Tumor-derived exosomal microRNAs and proteins as modulators of macrophage function

Tumor cells are able to modify their surrounding microenvironment by transmitting bioactive molecules via exosomes. In exosomes, proteins and nucleic acids that can be taken up by surrounding cells have been identified and modulate their functions. Tumor microenvironment consists of different cells such as macrophages. Tumors-associated macrophages (TAMs) express M2 phenotype and affect many processes including tumor initiation, angiogenesis, and metastasis. It has been demonstrated that a high number of TAMs is associated with poor prognosis of cancers. The contents of tumor-derived exosomes such as microRNAs and proteins induce macrophages to M2-like polarization to support tumor growth. Herein, we review the most recent studies on the effect of tumor-derived exosomes on macrophage polarization and function in different types of cancers.     

Expression of exosomal microRNAs during chondrogenic differentiation of human bone mesenchymal stem cells

The aim of the current study was to compare the expression of microRNAs (miRNAs) in exosomes derived from human bone mesenchymal stem cells (hBMSCs) with and without chondrogenic induction. Exosomes derived from hBMSCs were isolated and identified. Microarray analysis was performed to compare miRNA expression between exosomes derived from hBMSCs with and without chondrogenic induction, and quantitative real-time polymerase chain reaction (qRT-PCR) was used to verify the differentially expressed miRNAs. hBMSCs were transfected with miRNA mimic to extract miRNA-overexpressed exosomes. The results showed that most exosomes exhibited a cup-shaped or round-shaped morphology with a diameter of approximately 50-200 nm and expressed CD9 and CD63. We detected 141 miRNAs that were differentially expressed with and without chondrogenic induction by over a twofold change, including 35 upregulated miRNAs, such as miR-1246, miR-1290, miR-193a-5p, miR-320c, and miR-92a, and 106 downregulated miRNAs, such as miR-377-3p and miR-6891-5p. qRT-PCR analysis validated these results. Exosomes derived from hBMSCs overexpressing miR-320c were more efficient than normal exosomes derived from control hBMSCs at promoting osteoarthritis chondrocyte proliferation, down-regulated matrix metallopeptidase 13 and up-regulated (sex determining region Y)-box 9 expression during hBMSC chondrogenic differentiation. In conclusion, we identified a group of upregulated miRNAs in exosomes derived from hBMSCs with chondrogenic induction that may play an important role in mesenchymal stem cell-derived exosomes in cartilage regeneration and, ultimately, the treatment of arthritis. We demonstrated the potential of these modified exosomes in the development of novel therapeutic strategies.     

Defining lung cancer stem cells exosomal payload of miRNAs in clinical perspective

Since the first publication regarding the existence of stem cells in cancer [cancer stem cells(CSCs)] in 1994, many studies have been published providing in-depth information about their biology and function. This research has paved the way in terms of appreciating the role of CSCs in tumour aggressiveness, progression,recurrence and resistance to cancer therapy. Targeting CSCs for cancer therapy has still not progressed to a sufficient degree, particularly in terms of exploring the mechanism of dynamic interconversion between CSCs and non-CSCs. Besides the CSC scenario, the problem of cancer dissemination has been analyzed indepth with the identification and isolation of microRNAs(miRs), which are now considered to be compelling molecular markers in the diagnosis and prognosis of tumours in general and specifically in patients with non-small cell lung cancer.Paracrine release of miRs via "exosomes"(small membrane vesicles(30-100 nm),the derivation of which lies in the luminal membranes of multi-vesicular bodies)released by fusion with the cell membrane is gaining popularity. Whether exosomes play a significant role in maintaining a dynamic equilibrium state between CSCs and non-CSCs and their mechanism of activity is as yet unknown.Future studies on CSC-related exosomes will provide new perspectives for precision-targeted treatment strategies.     

Exosome biogenesis,secretion and function of exosomal miRNAs in skeletal muscle myogenesis

Exosomes are membrane‐bound extracellular vesicles that are produced in the endosomal compartment of most mammalian cell types and then released. Exosomes are effective carriers for the intercellular material transfer of material that can influence a series of physiological and pathological processes in recipient cells. Among loaded cargoes, non‐coding RNAs (ncRNAs) vary for the exosome‐producing cell and its homeostatic state, and characterization of the biogenesis and secretion of exosomal ncRNAs and the functions of these ncRNAs in skeletal muscle myogenesis remain preliminary. In this review, we will describe what is currently known of exosome biogenesis, release and uptake of exosomal ncRNAs, as well as the varied functions of exosomal miRNAs in skeletal muscle myogenesis.     

Detection of exosomal tyrosine receptor kinase B as a potential biomarker in ovarian cancer

Ovarian cancer (OC) is a lethal disease diagnosed at advanced stages due to the lack of specific biomarkers. Tyrosine receptor kinase B (TrkB), which has recently been found to be related to OC progression, represents a promising potential biomarker for OC diagnosis and prognosis. The discovery of circulating exosomes as biomarkers for various diseases led us to explore exosomal TrkB in OC. Our previous study proved that the expression of TrkB was elevated in OC tissues. In this study, we focused on the detection of exosomal TrkB in OC. Exosomes were first gathered from three different OC cell lines’ conditioned medium, serum samples of patients with OC as well as xenograft mice serum by serial centrifugation method. Then, we identified exosomes by transmission electron microscopy, NanoSight analysis, and expression of typical exosomal protein markers. The existence of TrkB in exosomes was measured by Western blot analysis, and the expression was detected by enzyme-linked immunosorbent assay. In this study, we demonstrated that exosomes could derive from OC cell lines, serum from OC xenograft nude mice, and clinical patients. Our study shows that serum exosomal TrkB may be considered a minimally invasive biomarker for OC.     

Key microRNAs in the biology of breast cancer; emerging evidence in the last decade

microRNAs (miRNAs) are a family of small noncoding RNAs that play a pivotal role in the regulation of main biological and physiological processes, including cell cycle regulation, proliferation, differentiation, apoptosis, stem cell maintenance, and organ development. Dysregulation of these tiny molecules has been related to different human diseases, such as cancer. It has been estimated that more than 50% of these noncoding RNA sequences are placed on fragile sites or cancer-associated genomic regions. After the discovery of the first specific miRNA signatures in breast cancer, many studies focused on the involvement of these small RNAs in the pathophysiology of breast tumors and their possible clinical implications as reliable prognostic biomarkers or as a new therapeutic approach. Therefore, the present review will focus on the recent findings on the involvement of miRNAs in the biology of breast cancer associated with their clinical implications.     

Clinical implications of microRNAs in cancer

Abstract

MicroRNAs (miRNAs) are endogenously produced non-coding RNAs that serve as micromanagers by negatively regulating gene expression. MiRNAs are implicated in several biological pathways including development of neoplasia. Because altered miRNA expression is implicated in the pathobiology of various cancers, these molecules serve as potential therapeutic targets. Using miRNA mimics to restore levels of aberrantly down-regulated miRNAs or miRNA inhibitors to inactivate over-expressed miRNAs shows promise as the next generation of therapeutic strategies. Manipulation of miRNAs offers an alternative therapeutic approach for chemo- and radiation-resistant tumors. Similarly, miRNA expression patterns can be used for diagnosis and to predict prognosis and efficacy of therapy. We present here an overview of how miRNAs affect cancers, how they may be used as biomarkers, and the clinical implications of miRNAs in cancer.     

Coupling factors and exosomal packaging microRNAs involved in the regulation of bone remodelling

Bone remodelling is a continuous process by which bone resorption by osteoclasts is followed by bone formation by osteoblasts to maintain skeletal homeostasis. These two forces must be tightly coordinated not only quantitatively, but also in time and space, and its malfunction leads to diseases such as osteoporosis. Recent research focusing on the cross‐talk and coupling mechanisms associated with the sequential recruitment of osteoblasts to areas where osteoclasts have removed bone matrix have identified a number of osteogenic factors produced by the osteoclasts themselves. Osteoclast‐derived factors and exosomal‐containing microRNA (miRNA) can either enhance or inhibit osteoblast differentiation through paracrine and juxtacrine mechanisms, and therefore may have a central coupling role in bone formation. Entwined with angiocrine factors released by vessel‐specific endothelial cells and perivascular cells or pericytes, these factors play a critical role in angiogenesis–osteogenesis coupling essential in bone remodelling.     

Axl-altered microRNAs regulate tumorigenicity and gefitinib resistance in lung cancer

The involvement of Axl kinase in non-small cell lung cancer''s (NSCLC) acquired resistance to tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib has been identified recently, but the mechanism by which Axl contributes to TKI resistance is largely unknown. MicroRNAs (miRNAs) repress gene expression and their critical role in tumorigenesis has been implicated. To investigate the role of miRNAs in the Axl-mediated acquired gefitinib resistance, we examined the Axl-mediated miRNA changes in gefitinib-resistant lung cancers. A panel of Axl kinase-altered miRNAs was identified. In this study, we validate and report that miR-374a and miR-548b modulated by Axl have essential roles in cell cycle arrest, gefitinib-induced apoptosis, epithelial-to-mesenchymal transition, migration and tumorigenesis of gefitinib-resistant lung cancer cells in vitro and in vivo by targeting Wnt5a and CCNB1 genes, respectively. Of clinical significance, high expression of Axl and miR-374a and low expression of miR-548b are associated with poor disease-free survival postoperatively. These findings indicate that the modulation of specific miRNAs may provide a therapeutic target to treat or reverse gefitinib resistance in NSCLC with high expression of Axl in the future.     

外泌体源性miRNAs在肺癌发生发展中的作用

外泌体(exosomes)是细胞分泌的纳米级细胞外囊泡.外泌体通过释放其内的生物活性大分子,比如微小RNA(microRNA,miRNA)到受体细胞,从而介导细胞间交流通讯. MiRNAs作为一类主要在转录后水平负向调控靶mRNAs的非编码RNAs,其在外泌体中含量最为丰富.在肺癌中,miRNAs经肿瘤细胞分泌的外泌体转运释放而发挥重要的作用.本文主要讨论了外泌体源性miRNAs在肺癌发生发展的各个阶段,包括血管生成、细胞增殖、侵袭转移、免疫逃逸、耐药等方面的作用,以及其在作为新型肺癌诊断和预后标志物方面的临床价值.     

Gene therapy for lung cancer

Lung cancer patients suffer a 15% overall survival despite advances in chemotherapy, radiation therapy, and surgery. This unacceptably low survival rate is due to the usual finding of advanced disease at diagnosis. However, multimodality strategies using conventional therapies only minimally improve survival rates even in early stages of lung cancer. Attempts to improve survival in advanced disease using various combinations of platinum-based chemotherapy have demonstrated that no regimen is superior, suggesting a therapeutic plateau and the need for novel, more specific, and less toxic therapeutic strategies. Over the past three decades, the genetic etiology of cancer has been gradually delineated, albeit not yet completely. Understanding the molecular events that occur during the multistep process of bronchogenic carcinogenesis may make these tasks more surmountable. During these same three decades, techniques have been developed which allow transfer of functional genes into mammalian cells. For example, blockade of activated tumor-promoting oncogenes or replacement of inactivated tumor-suppressing or apoptosis-promoting genes can be achieved by gene therapy. This article will discuss the therapeutic implications of these molecular changes associated with bronchogenic carcinomas and will then review the status of gene therapies for treatment of lung cancer.     

Role of toll-like receptors in lung cancer

Abstract

Lung cancer is a leading cause of death world-wide and the long-term survival rate for patients with lung cancer is one of the lowest for any cancer. Toll-like receptors (TLRs), evolutionarily conserved innate, are expressed in a wide variety of tissues and cell types, and they play key role in the innate immune system. TLRs have been found to be expressed by some kinds of tumor cells. However, what is the biological function of TLRs on tumor cells and whether human lung cancer cells can express TLRs remain to be fully understood. This review was performed to sum up the role of TLRs in lung cancer.