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转移和耐药的发生是黑色素瘤逃脱靶向化疗药物毒性伤害的主要方式,也是导致临床靶向治疗失败和病情复发的最重要因素。外泌体是由细胞分泌的外囊泡,内含微小RNA(miRNA)、mRNA、小分子蛋白等多种生物活性物质,在肿瘤进展、诊断等方面发挥重要作用。外泌体miRNA通过协助黑色素瘤细胞穿过基底膜,诱导上皮间质转化(epithelial-mesenchymal transition,EMT),促进转移前微环境建立,参与黑色素瘤转移。同时在化疗药物治疗过程中,外泌体miRNA通过进入黑色素瘤细胞中重新激活MAPK/PI3K信号通路,进而导致耐药产生。因此,探究外泌体miRNA在黑色素瘤转移和耐药过程中的功能和机制作用对于提高和改善癌症患者的治愈率和预后状态具有重要意义。 相似文献
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Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis 总被引:1,自引:0,他引:1
Exosomes are naturally occurring biological nanovesicles utilized by tumors to communicate signals to local and remote cells and tissues. Melanoma exosomes can incite a proangiogenic signaling program capable of remodeling tissue matrices. In this study, we show exosome-mediated conditioning of lymph nodes and define microanatomic responses that license metastasis of melanoma cells. Homing of melanoma exosomes to sentinel lymph nodes imposes synchronized molecular signals that effect melanoma cell recruitment, extracellular matrix deposition, and vascular proliferation in the lymph nodes. Our findings highlight the pathophysiologic role and mechanisms of an exosome-mediated process of microanatomic niche preparation that facilitates lymphatic metastasis by cancer cells. 相似文献
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Matrix metalloproteinase 13‐containing exosomes promote nasopharyngeal carcinoma metastasis 下载免费PDF全文
Yiwen You Ying Shan Jing Chen Huijun Yue Bo You Si Shi Xingyu Li Xiaolei Cao 《Cancer science》2015,106(12):1669-1677
Nasopharyngeal cancer (NPC) is an endemic type of head and neck cancer with a high rate of cervical lymph node metastasis. Metastasis is the major cause of death in NPC patients. Increasing evidence indicates that exosomes play a pivotal role in promoting cancer metastasis by enhancing angiogenesis and ECM degradation. Matrix metalloproteinase 13 is an important kind of matrix proteinase that is often overexpressed in various tumors and increases the risk of metastasis. However, little is known about the potential role of MMP13‐containing exosomes in NPC. In this study, we found that MMP13 was overexpressed in NPC cells and exosomes purified from conditioned medium (CM) as well as NPC patients’ plasma. Transwell analysis revealed that MMP13‐containing exosomes facilitated the metastasis of NPC cells. Furthermore, siRNA inhibited the effect of MMP13‐containing exosomes on tumor cells metastasis as well as angiogenesis. The current findings provided novel insight into the vital role of MMP13‐containing exosomes in NPC progression which might offer unique insights for potential therapeutic strategies for NPC progressions. 相似文献
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Zhangjun Cheng Zhengqing Lei Pinghua Yang Anfeng Si Daimin Xiang Xuewu Tang Guangmeng Guo Jiahua Zhou Norbert Hüser 《Molecular carcinogenesis》2019,58(8):1389-1399
Hepatocellular carcinoma (HCC) is a fatal disease with increasing morbidity and poor prognosis due to surgical recurrence and metastasis. Moreover, the molecular mechanism of HCC progression remains unclear. Although the role of p120‐catenin (p120ctn) in liver cancer is well studied, the effects of secreted p120ctn transported by exosomes are less understood. Here, we show that p120ctn in exosomes secreted from liver cancer cells suppresses HCC cell proliferation and metastasis and expansion of liver cancer stem cells (CSCs). Mechanically, exosome p120ctn inhibits HCC cell progression via the STAT3 pathway, and the STAT3 inhibitor S3I‐201 abolishes the observed effects on growth, metastasis, and self‐renewal ability between exosome p120ctn‐treated HCC cells and control cells. Taken together, we propose that p120ctn‐containing exosomes derived from cancer cells inhibit the progression of liver cancer and may offer a new therapeutic strategy. 相似文献
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Hua Min Xiangdong Sun Xi Yang Hongcheng Zhu Jia Liu Yuandong Wang Guangzong Chen Xinchen Sun 《Pathology oncology research : POR》2018,24(1):11-18
Exosomes are nanovesicles derived from tumor and normal cells that are detectable in human biological fluids, such as plasma, and cell culture supernatants. The function of exosome secretion from “normal” cells is unclear. Although numerous studies have investigated exosomes derived from hematopoietic cells, little is known regarding exosomes fromT cells, even though these cells play significant roles in innate and acquired immunity. A CCK-8 assay was used to examine the ability of exosomes to inhibit TE13 cell proliferation. In vitro invasion and wound healing assays were conducted to explore the effects of exosomes on TE13 cell migration and invasion. A Western blottinganalys is was performed to investigate the effects of exosomes on the expression of the EMT-related moleculesβ-catenin, NF-κB and snail. This study aimed to investigate the effects of exosomes from irradiated T cells on the human esophageal squamous cell carcinoma (ESCC) cell line TE13 and revealed that exosomes inhibit the proliferation but promote the metastasis of TE13 cells in a dose-and time-dependent manner. Furthermore, exosomes significantly increased the expression of β-catenin, NF-κB and snail in TE13 cells. The results of this study suggest an important role for T cell-derived exosomes in the progression of esophageal carcinoma: T cell-derived exosomes promote esophageal cancer metastasis, likely by promoting the EMT through the upregulation of β-catenin and the NF-κB/snail pathway. Moreover, this study supports the use of exosomes as a nearly perfect example of biomimetic nanovesicles that could be utilized in future therapeutic strategies against various diseases, including cancer. 相似文献
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Tzlil Gener Lahav Omer Adler Yael Zait Ophir Shani Malak Amer Hila Doron Lilach Abramovitz Ido Yofe Noam Cohen Neta Erez 《International journal of cancer. Journal international du cancer》2019,145(9):2521-2534
The major cause of melanoma mortality is metastasis to distant organs, including lungs and brain. Reciprocal interactions of metastasizing tumor cells with stromal cells in secondary sites play a critical role in all stages of tumorigenesis and metastasis. Changes in the metastatic microenvironment were shown to precede clinically relevant metastases, and may occur prior to the arrival of disseminated tumor cells to the distant organ, thus creating a hospitable “premetastatic niche.” Exosomes secreted by tumor cells were demonstrated to play an important role in the preparation of a hospitable metastatic niche. However, the functional role of melanoma-derived exosomes on metastatic niche formation, and the downstream pathways activated in stromal cells at the metastatic niche are largely unresolved. Here we show that extracellular vesicles (EVs) secreted by metastatic melanoma cells that spontaneously metastasize to lungs and to brain, activate proinflammatory signaling in lung fibroblasts and in astrocytes. Interestingly, unlike paracrine signaling by melanoma cells, EVs secreted by metastatic melanoma cells instigated a proinflammatory gene signature in lung fibroblasts but did not activate wound-healing functions, suggesting that tumor cell-secreted EVs activate distinct CAF characteristics and tumor-promoting functions. Moreover, melanoma-secreted EVs also activated proinflammatory signaling in astrocytes, indicating that EV-mediated reprogramming of stromal cells is a general mechanism of modulating the metastatic niche in multiple distant organs. Thus, our study demonstrates that melanoma-derived EVs reprogram tumor-promoting functions in stromal cells in a distinct manner, implicating a central role for tumor-derived EV signaling in promoting the formation of an inflammatory metastatic niche. 相似文献
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Kazuhiko Yoshida Masumi Tsuda Ryuji Matsumoto Shingo Semba Lei Wang Hirokazu Sugino Mishie Tanino Tsunenori Kondo Kazunari Tanabe Shinya Tanaka 《Cancer science》2019,110(7):2119-2132
Locally advanced and metastatic invasive bladder cancer (BC) has a poor prognosis, and no advanced therapies beyond cisplatin‐based combination chemotherapy have been developed. Therefore, it is an urgent issue to elucidate the underlying mechanisms of tumor progression and metastasis of invasive BC for the development of new therapeutic strategies. Here, we clarified a novel role of exosomes containing ErbB2 and CRK in a formation of premetastatic niches and subsequent metastases. CRK adaptors were overexpressed in invasive UM‐UC‐3 BC cells. In an orthotopic xenograft model, metastases to lung, liver, and bone of UM‐UC‐3 cells were completely abolished by CRK elimination. Mass spectrometry analysis identified that ErbB2 was contained in UM‐UC‐3‐derived exosomes in a CRK‐dependent manner; the exosomes significantly increased proliferation and invasion properties of low‐grade 5637 BC cells and HUVECs through FAK and PI3K/AKT signaling pathways. In athymic mice educated with UM‐UC‐3‐derived exosomes, i.v. implanted UM‐UC‐3 cells were trapped with surrounding PKH67‐labeled exosomes in lung and led to development of lung metastasis with disordered vascular proliferation. In contrast, exosomes derived from CRK‐depleted BC cells failed to induce these malignant features. Taken together, we showed that CRK adaptors elevated the expression of ErbB2/3 in BC cells, and these tyrosine kinase/adaptor units were transferred from host BC cells to metastatic recipient cells by exosomes, leading to vascular leakiness and proliferation and contributing to the formation of distant metastasis. Thus, CRK intervention with ErbB2/3 blockade might be a potent therapeutic strategy for patients with ErbB2 overexpressing advanced and metastatic BC. 相似文献
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Ji Chen Yang Song Feng Miao Gang Chen Yongjun Zhu Ning Wu Liewen Pang Zhiming Chen Xiaofeng Chen 《Cancer science》2021,112(9):3437-3454
Metastasis is the main cause of death in individuals with cancer. Immune checkpoint blockade (ICB) can potentially reverse CD8+ cytotoxic T lymphocytes (CTLs) dysfunction, leading to significant remission in multiple cancers. However, the mechanism underlying the development of CTL exhaustion during metastatic progression remains unclear. Here, we established an experimental pulmonary metastasis model with melanoma cells and discovered a critical role for melanoma-released exosomes in metastasis. Using genetic knockdown of nSMase2 and Rab27a, 2 key enzymes for exosome secretion, we showed that high levels of effector-like tumor-specific CD8+ T cells with transitory exhaustion, instead of terminal exhaustion, were observed in mice without exosomes; these cells showed limited inhibitory receptors and strong proliferation and cytotoxicity. Mechanistically, the immunosuppression of exosomes depends on exogenous PD-L1, which can be largely rescued by pretreatment with antibody blockade. Notably, we also found that exosomal PD-L1 acts as a promising predictive biomarker for ICB therapies during metastasis. Together, our findings suggest that exosomal PD-L1 may be a potential immunotherapy target, suggesting a new curative therapy for tumor metastasis. 相似文献
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Xiaoli Wang Hongwen Lan Jun Li Yushu Su Lijun Xu 《American journal of cancer research》2015,5(9):2590-2604
Early stages of melanoma can be successfully treated by surgical resection of the tumor, but there is still no effective treatment once it is progressed to metastatic phases. Although growing family of both melanoma metastasis promoting and metastasis suppressor genes have been reported be related to metastasis, the molecular mechanisms governing melanoma metastatic cascade are still not completely understood. Therefore, defining the molecules that govern melanoma metastasis may aid the development of more effective therapeutic strategies for combating melanoma. In the present study, we found that muc1 is involved in the metastasis of melanoma cells and demonstrated that muc1 disruption impairs melanoma cells migration and metastasis. The requirement of muc1 in the migration of melanoma cells was further confirmed by gene silencing in vitro. In corresponding to this result, over-expression of muc1 significantly promoted the migratory of melanoma cells. Moreover, down-regulation of muc1 expression strikingly inhibits melanoma cellular metastasis in vivo. Finally, we found that muc1 promotes melanoma migration through the protein kinase B (Akt) signaling pathway. To conclude, our findings suggest a novel mechanism underlying the metastasis of melanoma cells which might serve as a new intervention target for the treatment of melanoma. 相似文献
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间充质干细胞(mesenchymal stem cells,MSCs)是存在于各种组织中的多能基质细胞。外泌体为细胞间的通讯载体,能在细胞间传递脂质、核酸以及蛋白质等生物活性分子。MSCs分泌的外泌体(mesenchymal stem cell-derived exosomes,MSC-EXO)为肿瘤微环境(tumor microenvironment,TME)的主要组成部分,并且在肿瘤的发生发展、血管生成及转移过程中发挥重要作用。本文旨在对MSCs来源的外泌体在癌症研究及其对肿瘤的作用机制予以综述,为适当利用修饰的MSC-EXO作为肿瘤治疗的策略提供新思路。 相似文献
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Boukerche H Su ZZ Emdad L Baril P Balme B Thomas L Randolph A Valerie K Sarkar D Fisher PB 《Cancer research》2005,65(23):10901-10911
Metastasis is a significant event in cancer progression and continues to pose the greatest challenge for a cancer cure. Defining genes that control metastasis in vivo may provide new targets for intervening in this process with profound therapeutic implications. Melanoma differentiation associated gene-9 (mda-9) was initially identified by subtraction hybridization as a novel gene displaying biphasic expression during terminal differentiation in human melanoma cells. Mda-9, also known as syntenin, is a PDZ-domain protein overexpressed in many types of human cancers, where it is believed to function in tumor progression. However, a functional role of mda-9/syntenin in tumor growth and metastasis and the signaling pathways involved in mediating these biological activities remain to be defined. Evidence is now provided, using weakly and highly metastatic isogenic melanoma variants, that mda-9/syntenin regulates metastasis. Expression of mda-9/syntenin correlates with advanced stages of melanoma progression. Regulating mda-9/syntenin expression using a replication-incompetent adenovirus expressing either sense or antisense mda-9/syntenin modifies the transformed phenotype and alters metastatic ability in immortal human melanocytes and metastatic melanoma cells in vitro and in vivo in newborn rats. A direct relationship is observed between mda-9/syntenin expression and increased phosphorylation of focal adhesion kinase, c-Jun-NH2-kinase, and p38. This study provides the first direct link between mda-9/syntenin expression and tumor cell dissemination in vivo and indicates that mda-9/syntenin expression activates specific signal transduction pathways, which may regulate melanoma tumor progression. Based on its ability to directly alter metastasis, mda-9/syntenin provides a promising new focus for melanoma cancer research with potential therapeutic applications for metastatic diseases. 相似文献
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The multifaceted role of extracellular vesicles in metastasis: Priming the soil for seeding 下载免费PDF全文
Brunna dos Anjos Pultz Felipe Andrés Cordero da Luz Sara Socorro Faria Leandro Peixoto Ferreira de Souza Paula Cristina Brígido Tavares Vivian Alonso Goulart Wagner Fontes Luiz Ricardo Goulart Marcelo José Barbosa Silva 《International journal of cancer. Journal international du cancer》2017,140(11):2397-2407
Extracellular vesicles (EVs), including exosomes, play a key role in inter and intracellular communication, promoting the proliferation and invasion of recipient cells to support tumor growth and metastasis. Metastasis comprises multiple steps that first include the detachment of tumor cells through epithelial to mesenchymal transition (EMT), allowing the physical dissemination to distant organs. Thereafter, cancer‐derived exosomes are still critical components for preparing the tumor microenvironment by (i) enabling tumor cells to escape from the immunological surveillance and (ii) arranging the pre‐metastatic site for the engraftment of detached cancer cells. In this review, we discuss the multifaceted role of EVs in the multiple steps of metastasis. Future research directions draw attention to EVs as biological targets for cancer diagnosis, prognosis and therapy. However, due to their significant role in cell communication, they may become a valuable drug delivery system. 相似文献
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Vignesh Sundararajan Fazlul H. Sarkar Thamil Selvee Ramasamy 《Cellular oncology (Dordrecht)》2018,41(3):223-252
Background
Recent advances in cancer biology have highlighted the relevance of exosomes and nanovesicles as carriers of genetic and biological messages between cancer cells and their immediate and/or distant environments. It has been found that these molecular cues may play significant roles in cancer progression and metastasis. Cancer cells secrete exosomes containing diverse molecules that can be transferred to recipient cells and/or vice versa to induce a plethora of biological processes, including angiogenesis, metastasis formation, therapeutic resistance, epithelial-mesenchymal transition and epigenetic/stemness (re)programming. While exosomes interact with cells within the tumour microenvironment to promote tumour growth, these vesicles can also facilitate the process of distant metastasis by mediating the formation of pre-metastatic niches. Next to their tumour promoting effects, exosomes have been found to serve as potential tools for cancer diagnosis and therapy. The ease of isolating exosomes and their content from different body fluids has led to the identification of diagnostic and prognostic biomarker signatures, as well as to predictive biomarker signatures for therapeutic responses. Exosomes can also be used as cargos to deliver therapeutic anti-cancer drugs, and they can be engineered to serve as vaccines for immunotherapy. Additionally, it has been found that inhibition of exosome secretion, and thus the transfer of oncogenic molecules, holds promise for inhibiting tumour growth. Here we provide recent information on the diverse roles of exosomes in various cellular and systemic processes governing cancer progression, and discuss novel strategies to halt this progression using exosome-based targeted therapies and methods to inhibit exosome secretion and the transfer of pro-tumorigenic molecules.Conclusions
This review highlights the important role of exosomes in cancer progression and its implications for (non-invasive) diagnostics and the development of novel therapeutic strategies, as well as its current and future applications in clinical trials.18.
Biaoming Xu Yu Chen Mingjing Peng Jin Hai Zheng Chaohui Zuo 《International journal of cancer. Journal international du cancer》2023,152(2):110-122
Pancreatic cancer (PC) is a cancer of the digestive system, and pancreatic ductal adenocarcinoma (PDAC) accounts for approximately 90% of all PC cases. Exosomes derived from PDAC (PDAC-exosomes) promote PDAC development and metastasis. Exosomes are nanoscale vesicles secreted by most cells, which can carry biologically active molecules and mediate communication and cargo transportation among cells. Recent studies have focused on transforming exosomes into good drug delivery systems (DDSs) to improve the clinical treatment of PDAC. This review considers PDAC as the main research object to introduce the role of PDAC-exosomes in PDAC development and metastasis. This review focuses on the following two themes: (a) the great potential of PDAC-exosomes as new diagnostic markers for PDAC, and (b) the transformation of exosomes into potential DDSs. 相似文献
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Zheng Wu Ze-Xuan Fang Yan-Yu Hou Bing-Xuan Wu Yu Deng Hua-Tao Wu Jing Liu 《World journal of gastrointestinal oncology》2023,15(5):731-756
Colorectal cancer (CRC), the third most common type of cancer worldwide, threaten human health and quality of life. With multidisciplinary, including surgery, chemotherapy and/or radiotherapy, patients with an early diagnosis of CRC can have a good prognosis. However, metastasis in CRC patients is the main risk factor causing cancer-related death. To elucidate the underlying molecular mechanisms of CRC metastasis is the difficult and research focus on the investigation of the CRC mechanism. On the other hand, the tumor microenvironment (TME) has been confirmed as having an essential role in the tumorigenesis and metastasis of malignancies, including CRCs. Among the different factors in the TME, exosomes as extracellular vesicles, function as bridges in the communication between cancer cells and different components of the TME to promote the progression and metastasis of CRC. MicroRNAs packaged in exosomes can be derived from different sources and transported into the TME to perform oncogenic or tumor-suppressor roles accordingly. This article focuses on CRC exosomes and illustrates their role in regulating the metastasis of CRC, especially through the packaging of miRNAs, to evoke exosomes as novel biomarkers for their impact on the metastasis of CRC progression. 相似文献
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