Leukemia cancer cells and immune cells derived-exosomes: Possible roles in leukemia progression and therapy

Exosomes have a significant impact on tumor survival, proliferation, metastasis, and recurrence. They also open up new therapeutic options and aid in the pathological identification and diagnosis of cancers. Exosomes have been shown in numerous studies to be essential for facilitating cell-to-cell communication. In B-cell hematological malignancies, the proteins and RNAs that are encased by circulating exosomes are thought to represent prospective sources for therapeutic drugs as well as biomarkers for diagnosis and prognosis. Additionally, exosomes can offer a “snapshot” of the tumor and the metastatic environment at any given point in time. In this review study, we concluded that leukemia-derived exosomes could be utilized as prognostic, diagnostic, and therapeutic biomarkers for individuals suffering from leukemia. Moreover, clinical studies have demonstrated that immune cells like dendritic cells create exosomes, which have the ability to activate the immune system against leukemia.     

Tumor-associated macrophages promote prostate cancer progression via exosome-mediated miR-95 transfer

Tumor-associated macrophages (TAMs) are vital constituents in mediating cell-to-cell communication within the tumor microenvironment. However, the molecular mechanisms underlying the interplay between TAMs and tumor cells that guide cell fate are largely undetermined. Extracellular vesicles, also known as exosomes, which are derived from TAMs, are the components exerting regulatory effects. Thus, understanding the underlying mechanism of “onco-vesicles” is of crucial importance for prostate cancer (PCa) therapy. In this study, we analyzed micro RNA sequences in exosomes released by THP-1 and M2 macrophages and found a significant increase in miR-95 levels in TAM-derived exosomes, demonstrating the direct uptake of miR-95 by recipient PCa cells. In vitro and in vivo loss-of-function assays suggested that miR-95 could function as a tumor promoter by directly binding to its downstream target gene, JunB, to promote PCa cell proliferation, invasion, and epithelial–mesenchymal transition. The clinical data analyses further revealed that higher miR-95 expression results in worse clinicopathological features. Collectively, our results demonstrated that TAM-mediated PCa progression is partially attributed to the aberrant expression of miR-95 in TAM-derived exosomes, and the miR-95/JunB axis provides the groundwork for research on TAMs to further develop more-personalized therapeutic approaches for patients with PCa.     

Recent progress in the emerging role of exosome in hepatocellular carcinoma

Exosomes are small membrane vesicles 50‐150 nm in diameter released by a variety of cells, which contain miRNAs, mRNAs and proteins with the potential to regulate signalling pathways in recipient cells. Exosomes deliver nucleic acids and proteins to participate in orchestrating cell‐cell communication and microenvironment modulation. In this review, we summarize recent progress in our understanding of the role of exosomes in hepatocellular carcinoma (HCC). This review focuses on recent studies on HCC exosomes, considering biogenesis, cargo and their effects on the development and progression of HCC, including chemoresistance, epithelial‐mesenchymal transition, angiogenesis, metastasis and immune response. Finally, we discuss the clinical application of exosomes as a therapeutic agent for HCC.     

Exosomes in carcinogenesis: molecular palkis carry signals for the regulation of cancer progression and metastasis

Exosomes, which act as biological cargo vessels, are cell-released, phospholipid-enclosed vesicles. In eukaryotic cells, exosomes carry and exchange biological materials or signals for the benefit or detriment to the cells. Thereby, we consider exosomes to be molecular Palkis (carriers). Although exosomes are currently one of the most popularly researched cellular entities, they have remained largely enigmatic and warrant continued investigation into their structure and functions. These membraned vesicles are between 30 and 150 nm in diameter and are actively secreted by all cell types. While initially considered cellular “trash bags,” recent years have revealed exosomes to be dynamic and multi-functional vesicles that may play a crucial role in cancer development, progression and metastasis. Thereby, they have the potential to be used in development of therapeutic modalities for cancer and other diseases. As more research studies emerge, it’s becoming evident that exosomes are released by cells with a purpose and are representatives of certain cell types and disease conditions. Hence, they may also be used as biomarkers for the detection of cancer initiation, progression and organotropic metastatic growth of cancer cells. This review will focus on the recent developments achieved in identifying the role of exosomes in cancer development and progression as well as therapeutic implications. The review will also discuss the pitfalls of methodologies used for the extraction of exosomes.     

Focus on exosomes—From pathogenic mechanisms to the potential clinical application value in lymphoma

Exosomes are highly specialized and functional bilayer membranous particles. They have been considered as vehicles for transporting and delivering a large number of proteins, lipids, and nucleic acids (gene, noncoding RNA, DNA) from parental to recipient cells. In hematological malignancies, exosomes are involved in the tumorigenesis, including producing growth factors, hindering antitumor immunoreaction, promote inflammation, angiogenesis, and hypercoagulation. With the deepening of understanding, exosomes have ignited great interests and ever-increasing efforts into the therapeutic application among scientists, such as biomarkers, therapeutic target, drug delivery system, and vaccines. Here, we discuss the most recent studies on the functions and the emerging therapeutic applications of exosomes in lymphoma.     

Lung CSC-derived exosomal miR-210-3p contributes to a pro-metastatic phenotype in lung cancer by targeting FGFRL1

Lung cancer has the highest mortality rate among human cancers, and the majority of deaths can be attributed to metastatic spread. Lung cancer stem cells (CSCs) are a component of the tumour microenvironment that contributes to this process. Exosomes are small membrane vesicles secreted by all types of cells that mediate cell interactions, including cancer metastasis. Here, we show that lung CSC-derived exosomes promote the migration and invasion of lung cancer cells, up-regulate expression levels of N-cadherin, vimentin, MMP-9 and MMP-1, and down-regulate E-cadherin expression. Moreover, we verified that these exosomes contribute to a pro-metastatic phenotype in lung cancer cells via miR-210-3p transfer. The results of bioinformatics analysis and dual-luciferase reporter assays further indicated that miR-210-3p may bind to fibroblast growth factor receptor-like 1 (FGFRL1); silencing FGFRL1 enhanced the metastatic ability of lung cancer cells, whereas overexpressing FGFRL1 suppressed metastasis. Taken together, our results provide new insights into a potential molecular mechanism whereby lung CSC-derived exosomal miR-210-3p targets FGFRL1 to promote lung cancer metastasis. FGFRL1 may be a promising therapeutic target in lung cancer.     

The potential role of exosomes derived from ovarian cancer cells for diagnostic and therapeutic approaches

Most patients with ovarian cancer (OC) are diagnosed at the advanced stages due to the absence of appropriate early diagnostic markers. Thus, OC is a gynecological disease with a low-survival rate. Exosomes are extracellular vesicles that are widely being considered as mediators for the noninvasive diagnosis of OC. Exosomes are expected to aid in the effective diagnosis of OC because they carry components, such as RNAs, proteins, and lipids, the compositions of which vary depending on the pathological characteristics of the patient. In this review, we document the methods that have been developed to detect exosomes and their components in OC. We also assess the potential biomarkers contained in exosomes that could be clinically useful, such as proteins, microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and phospholipids. Moreover, we described the role played by exosomes in the tumor microenvironment and in OC angiogenesis, migration, and tumor growth. Various types of cells in the tumor microenvironment, including macrophages, fibroblasts, and mesenchymal stem cells (MSCs), interact directly with exosomes and promote or inhibit the progression of OC. Therefore, we summarize the studies that have suggested a therapeutic approach to OC using exosomes. Collectively, understanding the mechanism of exosome-based OC progression would broaden our knowledge regarding the diagnosis and therapy of OC.     

Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET

Tumor-derived exosomes are emerging mediators of tumorigenesis. We explored the function of melanoma-derived exosomes in the formation of primary tumors and metastases in mice and human subjects. Exosomes from highly metastatic melanomas increased the metastatic behavior of primary tumors by permanently 'educating' bone marrow progenitors through the receptor tyrosine kinase MET. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites and reprogrammed bone marrow progenitors toward a pro-vasculogenic phenotype that was positive for c-Kit, the receptor tyrosine kinase Tie2 and Met. Reducing Met expression in exosomes diminished the pro-metastatic behavior of bone marrow cells. Notably, MET expression was elevated in circulating CD45(-)C-KIT(low/+)TIE2(+) bone marrow progenitors from individuals with metastatic melanoma. RAB1A, RAB5B, RAB7 and RAB27A, regulators of membrane trafficking and exosome formation, were highly expressed in melanoma cells. Rab27A RNA interference decreased exosome production, preventing bone marrow education and reducing, tumor growth and metastasis. In addition, we identified an exosome-specific melanoma signature with prognostic and therapeutic potential comprised of TYRP2, VLA-4, HSP70, an HSP90 isoform and the MET oncoprotein. Our data show that exosome production, transfer and education of bone marrow cells supports tumor growth and metastasis, has prognostic value and offers promise for new therapeutic directions in the metastatic process.     

HFE genotype affects exosome phenotype in cancer

Neuroblastoma is the third most common childhood cancer, and timely diagnosis and sensitive therapeutic monitoring remain major challenges. Tumor progression and recurrence is common with little understanding of mechanisms. A major recent focus in cancer biology is the impact of exosomes on metastatic behavior and the tumor microenvironment. Exosomes have been demonstrated to contribute to the oncogenic effect on the surrounding tumor environment and also mediate resistance to therapy. The effect of genotype on exosomal phenotype has not yet been explored. We interrogated exosomes from human neuroblastoma cells that express wild-type or mutant forms of the HFE gene. HFE, one of the most common autosomal recessive polymorphisms in the Caucasian population, originally associated with hemochromatosis, has also been associated with increased tumor burden, therapeutic resistance boost, and negative impact on patient survival. Herein, we demonstrate that changes in genotype cause major differences in the molecular and functional properties of exosomes; specifically, HFE mutant derived exosomes have increased expression of proteins relating to invasion, angiogenesis, and cancer therapeutic resistance. HFE mutant derived exosomes were also shown to transfer this cargo to recipient cells and cause an increased oncogenic functionality in those recipient cells.     

Oncogenic effects of exosomes in γ-herpesvirus-associated neoplasms

Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein–Barr virus (EBV) are herpesviruses associated with human malignancies. As exosomes can shuttle many herpesvirus-associated biomolecules from host cells to recipient cells, the exosomal pathway is utilized by herpesviruses to achieve extensive infections and even oncogenesis. In this review, we discuss the oncogenic biomolecules present in exosomes derived from KSHV- and EBV-infected cells. Moreover, oncogenesis via exosomal biomolecules mainly occurs through three processes, including regulation of downstream signals, promotion of immune dysfunction and transformation of cells. Also, the exosomes may provide diagnostic markers and therapeutic targets specific for KSHV- and EBV-associated malignancies.     

HMSCs exosome-derived miR-199a-5p attenuates sulfur mustard-associated oxidative stress via the CAV1/NRF2 signalling pathway

Sulfur mustard (SM) is a blister-producing chemical warfare agent which could lead to a cascade of systemic damage, especially severe acute lung injury. Oxidative stress is considered to be vital processes for the SM toxicity mechanism. We previously proved the therapeutic effect of exosomes derived from bone marrow mesenchymal stromal cells in promoting the repair of alveolar epithelial barrier and inhibiting apoptosis. However, the key functional components in exosomes and the underlying mechanisms have not been fully elaborated. This research shed light on the function of the key components of human umbilical cord mesenchymal stem cell-derived exosomes (HMSCs-Ex). We noted that HMSCs-Ex-derived miR-199a-5p played a vital role in reducing pneumonocyte oxidative stress and apoptosis by reducing reactive oxygen species, lipid peroxidation products and increasing the activities of antioxidant enzymes in BEAS-2B cells and mouse models after exposure to SM for 24 h. Furthermore, we demonstrated that the overexpression of miR-199a-5p in HMSCs-Ex treatment induced a further decrease of Caveolin1 and the activation of the mRNA and protein level of NRF2, HO1 and NQO1, compared with HMSCs-Ex administration. In summary, miR-199a-5p was one of the key molecules in HMSCs-Ex that attenuated SM-associated oxidative stress via regulating CAV1/NRF2 signalling pathway.     

Osteosarcoma-derived exosomal miR-501-3p promotes osteoclastogenesis and aggravates bone loss

Emerging evidence indicates that osteoclasts from osteosarcoma patients have higher tartrate resistant acid phosphatase (TRAP) activity. Exosomes are important mediators of the cell-to-cell communication. However, whether osteosarcoma cell–derived exosomes mediate the osteoclastogenesis of bone marrow-derived monocytes (BMDMs) and its mechanisms are largely unknown. In this research, we validated the communication between osteosarcoma cells and BMDMs. Here, we found that osteosarcoma cell-derived exosomes can be transfered to BMDMs to promote osteoclast differentiation. The miR-501-3p is highly expressed in exosomes derived from osteosarcoma and could be transferred to BMDMs through the exosomes. Moreover, osteosarcoma-derived exosomal miR-501-3p mediate its role in promoting osteoclast differentiation and aggravates bone loss in vitro and in vivo. Mechanistically, osteosarcoma cell-derived exosomal miR-501-3p could promote osteoclast differentiation via PTEN/PI3K/Akt signaling pathway. Collectively, our results suggest that osteosarcoma-derived exosomal miR-501-3p promotes osteoclastogenesis and aggravates bone loss. Therefore, our study reveals a novel mechanism of osteoclastogenesis in osteosarcoma patients and provides a novel target for diagnosis or treatment.     

The methylation landscape of tumour metastasis

The metastatic cascade which leads to the death of cancer patients results from a multi‐step process of tumour progression caused by genetic and epigenetic alterations in key regulatory molecules. It is, therefore, crucial to improve our understanding of the regulation of genes controlling the metastatic process to identify predictive biomarkers and to develop more effective therapies to treat advanced disease. The study of epigenetic mechanisms of gene regulation offers a novel approach for innovative diagnosis and treatment of cancer patients. Recent discoveries provide compelling evidence that the methylation landscape (changes in both DNA methylation and histone post‐translational modifications) is profoundly altered in cancer cells and contributes to the altered expression of genes regulating tumour phenotypes. However, the impact of methylation events specifically on the advanced metastatic process is poorly understood compared with the initial oncogenic events. Moreover, the characterisation of a large number of histone‐modifying enzymes has revealed their active roles in cancer progression, via the regulation of specific target genes controlling different metastatic phenotypes. Here, we discuss two main methylating events (DNA methylation and histone‐tail methylation) involved in oncogenesis and metastasis formation. The potential reversibility of these molecular events makes them promising biomarkers of metastatic potential and potential therapeutic targets.     

Extracellular Vesicles in Glioma: From Diagnosis to Therapy

Increasing evidence indicates that extracellular vesicles (EVs) secreted from tumor cells play a key role in the overall progression of the disease state. EVs such as exosomes are secreted by a wide variety of cells and transport a varied population of proteins, lipids, DNA, and RNA species within the body. Gliomas constitute a significant proportion of all primary brain tumors and majority of brain malignancies. Glioblastoma multiforme (GBM) represents grade IV glioma and is associated with very poor prognosis despite the cumulative advances in diagnostic procedures and treatment strategies. Here, the authors describe the progress in understanding the role of EVs, especially exosomes, in overall glioma progression, and how new research is unraveling the utilities of exosomes in glioma diagnostics and development of next‐generation therapeutic systems. Finally, based on an understanding of the latest scientific literature, a model for the possible working of therapeutic exosomes in glioma treatment is proposed.     

Placenta-derived exosomal miR-135a-5p promotes gestational diabetes mellitus pathogenesis by activating PI3K/AKT signalling pathway via SIRT1

Most people are aware of gestational diabetes mellitus (GDM), a dangerous pregnancy complication in which pregnant women who have never been diagnosed with diabetes develop chronic hyperglycaemia. Exosomal microRNA (miRNA) dysregulation has been shown to be a key player in the pathophysiology of GDM. In this study, we looked into how placental exosomes and their miRNAs may contribute to GDM. When compared to exosomes from healthy pregnant women, it was discovered that miR-135a-5p was elevated in placenta-derived exosomes that were isolated from the maternal peripheral plasma of GDM women. Additionally, we discovered that miR-135a-5p encouraged HTR-8/SVneo cell growth, invasion and migration. Further research revealed that miR-135a-5p activates HTR-8/SVneo cells' proliferation, invasion and migration by promoting PI3K/AKT pathway activity via Sirtuin 1 (SIRT1). The transfer of exosomal miR-135a-5p generated from the placenta could be viewed as a promising agent for targeting genes and pertinent pathways involved in GDM, according to our findings.     

Research progress on the hedgehog signalling pathway in regulating bone formation and homeostasis

Bone formation is a complex regeneration process that was regulated by many signalling pathways, such as Wnt, Notch, BMP and Hedgehog (Hh). All of these signalling have been demonstrated to participate in the bone repair process. In particular, one promising signalling pathway involved in bone formation and homeostasis is the Hh pathway. According to present knowledge, Hh signalling plays a vital role in the development of various tissues and organs in the embryo. In adults, the dysregulation of Hh signalling has been verified to be involved in bone‐related diseases in terms of osteoarthritis, osteoporosis and bone fracture; and during the repair processes, Hh signalling could be reactivated and further modulate bone formation. In this chapter, we summarize our current understanding on the function of Hh signalling in bone formation and homeostasis. Additionally, the current therapeutic strategies targeting this cascade to coordinate and mediate the osteogenesis process have been reviewed.     

Exosomes: Isolation,characterization, and biomedical applications

Exosomes are nano-sized bioactive vesicles of 30–150 nm in diameter. They are secreted by exocytosis of nearly all type of cells in to the extracellular fluid. Thereby, they can be found in many biological fluids. Exosomes regulate intracellular communication between cells via delivery of their cargo which include lipids, proteins, and nucleic acid. Many desirable features of exosomes made them promising candidates in several therapeutic applications. In this review, we discuss the use of exosomes as diagnostic tools and their possible biomedical applications. Additionally, current techniques used for isolation, purification, and characterization of exosomes from both biological fluids and in vitro cell cultures were discussed.     

Roles of exosomes in liver metastases: Novel diagnosis and treatment choices

Tumors tend to metastasize to the liver. Premetastatic niche formation is a vital step in liver metastasis. Tumor-derived exosomes can influence premetastatic niche formation from three aspects: vascular leakiness and angiogenesis, recruitment of nonresident cells, and changes in local resident cells. Exosomes from other tissues, such as mesenchymal stem cell-derived exosomes and engineered exosomes, also have therapeutic potential, but further research on these exosomes is required. Based on the mechanism of premetastatic niche formation, we summarize the therapeutic and diagnostic potential of exosomes in inhibiting liver metastases in this review in an attempt to provide new avenues for the prevention and treatment of liver metastases.