bims-exocan 2022-12-18 papers

bims-exocan

Biomed News

on Exosomes roles in cancer

Issue of 2022–12–18
ten papers selected by
Muhammad Rizwan, COMSATS University

Immunocyte Derived Exosomes: Insight into the Potential Chemo-immunotherapeutic Nanocarrier Targeting the Tumor Microenvironment.
miR-221-5p and miR-186-5p Are the Critical Bladder Cancer Derived Exosomal miRNAs in Natural Killer Cell Dysfunction.
Tumor Cell Derived Exosomal GOT1 Suppresses Tumor Cell Ferroptosis to Accelerate Pancreatic Cancer Progression by Activating Nrf2/HO-1 Axis via Upregulating CCR2 Expression.
Extracellular Vesicles and Their Roles in the Tumor Immune Microenvironment.
Electrochemical biosensors in exosome analysis; a short journey to the present and future trends in early-stage evaluation of cancers.
Extracellular vesicles as a novel approach for breast cancer therapeutics.
Exosomal transfer of miR-181b-5p confers senescence-mediated doxorubicin resistance via modulating BCLAF1 in breast cancer.
CAF-Released Exosomal miR-20a-5p Facilitates HCC Progression via the LIMA1-Mediated β-Catenin Pathway.
Exosomal miR-655-3p inhibits growth, and invasion and macrophage M2 polarization through targeting CXCR4 in papillary thyroid carcinoma.
A liquid biopsy signature of circulating exosome-derived mRNAs, miRNAs and lncRNAs predict therapeutic efficacy to neoadjuvant chemotherapy in patients with advanced gastric cancer.

ACS Biomater Sci Eng. 2022 Dec 16.

Immunocyte Derived Exosomes: Insight into the Potential Chemo-immunotherapeutic Nanocarrier Targeting the Tumor Microenvironment.

Moumita Basak, Dharmendra Kumar Chaudhary, Ryou-U Takahashi, Yuki Yamamoto, Swasti Tiwari, Hidetoshi Tahara, Anupama Mittal.

  "Cancer" is a dreadful immune-pathological condition that is characterized by anti-inflammatory and tumorigenic responses, elicited by the infiltrating immune cells in the vicinity of an uncontrollably proliferative tumor in the tumor microenvironment (TME). The TME offers a conducive microenvironment that supports cancer cell survival by modulating the host immune defense. Recent advancement in exosomal research has shown exosomes, originating from immune cells as well as the cancer cells, have immense potential for suppressing cancer progression and survival in the TME. Additionally, exosomes, irrespective of their diverse sources, have been reported to be efficient nanocarriers for cancer therapeutics with the ability for targeted delivery due to their biogenic nature, ease of cellular uptake, and scope for functionalization with biomolecules like peptides, aptamers, targeting ligands, etc. Immune cell-derived exosomes per se have been found efficacious against cancer owing to their immune-stimulant properties (in either naive or antigen primed form) even without loading any of cancer therapeutics or targeting ligand conjugation. Nevertheless, exosomes are being primarily explored as nanovesicular carriers for therapeutic molecules with different loading and targeting strategies, and the synergism between immunotherapeutic behavior of exosomes and the anticancer effect of the therapeutic molecules is yet to be explored. Hence, this review focuses specifically on the possible strategies to modulate the immunological nature of the source immune cells to obtain immune stimulant exosomes and bring these into the spotlight as chemo-immunotherapeutic nanovesicles, that can easily target and modulate the TME.

Keywords:  antigen-priming; cancer; immunocyte derived exosomes; immunotherapy; nanocarrier; tumor microenvironment

DOI:  https://doi.org/10.1021/acsbiomaterials.2c00893
Int J Mol Sci. 2022 Dec 02. pii: 15177. [Epub ahead of print]23(23):

miR-221-5p and miR-186-5p Are the Critical Bladder Cancer Derived Exosomal miRNAs in Natural Killer Cell Dysfunction.

Ting Huyan, Lina Gao, Na Gao, Chaochao Wang, Wuli Guo, Xiaojie Zhou, Qi Li.

  Bladder cancer (BC) is the tenth most commonly diagnosed cancer worldwide, and its carcinogenesis mechanism has not been fully elucidated. BC is able to induce natural killer (NK) cell dysfunction and escape immune surveillance. The present study found that exosomes derived from the urinary bladder cancer cell line (T24 cell) contribute in generating NK cell dysfunction by impairing viability, and inhibiting the cytotoxicity of the NK cell on target cells. Meanwhile, T24 cell-derived exosomes inhibited the expression of the important functional receptors NKG2D, NKp30, and CD226 on NK cells as well as the secretion of perforin and granzyme-B. The critical miRNAs with high expression in T24 cell-derived exosomes were identified using high-throughput sequencing. Furthermore, following dual-luciferase reporter assay and transfection experiments, miR-221-5p and miR-186-5p were confirmed as interfering with the stability of the mRNAs of DAP10, CD96, and the perforin gene in NK cells and may be potential targets used in the therapy for BC.

Keywords:  bladder cancer (BC); exosome; miR-186-5p; miR-221-5p; miRNA; natural killer (NK) cells

DOI:  https://doi.org/10.3390/ijms232315177
Cells. 2022 Dec 02. pii: 3893. [Epub ahead of print]11(23):

Tumor Cell Derived Exosomal GOT1 Suppresses Tumor Cell Ferroptosis to Accelerate Pancreatic Cancer Progression by Activating Nrf2/HO-1 Axis via Upregulating CCR2 Expression.

Yao Guo, Taoyu Chen, Xueyi Liang, Shanmiao Gou, Jiongxin Xiong, Jing Cui, Tao Peng.

  Recently, evidence has shown that GOT1 expression is upregulated in pancreatic cancer tissues and promotes cancer development, but the specific mechanism remains unclear. We found that GOT1 expression was upregulated in pancreatic cancer cell-derived exosomes. When PANC-1 cells were incubated with exosomes alone or transfected together with si-GOT1, we found that exosomes enhanced cell proliferation, invasion and migration, promoted ferroptosis, and si-GOT1 reversed the effects of exosomes. The results of online bioinformatics database analysis indicated that CCR2 was a potential binding protein of GOT1 and is highly expressed in pancreatic cancer tissues. PANC-1 cells were transfected with pcDNA-CCR2 or si-CCR2, and it was found that pcDNA-CCR2 enhanced cell proliferation, invasion and migration, promoted ferroptosis, and si-CCR2 had an opposite effect. Next, exosome-treated cells were transfected with si-GOT1 alone or together with pcDNA-CCR2, and we found that exosomes promoted CCR2 expression, promoted cell proliferation and invasion, and inhibited ferroptosis, the transfection of si-GOT1 abolished the effect of exosomes, and the transfection of pcDNA-CCR2 again reversed the effect of si-GOT1. Furthermore, when exosome-treated cells were transfected with si-GOT1 alone or co-incubated with Nrf2 activator NK-252, we found that si-GOT1 reversed the promoting effect of exosomes on Nrf2 and HO-1 expression, as well as its inhibitory effect on ferroptosis, but this effect was abrogated by NK-252. In vivo studies showed that knockdown of GOT1 expression inhibited tumor formation compared with tumor tissues formed upon exosome induction, which was mediated by promoting ferroptosis via suppressing the protein expression of GOT1, CCR2, Nrf2 and HO-1 in tumor tissues.

Keywords:  CCR2; GOT1; exosome; ferroptosis; pancreatic cancer; the Nrf2/HO-1 axis

DOI:  https://doi.org/10.3390/cells11233893
J Clin Med. 2022 Nov 22. pii: 6892. [Epub ahead of print]11(23):

Extracellular Vesicles and Their Roles in the Tumor Immune Microenvironment.

Antonia Reale, Tiffany Khong, Andrew Spencer.

  Tumor cells actively incorporate molecules (e.g., proteins, lipids, RNA) into particles named extracellular vesicles (EVs). Several groups have demonstrated that EVs can be transferred to target (recipient) cells, making EVs an important means of intercellular communication. Indeed, EVs are able to modulate the functions of target cells by reprogramming signaling pathways. In a cancer context, EVs promote the formation of a supportive tumor microenvironment (TME) and (pre)metastatic niches. Recent studies have revealed that immune cells, tumor cells and their secretome, including EVs, promote changes in the TME and immunosuppressive functions of immune cells (e.g., natural killer, dendritic cells, T and B cells, monocytes, macrophages) that allow tumor cells to establish and propagate. Despite the growing knowledge on EVs and on their roles in cancer and as modulators of the immune response/escape, the translation into clinical practice remains in its early stages, hence requiring improved translational research in the EVs field. Here, we comprehensively review the current knowledge and most recent research on the roles of EVs in tumor immune evasion and immunosuppression in both solid tumors and hematological malignancies. We also highlight the clinical utility of EV-mediated immunosuppression targeting and EV-engineering. Importantly, we discuss the controversial role of EVs in cancer biology, current limitations and future perspectives to further the EV knowledge into clinical practice.

Keywords:  cancer; engineered EVs; extracellular vesicles; immune-oncology; immunosuppression; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3390/jcm11236892
Biosens Bioelectron. 2022 Dec 10. pii: S0956-5663(22)01020-X. [Epub ahead of print]222 114980

Electrochemical biosensors in exosome analysis; a short journey to the present and future trends in early-stage evaluation of cancers.

Ehsan Dezhakam, Balal Khalilzadeh, Mahdi Mahdipour, Ibrahim Isildak, Hadi Yousefi, Mahdi Ahmadi, Abdolhossein Naseri, Reza Rahbarghazi.

  The tumor microenvironment consists of a multiplicity of cells such as cancer cells, fibroblasts, endothelial cells, and immune cells within the specific parenchyma. It has been indicated that cancer cells can educate other cells within the tumor niche in a paracrine manner by the release of nano-sized extracellular vesicles namely exosomes (Exo), resulting in accelerated tumor mass growth. It is suggested that exosomal cargo with remarkable information can reflect any changes in metabolic and proteomic profiles in parent tumor cells. Therefore, exosomes can be touted as prognostic, diagnostic, and therapeutic elements with specific biomarkers in patients with different tumor types. Despite the advantages, conventional exosome separation and purification protocols are time-consuming and laborious with low abnormal morphology and purity rate. During the last decades, biosensor-based modalities, as emerging instruments, have been used to detect and analyze Exo in biofluids. Due to suitable specificity, sensitivity, and real-time readout, biosensors became promising approaches for the analysis of Exo in in vitro and in vivo settings. The inherent advantages and superiority of electrochemical biosensors in the determination of tumor grade based on exosomal cargo and profile were also debated. Present and future challenges were also discussed related to the application of electrochemical biosensors in the clinical setting. In this review, the early detection of several cancer types associated with ovaries, breast, brain, colon, lungs, T and B lymphocytes, liver and rare types of cancers were debated in association with released exosomes.

Keywords:  Cancer cells; Early-stage detection; Electrochemical biosensors; Exosomes

DOI:  https://doi.org/10.1016/j.bios.2022.114980
Cancer Lett. 2022 Dec 12. pii: S0304-3835(22)00523-7. [Epub ahead of print] 216036

Extracellular vesicles as a novel approach for breast cancer therapeutics.

Yujin Lee, Peter Graham, Yong Li.

  Breast cancer (BC) still lacks effective management approaches to control metastatic and therapy-resistant disease. Extracellular vesicles (EVs), with a diameter of 50-1000 nm, are secreted by all types of living cells, are protected by a lipid bilayer and encapsulate biological cargos including RNAs, proteins and lipids. They play an important role in intercellular communications and are significantly associated with pathological conditions. Accumulating evidence indicates that cancer cells secrete EVs and communicate with neighboring cells within the tumor microenvironment (TME), which plays an important role in BC metastasis, immune escape and chemoresistance, thus providing a new therapeutic window. EVs can stimulate angiogenesis and extracellular matrix remodeling, establish premetastatic niches, inhibit immune response and promote cancer metastasis. Recent advances have demonstrated that EVs are a potential therapeutic target or carrier and have emerged as promising strategies for BC treatment. In this review, we summarize the role of EVs in BC metastasis, chemoresistance and immune escape, which provides the foundation for developing novel therapeutic approaches. We also focus on current EV-based drug delivery strategies in BC and EV cargo-targeted BC therapy and discuss the limitations and future perspectives of EV-based drug delivery in BC.

Keywords:  Breast cancer therapy; Drug delivery; Extracellular vesicle engineering; Nanocarrier; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2022.216036
Br J Cancer. 2022 Dec 15.

Exosomal transfer of miR-181b-5p confers senescence-mediated doxorubicin resistance via modulating BCLAF1 in breast cancer.

Shaorong Zhao, Teng Pan, Jinhai Deng, Lixia Cao, Jose M Vicencio, Jingjing Liu, Guanglin Zhou, Tony Ng, Jin Zhang.

BACKGROUND: Doxorubicin resistance represents a major clinical challenge for treating patients with advanced breast cancer (BC). Exosomes, exchanging genetic cargo between heterogeneous populations of tumour cells, have been proposed to mediate drug resistance and cancer progression in other cancer types. However, their specific role in mediating doxorubicin resistance in BC remains unclear. Here, we demonstrate the important role of exosomal miR-181b-5p (exo-miR-181b-5p) in mediating doxorubicin resistance.
METHODS: Small-RNA sequencing and bioinformatic analyses were used to screen miRNAs mediating doxorubicin resistance in BC, which were further verified by RT-qPCR. SA-β-gal staining assays allowed us to measure cellular senescence. Exosomes from patients' serum before and after neoadjuvant chemotherapy were isolated for exo-miR-181b-5p quantification.
RESULTS: Doxorubicin-resistant BC cell lines exhibited upregulated exosomal miR-181b-5p. Addition of exo-miR-181b-5p actively fused with recipient cells and transferred a drug-resistant phenotype. Overexpression of miR-181b-5p downregulated p53/p21 levels and inhibited doxorubicin-induced G1 arrest and senescence by suppressing BCLAF1 expression in vitro. Further, in vivo experiments showed treatment of exo-miR-181b-5p inhibitors exhibited superior tumour control and reversed the doxorubicin-resistance phenotype, accompanied with increased tumoral BCLAF1.
CONCLUSION: Our data suggests exo-miR-181b-5p as a prognostic biomarker and a therapeutic potential for exo-miR-181b-5p inhibitors in the treatment of doxorubicin-resistant BC patients.

DOI: https://doi.org/10.1038/s41416-022-02077-x
Cells. 2022 Nov 30. pii: 3857. [Epub ahead of print]11(23):

CAF-Released Exosomal miR-20a-5p Facilitates HCC Progression via the LIMA1-Mediated β-Catenin Pathway.

Yong Qi, Haibo Wang, Qikun Zhang, Zhiqiang Liu, Tianbing Wang, Zhengsheng Wu, Wenyong Wu.

  Currently, exosomes derived from Cancer-associated fibroblast (CAF) have reportedly been involved in regulating hepatocellular carcinoma (HCC) tumour microenvironment (TME). LIM domain and actin binding 1 (LIMA1) is an actin-binding protein that is involved in controlling the biological behaviour and progression of specific solid tumours. We aimed to determine the effect of LIMA1 and exosome-associated miR-20a-5p in HCC development. LIMA1 and miR-20a-5p expression levels were examined by real-time quantitative PCR (qRT-PCR), western blotting or immunohistochemistry (IHC). Functional experiments, including Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) assays, colony formation assays, wound healing assays, and Transwell invasion assays, were performed to investigate the effect of LIMA1 and miR-20a-5p. A dual-luciferase reporter gene assay was performed to confirm the interaction of miR-20a-5p and LIMA1. Exosomes were characterised by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blotting. We noted that LIMA1 was downregulated in human HCC tissues and cells and remarkably correlated with overall survival (OS) and recurrence-free survival (RFS). LIMA1 overexpression suppressed HCC cell proliferation and metastasis in vitro and in vivo, while LIMA1 knockdown had the opposite effects. A mechanistic investigation showed that LIMA1 inhibited the Wnt/β-catenin signalling pathway by binding to BMI1 and inducing its destabilisation. Additionally, we found that LIMA1 expression in HCC cells could be suppressed by transferring CAF-derived exosomes harbouring oncogenic miR-20a-5p. In summary, LIMA1 is a tumour suppressor that inhibits the Wnt/β-catenin signalling pathway and is downregulated by CAF-derived exosomes carrying oncogenic miR-20a-5p in HCC.

Keywords:  CAFs; LIMA1; exosomes; hepatocellular cancer; miR-20a-5p

DOI:  https://doi.org/10.3390/cells11233857
Acta Biochim Pol. 2022 Dec 13. 69(4): 767-773

Exosomal miR-655-3p inhibits growth, and invasion and macrophage M2 polarization through targeting CXCR4 in papillary thyroid carcinoma.

Lei Qiao, Chao Dong, Wenlei Jia, Binlin Ma.

Papillary thyroid cancer (PTC) is an endocrine malignancy whose incidence has increased rapidly worldwide. Exosome-miR-655-3p was down-regulated in patients with PTC. However, the effect and molecular mechanism of exosome-miR-655-3p in PTC was indistinct until now. Our study found that exosome-miR-655-3p was decreased in serum of PTC patients. Overexpression of miR-655-3p with mimics significantly shrunk the cell viability, reduced the number of chemotactic and invasive PTC cells. Besides, the proportion of CD163 positive cells and the expression of markers of M2 subtype macrophages was markedly decreased when mononuclear macrophage THP-1 was cultured with exosomes of miR-655-3p mimics. Oppositely, the inhibitor of miR-655-3p exacerbated growth, chemotaxis and invasion of PTC cells, and enhanced the M2 subtype macrophages. Structurally, miR-655-3p could target the 3' untranslated region (3'UTR) of CXCR4 and restrict the expression of CXCR4. In Xenograft tumor experiment, upregulated exosome-miR-655-3p effectively inhibited the growth of tumor and reduced the expression of CXCR4, Ki67 and CD163 in vivo. In summary, exosomal miR-655-3p inhibited growth, invasion and macrophage M2 polarization through targeting CXCR4 in papillary thyroid carcinoma. Regulating exosome-miR-655-3p/CXCR4 may be a potential treatment strategy for PTC.

DOI: https://doi.org/10.18388/abp.2020_6027
Mol Cancer. 2022 Dec 12. 21(1): 216

A liquid biopsy signature of circulating exosome-derived mRNAs, miRNAs and lncRNAs predict therapeutic efficacy to neoadjuvant chemotherapy in patients with advanced gastric cancer.

Ting Guo, Xiao-Huan Tang, Xiang-Yu Gao, Yuan Zhou, Bo Jin, Zi-Qian Deng, Ying Hu, Xiao-Fang Xing, Zi-Yu Li, Jia-Fu Ji.

  At present, there is no validated marker to identify the subpopulation of patients with advanced gastric cancer (AGC) who might benefit from neoadjuvant chemotherapy (NACT). In view of this clinical challenge, the identification of non-invasive biomarkers for efficacy prediction of NACT in patients with AGC is imperative. Herein, we aimed to develop a non-invasive, liquid-biopsy-based assay by using an exosome-derived RNAs model based on multi-omics characteristics of RNAs. We firstly used a multi-omics strategy to characterize the mRNAs, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) profiles of circulating exosome enriched fractions in responders to NACT paired with non-responders, using RNA sequencing. Finally, numerous miRNAs, mRNAs and lncRNAs were identified to be associated with the response to NACT in patients with AGC, and it was validated in an independent cohort with promising AUC values. Furthermore, we established a 6-exosome-RNA panel that could robustly identified responders from non-responders treated with fluorouracil-based neoadjuvant chemotherapy.

Keywords:  Advanced gastric cancer; Biomarker panel for efficacy prediction; Exosome; Multi-omics characteristics of RNAs; Neoadjuvant chemotherapy

DOI:  https://doi.org/10.1186/s12943-022-01684-9