Exosomes derived from imatinib-resistant chronic myeloid leukemia cells mediate a horizontal transfer of drug-resistant trait by delivering miR-365

Min, Qing‐Hua; Wang, Xiaozhong; Zhang, Jing; Chen, Qing-Gen; Li, Shu-Qi; Liu, Xiaoqing; Li, Jing; Liu, Jing; Yang, Weiming; Jiang, Yulin; Xu, Ye; Lin, Jen‐Kou; Gao, Qiu-Fang; Sun, Fan; Zhang, Lei; Huang, Bo

doi:10.1016/j.yexcr.2017.12.001

Cited by 67 publications

(63 citation statements)

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“…Interactions of CSCs with their microenvironment are critical for drug resistance [32]. Recently, exosomes have been investigated as novel messengers in cell-to-cell communication, and it was reported that exosomes mediated the horizontal transfer of drug-resistant traits from imatinib-resistant chronic myeloid leukemia cells to imatinib-sensitive cells [21]. CSCs secrete exosomes to interact with both surrounding cancer cells and stromal cells [9].…”

Section: Discussionmentioning

confidence: 99%

“…Proteins in the exosomes were extracted using a radioimmunoprecipitation assay lysis buffer (Thermo Fisher Scientific), and expression of the exosome markers CD81, CD63 and GM130 was assessed by Western blotting. The morphology of the exosomes was evaluated by transmission electron microscopy, as described previously [21].…”

Section: Isolation and Characterization Of Csc-derived Exosomesmentioning

confidence: 99%

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Exosomes derived from cancer stem cells of gemcitabine-resistant pancreatic cancer cells enhance drug resistance by delivering miR-210

et al. 2019

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Purpose Gemcitabine (GEM)-based chemotherapy is the first-line treatment for locally advanced pancreatic cancer. GEM resistance, however, remains a significant clinical challenge. Here, we investigated whether exosomes derived from GEMresistant pancreatic cancer stem cells (CSCs) mediate cell-cell communication between cells that are sensitive or resistant to GEM and, by doing so, regulate drug resistance. Methods GEM-sensitive BxPC-3-derived Bx S and PANC-1 pancreatic cancer cells were cultured with exosomes extracted from CSCs isolated from GEM-resistant BxPC-3-derived Bx R cells (Bx R -CSC). The effect of exosomes on drug resistance, cell cycle progression, apoptosis and miRNA expression was evaluated in Bx S and PANC-1 cells. Relevant miRNAs associated with GEM resistance were identified and the role of miR-210 in conferring drug resistance was examined in vitro and in vivo. Results Bx R -CSC-derived exosomes induced GEM resistance, inhibited GEM-induced cell cycle arrest, antagonized GEMinduced apoptosis, and promoted tube formation and cell migration in Bx S and PANC-1 cells. Elevated miR-210 expression levels were detected in Bx R -CSCs and Bx R -CSC-derived exosomes compared to those in Bx S -CSCs and Bx S -CSC-derived exosomes. In addition, increased expression levels of miR-210 were observed in Bx S and PANC-1 cells cultured with Bx R -CSCderived exosomes upon exposure to GEM in a dose-dependent manner. Also, a series of biological changes was observed in Bx S cells after transfection with miR-210 mimics, including activation of the mammalian target of rapamycin (mTOR) signaling pathway, and these changes were similar to those triggered by Bx R -CSC-derived exosomes. Conclusions Our findings suggest that exosomes derived from GEM-resistant pancreatic cancer stem cells mediate the horizontal transfer of drug-resistant traits to GEM-sensitive pancreatic cancer cells by delivering miR-210.

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Section: Discussionmentioning

confidence: 99%

Section: Isolation and Characterization Of Csc-derived Exosomesmentioning

confidence: 99%

Exosomes derived from cancer stem cells of gemcitabine-resistant pancreatic cancer cells enhance drug resistance by delivering miR-210

et al. 2019

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“…Similarly, exosomes derived from gemcitabine-resistant lung cancer and imatinib-resistant chronic myeloid leukemia (CML) cells contain miR-222-3p and miR-365, respectively [183,184]. Exosomes containing miR-222-3p are transferred to other cancer cells, where miR-222-3p directly regulates SOCS3 and develops malignant phenotypes of lung cancer cells along with gemcitabine resistance [183].…”

Section: Mir-222-3p and Mir-365mentioning

confidence: 99%

“…Exosomes containing miR-222-3p are transferred to other cancer cells, where miR-222-3p directly regulates SOCS3 and develops malignant phenotypes of lung cancer cells along with gemcitabine resistance [183]. In addition, the therapeutic resistance to imatinib could be triggered by exosomal miR-365, which targets Bcl-2 associated X (BAX) in CML cells [184] (Figure 3 Consistent with the above observations, other studies found that exosomal miRNAs, miR-432a-5p, miR-486-3p, and miR-501-5p, could be derived from drug-resistant cancer cells, and these miRNAs develop the resistance in surrounding cells [185][186][187]. Exosomal miR-432a-5p transmits palbociclib resistance to other cancer cells via down-regulating SMAD4 and subsequently inducing CDK6 expression in breast cancer cells [185].…”

Section: Mir-222-3p and Mir-365mentioning

confidence: 99%

MicroRNA-Based Combinatorial Cancer Therapy: Effects of MicroRNAs on the Efficacy of Anti-Cancer Therapies

Seo

Moeng

Sim³

et al. 2019

Cells

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The susceptibility of cancer cells to different types of treatments can be restricted by intrinsic and acquired therapeutic resistance, leading to the failure of cancer regression and remission. To overcome this problem, a combination therapy has been proposed as a fundamental strategy to improve therapeutic responses; however, resistance is still unavoidable. MicroRNA (miRNAs) are associated with cancer therapeutic resistance. The modulation of dysregulated miRNA levels through miRNA-based therapy comprising a replacement or inhibition approach has been proposed to sensitize cancer cells to other anti-cancer therapies. The combination of miRNA-based therapy with other anti-cancer therapies (miRNA-based combinatorial cancer therapy) is attractive, due to the ability of miRNAs to target multiple genes associated with the signaling pathways controlling therapeutic resistance. In this article, we present an overview of recent findings on the role of therapeutic resistance-related miRNAs in different types of cancer. We review the feasibility of utilizing dysregulated miRNAs in cancer cells and extracellular vesicles as potential candidates for miRNA-based combinatorial cancer therapy. We also discuss innate properties of miRNAs that need to be considered for more effective combinatorial cancer therapy.Cells 2020, 9, 29 2 of 32 to confer the ability to acquire CSC properties onto cancer cells, thereby contributing to therapeutic resistance [7]. Moreover, cell-to-cell communication via extracellular vesicles among different types of cells within the cancer microenvironment could affect the efficacy of cancer therapies by delivering miRNAs that regulate various signaling pathways connected to therapeutic resistance [8,9].Combination therapies have been proposed to overcome therapeutic resistance via the combined inhibition of different mechanisms. For example, the combination of cobimetinib and pictilisib was reported to be beneficial for the treatment of colorectal cancer cells. However, resistance is unavoidable even after the combination treatment [10]. Similarly, the simultaneous inhibition of phosphoinositide 3-kinase (PI3K) and a mechanistic target of rapamycin kinase (mTOR) was reported to activate extracellular signal-regulated kinase (ERK), a pro-survival factor, in acute myeloid leukemia [11]. Therefore, it is still necessary to explore new combination strategies to defeat therapeutic resistance. An improved understanding of the cellular basis of cancer therapeutic resistance can further provide promising opportunities to design and develop novel cancer treatment strategies to manage cancers.MicroRNAs (miRNAs) are widely recognized, small, regulatory RNAs modulating numerous intracellular signaling pathways in several diseases, including cancers. Based on the expression levels and intracellular functions of miRNAs, they could act as tumor-suppressive or oncogenic factors in cancer cells [12][13][14]. The abnormal expression of miRNAs is associated with therapeutic resistance in cancer, and the modulation of m...

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“…In addition, exosomes have been reported to be associated with drug resistance in these tumours [7]. For instance, it was reported that exosomes derived from imatinib-resistant chronic leukaemia cells could confer imatinib-resistance traits into sensitive cells by delivering miR-365 [10]. It was also reported that exosomes derived from bone marrow stromal cells decreased the sensitivity of acute lymphoblastic leukaemia cells to etoposide [11].…”

Section: Introductionmentioning

confidence: 99%

Comprehensive analysis of miRNA and protein profiles within exosomes derived from canine lymphoid tumour cell lines

Asada

Tomiyasu

Uchikai³

et al. 2018

Preprint

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17Exosomes are small extracellular vesicles released from almost all cell types, 18 which play roles in cell-cell communication. Recent studies have suggested that 19 microenvironmental crosstalk mediated by exosomes is an important factor in the 20 escape of tumour cells from the anti-tumour immune system in human haematopoietic 21 malignancies. Here, we conducted comprehensive analysis of the miRNA and protein 22 profiles within the exosomes released from four canine lymphoid tumour cell lines as a 23 model of human lymphoid tumours. The results showed that the miRNAs and proteins 24 abundantly contained in exosomes were similar among the four cell lines. However, the 25 profiles of miRNA within exosomes differed among the cell lines and reflected the 26 expression pattern of miRNAs of the parent cells. In the comparison of the amounts of 27 miRNAs and proteins among the cell lines, those of three miRNAs (miR-151, 28 miR-8908a-3p, and miR-486) and CD82 protein differed between exosomes derived 29 from vincristine-sensitive and resistant cell lines. Further investigations are needed to 30 elucidate the biological functions of the exosomal contents in the microenvironmental 31 crosstalk of lymphoid tumours.32 3 33 Introduction 34 Exosomes are small extracellular vesicles released from almost all cell types, 35 including immune cells and tumour cells [1], as the intracellular endosome component. 36 Although exosomes were initially considered cellular waste, they have been shown to 37 contain various molecules from the original cells, including proteins, functional mRNAs 38 and miRNAs, and deliver these biological messages into the recipient cells [1,2]. To 39 date, it has also been reported that tumour cells release a number of exosomes and they 40 stimulate tumour cell growth and modify the immune cell response to promote tumour 41 progression and metastasis in several human tumors, including colorectal cancer [3], 42 breast cancer [4], melanoma [5], and pancreatic cancer [6]. Thus, the interaction 43 between tumour cell-derived exosomes and recipient cells in the microenvironment of 44 solid tumours is considered an important factor in tumour progression, metastasis, cell 45 survival, and escape from the anti-tumour immune system. 46 Exosomes have also been suggested to play important roles in the 47 microenvironmental crosstalk of human haematopoietic tumours, including leukaemia 48 and lymphoma [7,8]. It has been reported that exosomes derived from acute/chronic 49 myeloid leukaemia and lymphoma cells inactivate natural killer cells and suppress the 50 anti-tumour immune response [7-9]. In addition, exosomes have been reported to be 4 51 associated with drug resistance in these tumours [7]. For instance, it was reported that 52 exosomes derived from imatinib-resistant chronic leukaemia cells could confer 53 imatinib-resistance traits into sensitive cells by delivering miR-365 [10]. It was also 54 reported that exosomes derived from bone marrow stromal cells decreased the 55 sensitivity of acute lymphoblasti...

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Exosomes derived from imatinib-resistant chronic myeloid leukemia cells mediate a horizontal transfer of drug-resistant trait by delivering miR-365

Cited by 67 publications

References 22 publications

Exosomes derived from cancer stem cells of gemcitabine-resistant pancreatic cancer cells enhance drug resistance by delivering miR-210

Exosomes derived from cancer stem cells of gemcitabine-resistant pancreatic cancer cells enhance drug resistance by delivering miR-210

MicroRNA-Based Combinatorial Cancer Therapy: Effects of MicroRNAs on the Efficacy of Anti-Cancer Therapies

Comprehensive analysis of miRNA and protein profiles within exosomes derived from canine lymphoid tumour cell lines

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