of a diverse range of cytokines, chemokines, and extracellular vesicles (EVs), MSCs convey regulatory messages to recipient immune cells in the microenvironment. In this review, we focus on the recent advances in how MSCs contribute to immunomodulation through the secretion of paracrine factors. The further improved understanding of the molecular mechanism underlying the interactions between MSCs and immune cells highlights the paracrine biology of MSCs in the modulation of the immune microenvironment and promotes the clinical application of MSCs in regenerative medicine and immune diseases.
5-Fluorouracil (5-FU) has been commonly prescribed for patients with colorectal cancer (CRC), but resistance to 5-FU is one of the main reasons for failure in CRC. Recently, microRNAs (miRNAs) have ...been established as a means of reversing the dilemma by regulating signaling pathways involved in initiation and progression of CRC. However, how to safely and effectively deliver miRNA to target cells becomes a main challenge.
In this study, Engineered exosomes were exploited to simultaneously deliver an anticancer drug 5-FU and miR-21 inhibitor oligonucleotide (miR-21i) to Her2 expressing cancer cells. Purified engineered exosomes from the donor cells loaded with 5-FU and miR-21i via electroporation to introduce into 5-FU-resistant colorectal cancer cell line HCT-116
. Furthermore, systematic administration of 5-FU and miR-21i loaded exosomes in tumor bearing mice indicated a significantly anti-tumor effect. The results showed that the engineered exosome-based 5-FU and miR-21i co-delivery system could efficiently facilitate cellular uptake and significantly down-regulate miR-21 expression in 5-FU resistant HCT-116
cell lines. Consequently, the down-regulation of miR-21 induced cell cycle arrest, reduced tumor proliferation, increased apoptosis and rescued PTEN and hMSH2 expressions, regulatory targets of miR-21. Of particular importance was the significant reduction in tumor growth in a mouse model of colon cancer with systematic administration of the targeting miR-21i. More excitedly, the combinational delivery of miR-21i and 5-FU with the engineered exosomes effectively reverse drug resistance and significantly enhanced the cytotoxicity in 5-FU-resistant colon cancer cells, compared with the single treatment with either miR-21i or 5-FU.
The strategy for co-delivering the functional small RNA and anticancer drug by exosomes foreshadows a potential approach to reverse the drug resistance in CRC and thus to enhance the efficacy of the cancer treatment.
Programmed cell death ligand-1 (PD-L1) overexpressed on cancer cells has emerged as a key inhibitor that maintains the immunosuppressive microenvironment through its interaction with the PD-1 ...receptor in cancer. Here, we demonstrated that miR-424-5p delivery via extracellular vesicles (EVs) derived from adipose tissue-mesenchymal stromal cells (AT-MSCs) partly promotes proinflammation and enhances antitumor cytotoxicity in vitro and in vivo. Triple negative breast cancer (TNBC) exhibits increased expression of
, and
is positively correlated with the overall survival of patients with TNBC. PD-L1 shows relatively higher expression in MDA-MB-231 (MM231) cells and can be downregulated by miR-424-5p. Furthermore, miR-424-5p transported by EVs can increase the secretion of proinflammatory cytokines, decrease the secretion of anti-inflammatory cytokines and promote the apoptosis of tumor cells. The intratumoral administration of miR-424-5p-EVs significantly slowed tumor growth. In conclusion, these results demonstrate that EVs may serve as a delivery system for novel immunotherapies for TNBC through the miR-424-5p/PD-L1 pathway.
•Feature extraction of microRNA data using an machine learning algorithm flow.•Machine learning models to distinguish cancer tissues from normal tissues.•10 miRNAs widely involved in cancer-related ...signaling pathways.•MiRNAs as biomarkers for prognosis of lung squamous cell carcinoma.
Lung squamous cell carcinoma (LUSC) is a common type of malignancy. The mechanism behind its tumor progression is not clear yet. The aim of this study is to use machine learning to identify the feature miRNAs, which can be reliably used as biomarkers for diagnosis LUSC. We downloaded microRNA expression data and clinical data from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus(GEO) database to identify differences in microRNA expression of primary tumor tissues and para-carcinoma tissues from LUSC. Construction of miRNA-mRNA interaction network, GO, KEGG pathway analysis and Kaplan-Meier survival analysis were used to explore the biological functions of the identified microRNAs. 21 feature miRNAs were identified between lung SCC tumor tissues and para-carcinoma tissues with the support of SVM and PCA methods. Among them, ten feature miRNAs: mir-143, mir-100, mir-101-1, mir-101-2, mir-182, mir-183, mir-205, mir-21, mir-30a, mir30-d were identified which could be used as a feature group to separate the cancer tissues from the adjacent tissues ultimately, and cross-validation of the obtained data showed that it can achieve extremely high accuracy and recall rate. Using KEGG, Reactome, GO databases, these 10 miRNAs and their target genes were found to be highly correlated with cancer. Survival analysis found that this group of miRNAs had a significant relationship with the survival rate of cancer patients, and the expression was significantly different between tumor tissues and healthy tissues. The dysregulated feature miRNAs might be involved in the pathology of LUSC and could be used as potential diagnostic biomarkers or therapeutic targets for LUSC.
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and a major cause of cancer death. However, the molecular mechanisms underlying CRC initiation, growth and metastasis are poorly ...understood. In this study, based on our previous work for comprehensively analyzing miRNA sequencing data, we examined a series of colorectal cancer microRNAs expression profiles data. Results show that all these CRC samples share the same four pathways including TGF-beta signaling pathway, which is important in colorectal carcinogenesis. Twenty-one microRNAs that evolved in the four overlapped pathways were then discovered. Further analysis selected miR-21 as an important regulator for CRC through TGF-beta pathways. This study develops methods for discovering tumor specific miRNA cluster as biomarker and for screening new cancer therapy targets based on miRNA sequencing.
Triple-negative breast cancer (TNBC) is a particularly aggressive and invasive breast cancer subtype and is associated with poor clinical outcomes. Treatment approaches for TNBC remain limited partly ...due to the lack of expression of well-known molecular targets. Small extracellular vesicles (sEVs) carrying a variety of bioactive contents play an important role in intercellular communications. The biomolecules including nucleic acids, proteins, and metabolites can be transferred locally or systematically to recipient cells and regulate their biological states and are involved in physiological and pathological processes. Recently, despite the extensive attraction to the physiological functions of sEVs, few studies focus on the roles of sEVs in TNBC. In this review, we will summarize the involvement of sEVs in the tumor microenvironment of TNBC. Moreover, we will discuss the potential roles of sEVs as diagnostic markers and treatment therapy in this heterogeneous breast cancer subtype. We finally summarize the clinical application of sEVs in TNBC.
Exosomal biomarkers including tumor-derived exosomes, exosomal surface proteins and exosomal nucleic acids have emerged as one of the most important and general cancer biomarkers in modern biomedical ...science. These indicators can provide momentous biological information for early diagnosis and treatment of cancer. Recently, numerous studies have been conducted to design biosensors for exosomal biomarkers detection and profiling with high sensitivity and strong applied ability. Among these biosensors, nanomaterial-based optical biosensors are prospective future platforms for rapid and cost-effective detection of exosomal biomarkers. Firstly, we have focused on the progress and advancements in different optical-transducing approaches (Surface-Enhanced Raman Scattering, Surface Plasmon Resonance, Colorimetry, Immunochromatographic assay, Chemiluminescence, Electrochemiluminescence, and fluorescence) for detecting and profiling exosomal biomarkers. Additionally, we have summarized strengths and drawbacks of each strategy. Finally, challenges and future outlooks in developing efficient nanomaterial-based optical biosensor systems for exosomal tumor biomarkers detection have been discussed. The review will exhibit an overview of this field and provide meaningful information for scientific researchers.
Display omitted
•Detection of exosomal biomarkers is a timely topic nowadays.•Nanomaterial-based optical biosensors for exosomal biomarkers detection are summarized.•Advantages and disadvantages of different optical biosensors are described.•Challenges and outlooks for exosomal biomarkers detection are discussed.
We theoretically investigate the signal-to-noise ratio (SNR) of a parallel array of leaky integrate-and-fire (LIF) neurons that receives a weak periodic signal and uses spatially nearest neighbor ...correlated noise. By using linear response theory, we derive the analytic expression of the SNR. The results show that the amplitude of internal noise can be increased up to an optimal value, which corresponds to a maximum SNR. Given the existence of spatially nearest neighbor correlated noise in the neural ensemble, the SNR gain of the collective ensemble response can exceed unity, especially for a negative correlation. This nonlinear collective phenomenon of SNR gain amplification may be related to the array stochastic resonance. In addition, we show that the SNR can be improved by varying the number of neurons, frequency, and amplitude of the weak periodic signal. We expect that this investigation will be useful for both controlling the collective response of neurons and enhancing weak signal transmission.
PDF
