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Therapeutic Prospects of Extracellular Vesicles in Cancer Treatment.
Juli 2018 | Chulpanova, Daria S; Kitaeva, Kristina V; James, Victoria; Rizvanov, Albert A; Solovyeva, Valeriya V
Extracellular vesicles (EVs) are released by all cells within the tumor microenvironment, such as endothelial cells, tumor-associated fibroblasts, pericytes, and immune system cells. The EVs carry the cargo of parental cells formed of proteins and nucleic acids, which can convey cell-to-cell communication influencing the maintenance and spread of the malignant neoplasm, for example, promoting angiogenesis, tumor cell invasion, and immune escape. However, EVs can also suppress tumor progression, either by the direct influence of the protein and nucleic acid cargo of the EVs or antigen presentation to immune cells as tumor-derived EVs carry on their surface some of the same antigens as the donor cells. Moreover, dendritic cell-derived EVs carry major histocompatibility complex class I and class II/peptide complexes and are able to prime other immune system cell types and activate an antitumor immune response. Given the relative longevity of vesicles within the circulation and their ability to cross blood-brain barriers, modification of these unique organelles offers the potential to create new biological-tools for cancer therapy. This review examines how modification of the EV cargo has the potential to target specific tumor mechanisms responsible for tumor formation and progression to develop new therapeutic strategies and to increase the efficacy of antitumor therapies. PMID 30018618

Targeting dendritic cells in pancreatic ductal adenocarcinoma.
Juni 2018 | Deicher, Anton; Andersson, Roland; Tingstedt, Bobby; Lindell, Gert; Bauden, Monika; Ansari, Daniel
Dendritic cells (DC) are an integral part of the tumor microenvironment. Pancreatic cancer is characterized by reduced number and function of DCs, which impacts antigen presentation and contributes to immune tolerance. Recent data suggest that exosomes can mediate communication between pancreatic cancer cells and DCs. Furthermore, levels of DCs may serve as prognostic factors. There is also growing evidence for the effectiveness of vaccination with DCs pulsed with tumor antigens to initiate adaptive cytolytic immune responses via T cells. Most experience with DC-based vaccination has been gathered for MUC1 and WT1 antigens, where clinical studies in advanced pancreatic cancer have provided encouraging results. In this review, we highlight the role of DC in the course, prognosis and treatment of pancreatic cancer. PMID 29946224

Rethinking liquid biopsy: Microfluidic assays for mobile tumor cells in human body fluids.
Juni 2018 | Neoh, Kuang Hong; Hassan, Ayon Ahmed; Chen, Anqi; Sun, Yukun; Liu, Peng; Xu, Kai-Feng; Wong, Alice S T; Han, Ray P S
Traditionally, liquid biopsy is a blood test involving the harvesting of tumor materials from peripheral blood. Tumor cells from non-blood body fluids have always been clinically available in cytological examinations but limited for use in differential diagnosis due to the low sensitivity of conventional cytopathology. With the recent significant progress in microfluidic and downstream molecular technologies, liquid biopsies have now evolved to include harvesting tumor cells and DNA fragments in all kinds of non-blood body fluids. This expansion into general body fluids presages the notion that liquid biopsy could soon be used in competition, as well as, in complementarity with tissue biopsy. Preliminary research of fluid-harvested tumor materials to spot early-stage tumors, monitor disease progression for metastasis and recurrence, and detect chemoresistance have been reported. To reflect the propagation of tumor cells in non-blood body fluids, we introduced the term Mobile Tumor Cells (MTCs), in lieu of the widely accepted term of circulating tumor cells (CTCs) resident in the bloodstream. Our review starts with a discussion on the clinical significance of MTCs, followed by a presentation of microfluidic techniques for MTC capture and various strategies for their identification. Hopefully, the phenotypic and genomic data acquired from harvested MTCs can be used to guide and improve cancer treatment decisions. PMID 29035737

Extracellular vesicles as emerging targets in cancer: Recent development from bench to bedside.
März 2018 | Wu, Kerui; Xing, Fei; Wu, Shih-Ying; Watabe, Kounosuke
Extracellular vesicles (EVs) have emerged as important players of cancer initiation and progression through cell-cell communication. They have been recognized as critical mediators of extracellular communications, which promote transformation, growth invasion, and drug-resistance of cancer cells. Interestingly, the secretion and uptake of EVs are regulated in a more controlled manner than previously anticipated. EVs are classified into three groups, (i) exosomes, (ii) microvesicles (MVs), and (iii) apoptotic bodies (ABs), based on their sizes and origins, and novel technologies to isolate and distinguish these EVs are evolving. The biologically functional molecules harbored in these EVs, including nucleic acids, lipids, and proteins, have been shown to induce key signaling pathways in both tumor and tumor microenvironment (TME) cells for exacerbating tumor development. While tumor cell-derived EVs are capable of reprogramming stromal cells to generate a proper tumor cell niche, stromal-derived EVs profoundly affect the growth, resistance, and stem cell properties of tumor cells. This review summarizes and discusses these reciprocal communications through EVs in different types of cancers. Further understanding of the pathophysiological roles of different EVs in tumor progression is expected to lead to the discovery of novel biomarkers in liquid biopsy and development of tumor specific therapeutics. This review will also discuss the translational aspects of EVs and therapeutic opportunities of utilizing EVs in different cancer types. PMID 29054476

Poly(I:C) enhanced anti-cervical cancer immunities induced by dendritic cells-derived exosomes.
Feb. 2018 | Chen, Shisheng; Lv, Mingfen; Fang, Shan; Ye, Wenxia; Gao, Yu; Xu, Yunsheng
Dendritic cell (DC)-derived exosomes (Dexo) has been confirmed to be able to induce the specific anti-tumor immune response ex vivo and in vivo. Here, the aim of this study was to evaluate the application of the antigen-pulsed Dexo as a new vaccination platform in immunotherapy for cervical cancer. The immunogenic profile of the different Dexo was assessed by the cell proliferation, cytokines secretion and effector functions of CD8 T cells and the splenocytes from Dexo-vaccinated mice. Furthermore, the anti-tumor immunity elicited by Dexo was further compared in cervical cancer-bearing mice. Dexo from DCs loaded with E7 peptide could efficiently induce the cytotoxic activity of CD8 T cells on TC-1 tumor cells ex vivo, the proliferation and IFN-γ excretion of CD8 T cells. Moreover, Dexo vaccine promoted the immune responses of vaccinated mice splenocytes induced by antigen E7 in vitro restimulation. Of note, poly(I:C) was significantly more potent inducer of the antigen-loaded Dexo mediated protective immunity responses for cervical cancer and further evidenced by that Dexo(E7+pIC) markedly inhibited the tumor growth and improved the survival rate of the tumor-bearing mice. We provided evidence that poly(I:C) dramatically increased the potent antitumoral immunity induced by antigen-pulsed Dexo for ameliorating cervical cancer. PMID 29427678

Co-delivery of tumor-derived exosomes with alpha-galactosylceramide on dendritic cell-based immunotherapy for glioblastoma.
Sep. 2017 | Liu, Hongyu; Chen, Ling; Liu, Jialin; Meng, Hengxing; Zhang, Rong; Ma, Lin; Wu, Liangliang; Yu, Songyan; Shi, Fei; Li, Ying; Zhang, Lijun; Wang, Lingxiong; Feng, Shiyu; Zhang, Qi; Peng, Yaojun; Wu, Qiyan; Liu, Chunxi; Chang, Xin; Yang, Lin; Uemura, Yasushi; Yu, Xinguang; Liu, Tianyi
Dendritic cell (DC) vaccine-based immunotherapy for glioblastoma multiforme (GBM) has shown apparent benefit in animal experiments and early-phase clinical trials, but the survival benefit is variable. In this work, we analyzed the mechanism of the potent antitumor immune response induced in vivo by tumor-associated antigen (TAA)-specific DCs with an invariant natural killer T (iNKT) cell adjuvant in orthotopic glioblastoma-bearing rats vaccinated with tumor-derived exosomes and α-galactosylceramide (α-GalCer) -pulsed DCs. Compared with traditional tumor lysate, exosomes were utilized as a more potent antigen to load DCs. iNKT cells, as an effective cellular adjuvant activated by α-GalCer, strengthened TAA presentation through their interaction with DCs. Co-delivery of tumor-derived exosomes with α-GalCer on a DC-based vaccine showed powerful effects in glioblastoma immunotherapy. This vaccine induced strong activation and proliferation of tumor-specific cytotoxic T lymphocytes, synergistically breaking the immune tolerance and improving the immunosuppressive environment. PMID 28947140

Tumor-derived exosomes elicit tumor suppression in murine hepatocellular carcinoma models and humans in vitro.
Juli 2017 | Rao, Quan; Zuo, Bingfeng; Lu, Zhen; Gao, Xianjun; You, Abin; Wu, Chenxuan; Du, Zhi; Yin, HaiFang
Hepatocellular carcinoma (HCC) remains a global challenge due to high morbidity and mortality rates and poor response to treatment. Immunotherapy, based on introduction of dendritic cells (DCs) activated by tumor cell lysates as antigens ex vivo, shows limited response rates in HCC patients. Here, we demonstrate that tumor cell-derived exosomes (TEXs), displaying an array of HCC antigens, can elicit a stronger immune response than cell lysates in vitro and in vivo. Significant tumor growth inhibition was achieved in ectopic and orthotopic HCC mice treated with TEX-pulsed DCs. Importantly, the tumor immune microenvironment was significantly improved in orthotopic HCC mice treated by TEX-pulsed DCs, demonstrated by increased numbers of T lymphocytes, elevated levels of interferon-γ, and decreased levels of interleukin-10 and tumor growth factor-β in tumor sites. As expected, T cells played an essential role in the TEX-pulsed DC-mediated immune response. Notably, exosomes from HCC cells not only promoted HCC-specific cytolysis but also provided cross-protective effects against pancreatic cancer cells. Moreover, HCC-specific cytolysis, elicited by DCs pulsed with human HepG2 cell-derived exosomes, was observed across different human HCC cells irrespective of human leukocyte antigen types. PMID 26990897

Efficacy of vaccination with tumor-exosome loaded dendritic cells combined with cytotoxic drug treatment in pancreatic cancer.
Juli 2017 | Xiao, Li; Erb, Ulrike; Zhao, Kun; Hackert, Thilo; Zöller, Margot
Pancreatic cancer (PaCa) has a dismal prognosis and adjuvant immunotherapy frequently is of low efficacy due to immunosuppressive features of PaCa and PaCa-stroma. We here explored, whether the efficacy of vaccination with tumor-exosome (TEX)-loaded dendritic cells (DC) can be improved by combining with drugs affecting myeloid-derived suppressor cells (MDSC). Experiments were performed with the UNKC6141 PaCa line. UNKC6141 TEX-loaded DC were weekly intravenously injected, mice additionally receiving Gemcitabine (GEM) and/or ATRA and/or Sunitinib (Sun). UNKC6141 grow aggressively after subcutaneous and orthotopic application and are consistently recovered in peripheral blood, bone marrow, lung and frequently liver. Vaccination with DC-TEX significantly prolonged the survival time, the efficacy of DC-TEX exceeding that of the cytotoxic drugs. However, ATRA, Sun and most efficiently GEM, sufficed for a pronounced reduction of MDSC including tumor-infiltrating MDSC, which was accompanied by a decrease in migrating and metastasizing tumor cells. When combined with DC-TEX vaccination, a higher number of activated T cells was recovered in the tumor and the survival time was prolonged compared with only DC-TEX vaccinated mice. As ATRA, GEM and Sun affect MDSC at distinct maturation and activation stages, a stronger support for DC-TEX vaccination was expected by the drug combination. Intrapancreatic tumor growth was prevented beyond the death of control mice. However, tumors developed after a partial breakdown of the immune system by the persisting drug application. Nonetheless, in combination with optimized drug tuning to prevent MDSC maturation and activation, vaccination with TEX-loaded DC appears a most promising option in PaCa therapy. PMID 28680753

Exosomes: From Garbage Bins to Promising Therapeutic Targets.
März 2017 | H Rashed, Mohammed; Bayraktar, Emine; K Helal, Gouda; Abd-Ellah, Mohamed F; Amero, Paola; Chavez-Reyes, Arturo; Rodriguez-Aguayo, Cristian
Intercellular communication via cell-released vesicles is a very important process for both normal and tumor cells. Cell communication may involve exosomes, small vesicles of endocytic origin that are released by all types of cells and are found in abundance in body fluids, including blood, saliva, urine, and breast milk. Exosomes have been shown to carry lipids, proteins, mRNAs, non-coding RNAs, and even DNA out of cells. They are more than simply molecular garbage bins, however, in that the molecules they carry can be taken up by other cells. Thus, exosomes transfer biological information to neighboring cells and through this cell-to-cell communication are involved not only in physiological functions such as cell-to-cell communication, but also in the pathogenesis of some diseases, including tumors and neurodegenerative conditions. Our increasing understanding of why cells release exosomes and their role in intercellular communication has revealed the very complex and sophisticated contribution of exosomes to health and disease. The aim of this review is to reveal the emerging roles of exosomes in normal and pathological conditions and describe the controversial biological role of exosomes, as it is now understood, in carcinogenesis. We also summarize what is known about exosome biogenesis, composition, functions, and pathways and discuss the potential clinical applications of exosomes, especially as biomarkers and novel therapeutic agents. PMID 28257101

A prospective highlight on exosomal nanoshuttles and cancer immunotherapy and vaccination.
Okt. 2015 | Rafi, Mohammad A; Omidi, Yadollah
Exosomes (EXOs) and ectosomes (ECTOs) are nanoscale membranous extracellular vesicles (EVs) derived from different cells mediating various cellular communications. EXOs are liberated based on the exocytosis of multivesicular bodies, while ECTOs are ubiquitously released from the plasma membranes. PMID 26457248

Improved vaccine efficacy of tumor exosome compared to tumor lysate loaded dendritic cells in mice.
Dez. 2014 | Gu, Xiaoyu; Erb, Ulrike; Büchler, Markus W; Zöller, Margot
Leukemia immunotherapy frequently does not meet expectation, one of the handicaps being tumor exosome (TEX)-promoted immunosuppression. We here asked, using the mouse myeloid leukemia WEHI3B and the renal cell carcinoma line RENCA, whether dendritic cell (DC) vaccination suffices to counterregulate TEX-induced immunosuppression and whether TEX could serve as tumor antigen for DC-loading. DC-vaccination significantly prolonged the survival time of WEHI3B-bearing mice, TEX-loaded DC (DC-TEX) being superior to lysate-loaded DC (DC-lys), even an excess of TEX not interfering with immune response induction. The superior response to DC-TEX was accompanied by an increase in WEHI3B-specific CD4+ T cells, evaluated by trogocytosis and proliferation. Similar findings accounted for DC loaded with RENCA TEX. TEX was efficiently taken-up by DC and TEX uptake supported CD11c, MHCII and IL12 upregulation in DC. Importantly, TEX was partly recruited into the MHCII-loading compartment such that "TEX" presentation time and recovery in T cells significantly exceeded that of tumor-lysate. Thus, TEX did not drive DC into a suppressive phenotype and were a superior antigen due to higher efficacy of TEX-presentation that is supported by prolonged persistence, preferential processing in the MHCII-loading compartment and pronounced trogocytosis by T helper cells. TEX is present in tumor patients' sera. TEX, recovered and enriched from patients' sera, might well provide an optimized, individual-specific antigen source for DC-loading and vaccination. PMID 25066479

Distinct RNA profiles in subpopulations of extracellular vesicles: apoptotic bodies, microvesicles and exosomes.
Nov. 2013 | Crescitelli, Rossella; Lässer, Cecilia; Szabó, Tamas G; Kittel, Agnes; Eldh, Maria; Dianzani, Irma; Buzás, Edit I; Lötvall, Jan
In recent years, there has been an exponential increase in the number of studies aiming to understand the biology of exosomes, as well as other extracellular vesicles. However, classification of membrane vesicles and the appropriate protocols for their isolation are still under intense discussion and investigation. When isolating vesicles, it is crucial to use systems that are able to separate them, to avoid cross-contamination. PMID 24223256

Tumour-derived exosomes as antigen delivery carriers in dendritic cell-based immunotherapy for malignant mesothelioma.
Nov. 2013 | Mahaweni, Niken M; Kaijen-Lambers, Margaretha E H; Dekkers, Jacqueline; Aerts, Joachim G J V; Hegmans, Joost P J J
In 2001, it was postulated that tumour-derived exosomes could be a potent source of tumour-associated antigens (TAA). Since then, much knowledge is gained on their role in tumorigenesis but only very recently tumour-derived exosomes were used in dendritic cell (DC)-based immunotherapy. For this, DCs were cultured ex-vivo and loaded with exosomes derived from immunogenic tumours such as melanoma or glioma and re-administrated to induce anti-tumour responses in primary and metastatic tumour mouse models. In contrast, malignant mesothelioma (MM) is a non-immunogenic tumour and because only a few mesothelioma-specific TAA are known to date, we investigated whether mesothelioma-derived exosomes could be used as antigen source in DC-based immunotherapy. PMID 24223258

Extracellular vesicles--vehicles that spread cancer genes.
Nov. 2012 | Rak, Janusz; Guha, Abhijit
Once regarded as cellular 'debris' extracellular vesicles (EVs) emerge as one of the most intriguing entities in cancer pathogenesis. Intercellular trafficking of EVs challenges the notion of cancer cell autonomy, and highlights the multicellular nature of such fundamental processes as stem cell niche formation, tumour stroma generation, angiogenesis, inflammation or immunity. Recent studies reveal that intercellular exchange mediated by EVs runs deeper than expected, and includes molecules causative for cancer progression, such as oncogenes (epidermal growth factor receptor, Ras), and tumour suppressors (PTEN). The uptake of oncogenic EVs (oncosomes) by various cells may profoundly change their biology, signalling patterns and gene expression, and in some cases cause their overt tumorigenic conversion. Moreover, EVs circulating in blood and present in body fluids provide an unprecedented access to the molecular circuitry driving cancer cells, and new technologies are being developed to exploit this property as a source of unique cancer biomarkers. PMID 22442051

The roles of tumor-derived exosomes in cancer pathogenesis.
Apr. 2012 | Yang, Chenjie; Robbins, Paul D
Exosomes are endosome-derived, 30-100 nm small membrane vesicles released by most cell types including tumor cells. They are enriched in a selective repertoire of proteins and nucleic acids from parental cells and are thought to be actively involved in conferring intercellular signals. Tumor-derived exosomes have been viewed as a source of tumor antigens that can be used to induce antitumor immune responses. However, tumor-derived exosomes also have been found to possess immunosuppressive properties and are able to facilitate tumor growth, metastasis, and the development of drug resistance. These different effects of tumor-derived exosomes contribute to the pathogenesis of cancer. This review will discuss the roles of tumor-derived exosomes in cancer pathogenesis, therapy, and diagnostics. PMID 22190973

Exosome-loaded dendritic cells elicit tumor-specific CD8+ cytotoxic T cells in patients with glioma.
Jan. 2012 | Bu, Ning; Wu, Haiqin; Sun, Bingzhong; Zhang, Guilian; Zhan, Shuqin; Zhang, Ru; Zhou, Le
In this study, we demonstrate that tumor-derived exosome-loaded dendritic cells can elicit a specific CD8(+) cytotoxic T-lymphocyte (CTL) response against autologous tumor cells in patients with malignant glioma. Exosomes were purified by ultrafiltration centrifugation and sucrose gradient ultracentrifugation. Exosomes had antigen-presenting molecules (MHC-I, HSP70), tumor antigen (MAGE-1) and adherent molecule (ICAM-1). After incubation with exosomes, the dendritic cells (DCs) could activate the T lymphocytes to become glioma-specialized CTL. The CTL had vigorous cytotoxicity to glioma cells as opposed to autologous lymphoblast cells. These data demonstrate that tumor exosome-loaded DC can be an effective tool in inducing glioma-specific CD8(+) CTLs able to kill autologous glioma cells in vitro. In conclusion, exosomes are a natural and new source of tumor-rejection antigens, opening up new avenues for immunization against glioma. PMID 21336773

Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming.
Apr. 2001 | Wolfers, J; Lozier, A; Raposo, G; Regnault, A; Théry, C; Masurier, C; Flament, C; Pouzieux, S; Faure, F; Tursz, T; Angevin, E; Amigorena, S; Zitvogel, L
The initiation of T-cell-mediated antitumor immune responses requires the uptake and processing of tumor antigens by dendritic cells and their presentation on MHC-I molecules. Here we show in a human in vitro model system that exosomes, a population of small membrane vesicles secreted by living tumor cells, contain and transfer tumor antigens to dendritic cells. After mouse tumor exosome uptake, dendritic cells induce potent CD8+ T-cell-dependent antitumor effects on syngeneic and allogeneic established mouse tumors. Therefore, exosomes represent a novel source of tumor-rejection antigens for T-cell cross priming, relevant for immunointerventions. PMID 11231627

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