bims-exocan 2023-02-12 papers

bims-exocan

Biomed News

on Exosomes roles in cancer

Issue of 2023–02–12
twenty-two papers selected by
Muhammad Rizwan, COMSATS University

The Roles of Exosomes in the Diagnose, Development and Therapeutic Resistance of Oral Squamous Cell Carcinoma.
Exosomes as drug delivery system in gastrointestinal cancer.
Exosomes: A potential tool for immunotherapy of ovarian cancer.
Exosomal circular RNAs: A chief culprit in cancer chemotherapy resistance.
Exosomal LncRNAs in Gastrointestinal Cancer: Biological Functions and Emerging Clinical Applications.
Combinational antitumor strategies of exosomes as drug carriers: Mini review.
The Role of Exosomes in Human Carcinogenesis and Cancer Therapy-Recent Findings from Molecular and Clinical Research.
NK cell-derived exosomes enhance the anti-tumor effects against ovarian cancer by delivering cisplatin and reactivating NK cell functions.
Shining the light on mesenchymal stem cell-derived exosomes in breast cancer.
Exosomes: Mediators in Microenvironment of Colorectal Cancer.
Tumour-derived small extracellular vesicles contribute to the tumour progression through reshaping the systemic immune macroenvironment.
Cancer-Associated Adipocytes and Breast Cancer: Intertwining in the Tumor Microenvironment and Challenges for Cancer Therapy.
Effects of Trauma Plasma-Derived Exosomes on Hematopoietic Progenitor Cells.
Research Progress of Tumor Microenvironment Targeted Therapy for Clear Cell Renal Cell Carcinoma.
Exosome-Transmitted tRF-16-K8J7K1B Promotes Tamoxifen Resistance by Reducing Drug-Induced Cell Apoptosis in Breast Cancer.
Mitochondrial cargo export in exosomes: Possible pathways and implication in disease biology.
Isolation and proteomic profiling of urinary exosomes from patients with colorectal cancer.
Circulating exosomal immuno-oncological checkpoints and cytokines are potential biomarkers to monitor tumor response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer patients.
Peripheral Blood of Vitiligo Patients-Derived Exosomal MiR-21-5p Inhibits Melanocytes Melanogenesis via Targeting SATB1.
Exosomes and ultrasound: The future of theranostic applications.
MUC1-C is a master regulator of MICA/B NKG2D ligand and exosome secretion in human cancer cells.
Loss of cancer-associated fibroblast-derived exosomal DACT3-AS1 promotes malignant transformation and ferroptosis-mediated oxaliplatin resistance in gastric cancer.

Int J Mol Sci. 2023 Jan 19. pii: 1968. [Epub ahead of print]24(3):

The Roles of Exosomes in the Diagnose, Development and Therapeutic Resistance of Oral Squamous Cell Carcinoma.

Shan Shi, Zi-Li Yu, Jun Jia.

  Oral cancer is one of the most common cancers worldwide, of which more than half of patients are diagnosed at a locally advanced stage with poor prognosis due to recurrence, metastasis and resistant to treatment. Thus, it is imperative to further explore the potential mechanism of development and drug resistance of oral cancer. Exosomes are small endosome-derived lipid nanoparticles that are released by cells. Since the cargoes of exosomes were inherited from their donor cells, the cargo profiles of exosomes can well recapitulate that of their donor cells. This is the theoretical basis of exosome-based liquid biopsy, providing a tool for early diagnosis of oral cancer. As an important intracellular bioactive cargo delivery vector, exosomes play a critical role in the development of oral cancer by transferring their cargoes to receipt cells. More importantly, recent studies have revealed that exosomes could induce therapy-resistance in oral cancer through multiple ways, including exosome-mediated drug efflux. In this review, we summarize and compare the role of exosomes in the diagnosis, development and therapy-resistant of oral cancer. We also highlight the clinical application of exosomes, and discuss the advantages and challenges of exosomes serving as predictive biomarker, therapy target and therapy vector in oral cancer.

Keywords:  biomarker; exosome; oral squamous cell carcinoma; therapeutic resistance

DOI:  https://doi.org/10.3390/ijms24031968
Front Oncol. 2022 ;12 1101823

Exosomes as drug delivery system in gastrointestinal cancer.

Fangyuan Xie, Yueying Huang, Yangyang Zhan, Leilei Bao.

  Gastrointestinal cancer is one of the most common malignancies with relatively high morbidity and mortality. Exosomes are nanosized extracellular vesicles derived from most cells and widely distributed in body fluids. They are natural endogenous nanocarriers with low immunogenicity, high biocompatibility, and natural targeting, and can transport lipids, proteins, DNA, and RNA. Exosomes contain DNA, RNA, proteins, lipids, and other bioactive components, which can play a role in information transmission and regulation of cellular physiological and pathological processes during the progression of gastrointestinal cancer. In this paper, the role of exosomes in gastrointestinal cancers is briefly reviewed, with emphasis on the application of exosomes as drug delivery systems for gastrointestinal cancers. Finally, the challenges faced by exosome-based drug delivery systems are discussed.

Keywords:  cancer therapy; drug delivery system; exosomes; extracellular vesicles; gastrointestinal cancer

DOI:  https://doi.org/10.3389/fonc.2022.1101823
Front Immunol. 2022 ;13 1089410

Exosomes: A potential tool for immunotherapy of ovarian cancer.

Xiangjin Gong, Hao Chi, Dorothee Franziska Strohmer, Alexander Tobias Teichmann, Zhijia Xia, Qin Wang.

  Ovarian cancer is a malignant tumor of the female reproductive system, with a very poor prognosis and high mortality rates. Chemotherapy and radiotherapy are the most common treatments for ovarian cancer, with unsatisfactory results. Exosomes are a subpopulation of extracellular vesicles, which have a diameter of approximately 30-100 nm and are secreted by many different types of cells in various body fluids. Exosomes are highly stable and are effective carriers of immunotherapeutic drugs. Recent studies have shown that exosomes are involved in various cellular responses in the tumor microenvironment, influencing the development and therapeutic efficacy of ovarian cancer, and exhibiting dual roles in inhibiting and promoting tumor development. Exosomes also contain a variety of genes related to ovarian cancer immunotherapy that could be potential biomarkers for ovarian cancer diagnosis and prognosis. Undoubtedly, exosomes have great therapeutic potential in the field of ovarian cancer immunotherapy. However, translation of this idea to the clinic has not occurred. Therefore, it is important to understand how exosomes could be used in ovarian cancer immunotherapy to regulate tumor progression. In this review, we summarize the biomarkers of exosomes in different body fluids related to immunotherapy in ovarian cancer and the potential mechanisms by which exosomes influence immunotherapeutic response. We also discuss the prospects for clinical application of exosome-based immunotherapy in ovarian cancer.

Keywords:  biomarker; exosome; immunotherapy; ovarian cancer; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2022.1089410
Drug Resist Updat. 2023 Feb 02. pii: S1368-7646(23)00020-1. [Epub ahead of print]67 100937

Exosomal circular RNAs: A chief culprit in cancer chemotherapy resistance.

Xu Guo, Congying Gao, Dong-Hua Yang, Shenglong Li.

  Chemotherapy is one of the primary treatments for malignant tumors. However, the acquired drug resistance hinders clinical efficacy and leads to treatment failure in most patients. Exosomes are cell-derived vesicles with a diameter of 30-150 nm carrying and delivering substances such as DNAs, RNAs, lipids, and proteins for cellular communication in tumor development. Circular RNAs (circRNAs) present covalently closed-loop RNA structures, which regulate tumor cell proliferation, apoptosis, and metastasis by controlling different genes and signaling pathways. CircRNAs are abundant and stably expressed in exosomes. Recent studies have shown that they play critical roles in chemotherapy resistance in various cancers. In this review, we summarized the origin of exosomes and discussed the regulation mechanism of exosomal circRNAs in cancer drug resistance.

Keywords:  Cancer; Chemotherapy resistance; Circular RNA (circRNA); Exosome

DOI:  https://doi.org/10.1016/j.drup.2023.100937
Cancers (Basel). 2023 Feb 02. pii: 959. [Epub ahead of print]15(3):

Exosomal LncRNAs in Gastrointestinal Cancer: Biological Functions and Emerging Clinical Applications.

Yuntong Sun, Fengtian Sun, Jianhua Jin, Wenrong Xu, Hui Qian.

  Due to the lack of specific and effective biomarkers and therapeutic targets, the early diagnosis and treatment of gastrointestinal cancer remain unsatisfactory. As a type of nanosized vesicles derived from living cells, exosomes mediate cell-to-cell communication by transporting bioactive molecules, thus participating in the regulation of many pathophysiological processes. Recent evidence has revealed that several long non-coding RNAs (lncRNAs) are enriched in exosomes. Exosomes-mediated lncRNAs delivery is critically involved in various aspects of gastrointestinal cancer progression, such as tumor proliferation, metastasis, angiogenesis, stemness, immune microenvironment, and drug resistance. Exosomal lncRNAs represent promising candidates to act as the diagnosis biomarkers and anti-tumor targets. This review introduces the major characteristics of exosomes and lncRNAs and describes the biological functions of exosomal lncRNAs in gastrointestinal cancer development. The preclinical studies on using exosomal lncRNAs to monitor and treat gastrointestinal cancer are also discussed, and the opportunities and challenges for translating them into clinical practice are evaluated.

Keywords:  biomarker; exosomes; gastrointestinal cancer; lncRNAs; therapeutic target

DOI:  https://doi.org/10.3390/cancers15030959
Front Pharmacol. 2022 ;13 1107329

Combinational antitumor strategies of exosomes as drug carriers: Mini review.

Guixiu Xiao, Zihan Xu, Feng Luo.

  Cancer therapies have made tremendous progress in the last decade, but monotherapy still has apparent limitations and lacks therapeutic efficacy. Thus, the simultaneous administration of multiple drugs has been widely explored and has shown better outcomes. Exosomes, deriving from almost all living cells, are natural nanocarriers designed to deliver drugs to tumor sites. Therefore, combinational antitumor therapies based on exosomes, such as engineered exosomes and different combinations of chemotherapeutic agents, therapeutic nucleic acids, photosensitizers, immunotherapy and phytochemicals, have considerable prospects and potential for clinical translation. Here, we summarize current strategies of cancer combination therapy in exosomes and propose opportunities and challenges in the future.

Keywords:  cancer; combinational therapy; drug carriers; engineered exosomes; exosome

DOI:  https://doi.org/10.3389/fphar.2022.1107329
Cells. 2023 Jan 18. pii: 356. [Epub ahead of print]12(3):

The Role of Exosomes in Human Carcinogenesis and Cancer Therapy-Recent Findings from Molecular and Clinical Research.

Katarzyna Stefańska, Małgorzata Józkowiak, Ana Angelova Volponi, Jamil Awad Shibli, Afsaneh Golkar-Narenji, Paweł Antosik, Dorota Bukowska, Hanna Piotrowska-Kempisty, Paul Mozdziak, Piotr Dzięgiel, Marzenna Podhorska-Okołów, Maciej Zabel, Marta Dyszkiewicz-Konwińska, Bartosz Kempisty.

  Exosomes are biological nanoscale spherical lipid bilayer vesicles, 40-160 nm in diameter, produced by most mammalian cells in both physiological and pathological conditions. Exosomes are formed via the endosomal sorting complex required for transport (ESCRT). The primary function of exosomes is mediating cell-to-cell communication. In terms of cancer, exosomes play important roles as mediators of intercellular communication, leading to tumor progression. Moreover, they can serve as biomarkers for cancer detection and progression. Therefore, their utilization in cancer therapies has been suggested, either as drug delivery carriers or as a diagnostic tool. However, exosomes were also reported to be involved in cancer drug resistance via transferring information of drug resistance to sensitive cells. It is important to consider the current knowledge regarding the role of exosomes in cancer, drug resistance, cancer therapies, and their clinical application in cancer therapies.

Keywords:  cancer; cancer therapies; drug resistance; exosomes

DOI:  https://doi.org/10.3390/cells12030356
Front Immunol. 2022 ;13 1087689

NK cell-derived exosomes enhance the anti-tumor effects against ovarian cancer by delivering cisplatin and reactivating NK cell functions.

Heyong Luo, Yanhua Zhou, Jing Zhang, Yingchun Zhang, Shiqi Long, Xiaojin Lin, Anqing Yang, Jiangyao Duan, Na Yang, Zhiru Yang, Qiyuan Che, Yuxin Yang, Ting Guo, Dan Zi, Weiwei Ouyang, Wei Yang, Zhu Zeng, Xing Zhao.

  Exosomes are membranous vesicles actively secreted by almost all cells and they deliver certain intracellular molecules, including nucleic acids, proteins, and lipids, to target cells. They are also considered to be good carriers for drug delivery due to their biocompatibility, high permeability, low immunogenicity, and low toxicity. Exosomes from immune cells were also reported to have immunomodulatory activities. Herein we evaluated the application of exosomes derived from expanded natural killer cells (eNK-EXO) for the treatment of ovarian cancer (OC). We demonstrate that eNK-EXO express typical protein markers of natural killer (NK) cells, can be preferentially uptaken by SKOV3 cells, and display cytotoxicity against OC cells. Furthermore, eNK-EXO loaded with cisplatin could sensitize drug-resistant OC cells to the anti-proliferation effect of cisplatin. In addition, we show that eNK-EXO could activate NK cells from immunosuppressive tumor microenvironment, the mechanism of which is explored by transcriptional analysis. In summary, eNK-EXO exhibit anti-tumor activity against OC on its own, could be used to deliver cisplatin and enhance its cytotoxic effect against drug-resistant OC cells and also reverse the immunosuppression of NK cells, which may lead to great prospect of using eNK-EXO in the treatment of OC in the clinic. Our work also builds a strong foundation for further evaluation of eNK-EXO in other solid tumor therapies.

Keywords:  cisplatin; exosomes; immunomodulatory; natural killer cells; ovarian cancer

DOI:  https://doi.org/10.3389/fimmu.2022.1087689
Stem Cell Res Ther. 2023 Feb 08. 14(1): 21

Shining the light on mesenchymal stem cell-derived exosomes in breast cancer.

Ghaidaa Raheem Lateef Al-Awsi, Fahad Alsaikhan, Ria Margiana, Irfan Ahmad, Indrajit Patra, Mazin A A Najm, Ghulam Yasin, Iroda Rasulova, Ali Thaeer Hammid, Hamzah H Kzar, Moaed E Al-Gazally, Homayoon Siahmansouri.

  In women, breast cancer (BC) is the second most frequently diagnosed cancer and the leading cause of cancer death. Mesenchymal stem cells (MSCs) are a subgroup of heterogeneous non-hematopoietic fibroblast-like cells that have the ability to differentiate into multiple cell types. Recent studies stated that MSCs can migrate into the tumor sites and exert various effect on tumor growth and development. Multiple researches have demonstrated that MSCs can favor tumor growth, while other groups have indicated that MSCs inhibit tumor development. Emerging evidences showed exosomes (Exo) as a new mechanism of cell communication which are essential for the crosstalk between MSCs and BC cells. MSC-derived Exo (MSCs-Exo) could mimic the numerous effects on the proliferation, metastasis, and drug response through carrying a wide scale of molecules, such as proteins, lipids, messenger RNAs, and microRNAs to BC cells. Consequently, in the present literature, we summarized the biogenesis and cargo of Exo and reviewed the role of MSCs-Exo in development of BC.

Keywords:  Breast cancer; Exosome; Extracellular vesicles; Mesenchymal stem cell; Tumor

DOI:  https://doi.org/10.1186/s13287-023-03245-3
Int J Cancer. 2023 Feb 09.

Exosomes: Mediators in Microenvironment of Colorectal Cancer.

Jiali Yao, Yingrui Chen, Zhijie Lin.

  Tumor microenvironment, the soil where tumor thrives, plays a critical role in the development and progression of colorectal cancer (CRC). Various cell signaling molecules in the environment promote tumor angiogenesis, immune tolerance and facilitate immune escape. Exosomes, as messengers between tumor and host cells, are considered key mediators involved in the tumor-accelerating environment. However, the exosome-mediated communication networks in the CRC microenvironment are still largely unclear. In this review, we summarized the relationship between TME and CRC based on recent literature. Then, we revealed the unique impacts and signal molecules of exosomes on account of their regulatory role in the flora, hypoxia, inflammatory, and immunological microenvironment of CRC. Finally, we summarized the therapeutically effective of exosomes in CRC microenvironment and discussed their current status and prospects, aiming to provide new molecular targets and a theoretical basis for the CRC treatment.

Keywords:  Colorectal cancer; Exosome; Tumor microenvironment

DOI:  https://doi.org/10.1002/ijc.34471
Br J Cancer. 2023 Feb 08.

Tumour-derived small extracellular vesicles contribute to the tumour progression through reshaping the systemic immune macroenvironment.

Zhimin Du, Hui Zhang, Yueyuan Feng, Dewen Zhan, Shuya Li, Chenggong Tu, Jinbao Liu, Jinheng Wang.

BACKGROUND: Tumour-derived small extracellular vesicles (sEVs) play a crucial role in cancer immunomodulation. In addition to tumour immune microenvironment, the peripheral immune system also contributes significantly to cancer progression and is essential for anticancer immunity. However, a comprehensive definition of which and how peripheral immune lineages are regulated by tumour-derived sEVs during cancer development remains incomplete.
METHODS: In this study, we used mass cytometry with extensive antibody panels to comprehensively construct the systemic immune landscape in response to tumour development and tumour-derived sEVs.
RESULTS: Systemic immunity was dramatically altered by tumour growth and tumour-derived sEVs. Tumour-derived sEVs significantly and extensively affected immune cell population composition as well as intracellular pathways, resulting in an immunosuppressive peripheral and tumour immune microenvironment, characterised by increased myeloid-derived suppressor cells and decreased Ly6C+CD8 T cells. These sEVs largely promoted hematopoietic recovery and accelerate the differentiation towards myeloid-derived suppressor cells. The knockdown of Rab27a reduced sEV secretion from tumour cells and delayed tumour growth and metastasis in vivo.
CONCLUSIONS: These results highlight that tumour-derived sEVs function as a bridge between peripheral immunity regulation and the tumour microenvironment, and contribute to cancer progression through altering the composition and function of the global immune macroenvironment.

DOI: https://doi.org/10.1038/s41416-023-02175-4
Cancers (Basel). 2023 Jan 24. pii: 726. [Epub ahead of print]15(3):

Cancer-Associated Adipocytes and Breast Cancer: Intertwining in the Tumor Microenvironment and Challenges for Cancer Therapy.

Chenghui Wu, Shuwen Dong, Renhong Huang, Xiaosong Chen.

  Adipocytes are the main components in breast tissue, and cancer-associated adipocytes (CAAs) are one of the most important components in the tumor microenvironment of breast cancer (BC). Bidirectional regulation was found between CAAs and BC cells. BC facilitates the dedifferentiation of adjacent adipocytes to form CAAs with morphological and biological changes. CAAs increase the secretion of multiple cytokines and adipokines to promote the tumorigenesis, progression, and metastasis of BC by remodeling the extracellular matrix, changing aromatase expression, and metabolic reprogramming, and shaping the tumor immune microenvironment. CAAs are also associated with the therapeutic response of BC and provide potential targets in BC therapy. The present review provides a comprehensive description of the crosstalk between CAAs and BC and discusses the potential strategies to target CAAs to overcome BC treatment resistance.

Keywords:  adipokines; breast cancer; cancer-associated adipocytes; cytokines; treatment resistance; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers15030726
Shock. 2023 Feb 13.

Effects of Trauma Plasma-Derived Exosomes on Hematopoietic Progenitor Cells.

Jennifer A Munley, Lauren S Kelly, Gwendolyn S Gillies, Kolenkode B Kannan, Erick E Pons, Letitia E Bible, Philip A Efron, Alicia M Mohr.

BACKGROUND: Severe trauma disrupts bone marrow function resulting in persistent anemia and immunosuppression. Exosomes are extracellular vesicles implicated in disease, cellular functions, and immunomodulation. The effects of trauma plasma-derived exosomes on bone marrow hematopoiesis are unstudied; we hypothesized that trauma plasma-derived exosomes suppress bone marrow hematopoietic progenitor cell (HPC) growth and contribute to increased inflammatory cytokines and HPC mobilization.
METHODS: Plasma was collected from a prospective, cohort study of trauma patients (n = 15) with hip and/or femur fractures and an ISS > 15 and elective total hip arthroplasty (THA) patients (n = 15). Exosomes were isolated from both groups using the Invitrogen Total Exosome Isolation Kit. Healthy bone marrow was cultured with 2% plasma, 50 μg, 100 μg or 200 μg of exosomal protein and HPC (CFU-GEMM, BFU-E, and CFU-GM) growth assessed. After culturing healthy bone marrow stroma with 100 μg of exosomal protein, expression of cytokines and factors influencing HPC mobilization were assessed by qPCR. Differences were compared using ANOVA, with significance defined as *p < 0.05.
RESULTS: The only demographic difference was age; trauma patients were significantly younger than THA (mean 44 vs. 63 years). In vitro exposure to trauma plasma significantly decreased growth of all HPCs. In vitro exposure to 100 μg or 200 μg of trauma exosomal protein significantly decreased growth of BFU-E and CFU-GM, while 50 μg had no effect. Culture of trauma exosomal protein with bone marrow stromal cells resulted in increased expression of IFN-γ, IL-1α, TNF-α, G-CSF, CXCR4, SDF-1, and VCAM-1 in bone marrow stroma.
CONCLUSION: Both plasma and plasma-derived exosomes from trauma patients adversely affect bone marrow function. Plasma-derived exosomes may contribute to altered hematopoiesis following severe trauma; analysis of exosomal content may improve our understanding of altered bone marrow function.

DOI: https://doi.org/10.1097/SHK.0000000000002094
Cancer Control. 2023 Jan-Dec;30:30 10732748231155700

Research Progress of Tumor Microenvironment Targeted Therapy for Clear Cell Renal Cell Carcinoma.

Yongqiang Huang, Hong Sun, Pu Guo.

  Renal clear cell carcinoma (ccRCC) and the tumor microenvironment (TME) influence each other, leading to the tumor microenvironment that can guide the corresponding treatment. With the deepening of research, some treatment options have achieved good results, such as tyrosine kinase inhibitors, immune checkpoint inhibitors, and so on. As the link between TME and malignancy is constantly discovered, more targeted studies on different components of TME are increasing, and this targeted therapy is a new method for treating ccRCC, and also a current research hotspot. This review summarizes the characteristics of the ccRCC tumor microenvironment, the outcomes of different treatments, and some potential targets.

Keywords:  cancer-associated fibroblasts; clear cell renal cell carcinoma; combined treatment; exosomes; immune metabolism; the extracellular matrix; the immune system; tumor microenvironment

DOI:  https://doi.org/10.1177/10732748231155700
Cancers (Basel). 2023 Jan 31. pii: 899. [Epub ahead of print]15(3):

Exosome-Transmitted tRF-16-K8J7K1B Promotes Tamoxifen Resistance by Reducing Drug-Induced Cell Apoptosis in Breast Cancer.

Chunxiao Sun, Xiang Huang, Jun Li, Ziyi Fu, Yijia Hua, Tianyu Zeng, Yaozhou He, Ningjun Duan, Fan Yang, Yan Liang, Hao Wu, Wei Li, Yuchen Zhang, Yongmei Yin.

  Tamoxifen resistance remains a challenge in hormone receptor-positive (HR+) breast cancer. Recent evidence suggests that transfer ribonucleic acid (tRNA)-derived fragments play pivotal roles in the occurrence and development of various tumors. However, the relationship between tRNA-derived fragments and tamoxifen resistance remains unclear. In this study, we found that the expression of tRF-16-K8J7K1B was upregulated in tamoxifen-resistant cells in comparison with tamoxifen-sensitive cells. Higher levels of tRF-16-K8J7K1B were associated with shorter disease-free survival in HR+ breast cancer. Overexpression of tRF-16-K8J7K1B promotes tamoxifen resistance. Moreover, extracellular tRF-16-K8J7K1B could be packaged into exosomes and could disseminate tamoxifen resistance to recipient cells. Mechanistically, exosomal tRF-16-K8J7K1B downregulates the expression of apoptosis-related proteins, such as caspase 3 and poly (ADP-ribose) polymerase, by targeting tumor necrosis factor-related apoptosis-inducing ligand in receptor cells, thereby reducing drug-induced cell apoptosis. Therapeutically, the inhibition of exosomal tRF-16-K8J7K1B increases the sensitivity of breast cancer cells to tamoxifen in vivo. These data demonstrate that exosomal tRF-16-K8J7K1B may be a novel therapeutic target to overcome tamoxifen resistance in HR+ breast cancer.

Keywords:  breast cancer; exosomes; tRNA-derived fragments; tamoxifen resistance

DOI:  https://doi.org/10.3390/cancers15030899
J Cell Physiol. 2023 Feb 06.

Mitochondrial cargo export in exosomes: Possible pathways and implication in disease biology.

Aman Sharma.

  Exosome biogenesis occurs parallel to multiple endocytic traffic routes. These coexisting routes drive cargo loading in exosomes via overlapping of exosome biogenesis with endosomal pathways. One such pathway is autophagy which captures damaged intracellular organelles or their components in an autophagosome vesicle and route them for lysosomal degradation. However, in case of a noncanonical fusion event between autophagosome and maturing multivesicular body (MVB)-a site for exosome biogenesis, the autophagic cargo is putatively loaded in exosomes and subsequent released out of the cell via formation of an "amphisome" like structure. Similarly, during "mitophagy" or mitochondrial (mt) autophagy, amphisome formation routes mitophagy cargo to exosomes. These mt-cargo enriched exosomes or mt-enREXO are often positive for LC3 protein-an autophagic flux marker, and potent regulators of paracrine signaling with both homeostatic and pathological roles. Here, I review this emerging concept and discuss how intracellular autophagic routes helps in generation of mt-enREXO and utility of these vesicles in paracrine cellular signaling and diagnostic areas.

Keywords:  cancer; exosomes; heart disease; mitochondria cargo

DOI:  https://doi.org/10.1002/jcp.30967
Proteome Sci. 2023 Feb 09. 21(1): 3

Isolation and proteomic profiling of urinary exosomes from patients with colorectal cancer.

Ling Ma, Haijiao Yu, Yubing Zhu, Kaiyu Xu, Aimin Zhao, Lei Ding, Hong Gao, Man Zhang.

  Exosomes in the body fluid are effective cell-derived membranous structures transferring various molecules to mediate intercellular communication. The expression of protein in the urinary exosomes from the colorectal cancer (CRC) patients could reflect the characteristics of tumorigenesis. The urinary exosomes with globular membrane structure, the size of 30 ~ 100 nm and positive expression of CD9, CD63 and CD81 were successfully isolated from 9 CRC patients and 3 heathy adults using the density gradient ultracentrifugation. Proteome profiles revealed by label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) indicated that several proteins were differentially expressed among different stages of CRC. Compared with normal controls, 67 proteins in CRC urinary exosomes were upregulated and 74 proteins were downregulated. The bioinformatics analysis revealed the decreased proteins were related to ESCRT III complex disassembly. The CHMP family was further determined to be the hub of interaction network of proteins enriched in ESCRT signaling. The significant decrease of CHMP4A, CHMP4B, CHMP2A, CHMP2B and CHMP1B were respectively found in the total CRC group and distant metastasis group compared with NC group. Moreover, the CEACAM family also showed significant aberrant changes in the urinary exosomes of CRC patients. The CEACAM7 and CEACAM1 were increased in the CRC patients compared with healthy individuals (P < 0.05). Significant changes of proteomic profile could be found in the urinary exosomes in the CRC patients. The differential expressed urinary exosomes derived proteins showed potential usage in diagnosis and prognosis of CRC.

Keywords:  Bioinformatics analysis; Colorectal cancer; Exosome; Mass spectrometry; Urine

DOI:  https://doi.org/10.1186/s12953-023-00203-y
Front Immunol. 2022 ;13 1097117

Circulating exosomal immuno-oncological checkpoints and cytokines are potential biomarkers to monitor tumor response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer patients.

Shayista Akbar, Afsheen Raza, Reyad Mohsin, Aladdin Kanbour, Shahnaz Qadri, Aijaz Parray, Abdul Rehman Zar Gul, Anite Philip, Suma Vijayakumar, Maysaloun Merhi, Shereena Hydrose, Varghese Philipose Inchakalody, Rajaa Al-Abdulla, Wafa Abualainin, Shaza Abu Sirriya, Issam Al-Bozom, Shahab Uddin, Omar Muhammad Khan, Mohamed Izham Mohamed Ibrahim, Ussama Al Homsi, Said Dermime.

  Immune checkpoint inhibitors (ICIs) including anti-PD-1 and anti-PD-L1 antibodies, have significantly changed the treatment outcomes of NSCLC patients with better overall survival. However, 15-40% of the patients still fail to respond to ICIs therapy. Identification of biomarkers associated with responses are mandated in order to increase the efficacy of such therapy. In this study we evaluated 27 serum-derived exosomal immuno-oncological proteins and 44 cytokines/chemokines before and after ICIs therapy in 17 NSCLC patients to identify surrogate biomarkers for treatment/monitoring patient stratification for maximum therapeutic benefit. We first confirmed the identity of the isolated exosomes to have their specific markers (CD63, CD81, HSP70 and CD91). We have demonstrated that baseline concentration of exosomal-PD-L1 (p<0.0001), exosomal-PD-L2 (p=0.0413) and exosomal-PD-1 (p=0.0131) from NSCLC patients were significantly higher than their soluble-free forms. Furthermore, the exosomal-PD-L1 was present in all the patients (100%), while only 71% of patients expressed tissue PD-L1. This indicates that exosomal-PD-L1 is a more reliable diagnostic biomarker. Interestingly, exosomal-PD-L2 expression was significantly higher (p=0.0193) in tissue PD-L1-negative patients compared to tissue PD-L1-positive patients. We have also shown that immuno-oncological proteins isolated from pre-ICIs treated patients were significantly higher in exosomes compared to their soluble-free counterparts (CD152, p=0.0008; CD80, p=0.0182; IDO, p=0.0443; Arginase, p<0.0001; Nectin-2, p<0.0001; NT5E, p<0.0001; Siglec-7, p<0.0001; Siglec-9, p=0.0335; CD28, p=0.0092; GITR, p<0.0001; MICA, p<0.0001). Finally, the changes in the expression levels of exosomal immuno-oncological proteins/cytokines and their correlation with tumor response to ICIs treatment were assessed. There was a significant downregulation of exosomal PD-L1 (p=0.0156), E-Cadherin (p=0.0312), ULBP1 (p=0.0156), ULBP3 (p=0.0391), MICA (p=0.0391), MICB (p=0.0469), Siglec7 (p=0.0078) and significant upregulation of exosomal PD-1 (p=0.0156) and IFN- γ (p=0.0156) in responding patients. Non-responding patients showed a significant increase in exosomal-PD-L1 (p=0.0078). Furthermore, responding-patients without liver-metastasis showed significant-upregulation of PD-1 (p=0.0070), and downregulation of ULBP1 (p=0.0137) and Siglec-7 (p=0.0037). Non-responding patients had significant-downregulation of ULBP3 (p=0.0317) in patient without brain-metastasis and significant-upregulation/downregulation of PD-L1 and ULBP3 (p=0.0262/0.0286) in patients with pulmonary-metastasis. We demonstrated for the first time that exosomal immuno-oncological proteins/cytokines are potential biomarkers to monitor response to ICIs therapy and can predict the clinical outcomes in NSCLC patients.

Keywords:  NSCLC; biomarkers; cytokines; exosomes; follow-up; immune-checkpoint inhibitors; immune-oncological-checkpoints

DOI:  https://doi.org/10.3389/fimmu.2022.1097117
Iran J Public Health. 2022 Dec;51(12): 2706-2716

Peripheral Blood of Vitiligo Patients-Derived Exosomal MiR-21-5p Inhibits Melanocytes Melanogenesis via Targeting SATB1.

Change Zhang, Wu Guo, Sheng Wang, Yuzi Di, Dengting Wu.

   Background: Vitiligo is a common depigmentation disease characterized by progressive destruction and disappearance of epidermal melanocytes. Exosomes have been discovered to regulate the pigment status of melanocytes. We aimed to explore the role of exosomes from peripheral blood of vitiligo patients on melanogenesis.
Methods: Human melanocytes cell line PIG1 was treated with exosomes from the healthy volunteers or exosomes from the vitiligo patients referred to the Department of Dermatology, Children's Hospital Affiliated to Zhengzhou University, China and transfected with miR-21-5p mimic or inhibitor. Exosome labeling assay was used to assess whether exosomes were absorbed by melanocytes. Melanin content and tyrosinase activity assays were performed to investigate melanogenesis in melanocytes. The levels of melanogenesis-related genes and proteins were detected by RT-qPCR and western blot assays. Dual-luciferase reporter assay was performed to confirm the relationship between miR-21-5p and special AT-rich sequence binding protein-1 (SATB1).
Results: Exosomes from peripheral blood of vitiligo patients were transferred into melanocytes and suppressed melanin content, tyrosinase activity and melanogenesis-related genes and proteins levels. Besides, miR-21-5p was highly expressed in exosomes from peripheral blood of vitiligo patients. The results of the gain- and loss-of-function experiments demonstrated that miR-21-5p inhibited the melanogenesis of melanocytes. Furthermore, miR-21-5p inhibitor abolished the inhibitory role of exosomes from peripheral blood of vitiligo patients. Subsequently, miR-21-5p directly targeted SATB1 in melanocytes. Furthermore, overexpression of SATB1 reversed the inhibitory roles of miR-21-5p mimic on melanin content, tyrosinase activity, and melanogenesis-related protein expression.
Conclusion: Peripheral blood of vitiligo patients-derived exosomal miR-21-5p inhibited melanocytes melanogenesis via targeting SATB1.

Keywords:  Exosome; Human; MIRN21 microRNA; Melanogenesis; SATB1 protein; Vitiligo

DOI:  https://doi.org/10.18502/ijph.v51i12.11461
Mater Today Bio. 2023 Apr;19 100556

Exosomes and ultrasound: The future of theranostic applications.

Badrinathan Sridharan, Hae Gyun Lim.

  Biomaterials and pertaining formulations have been very successful in various diagnostic and therapeutic applications because of its ability to overcome pharmacological limitations. Some of them have gained significant focus in the recent decade for their theranostic properties. Exosomes can be grouped as biomaterials, since they consist of various biological micro/macromolecules and possess all the properties of a stable biomaterial with size in nano range. Significant research has gone into isolation and exploitation of exosomes as potential theranostic agent. However, the limitations in terms of yield, efficacy, and target specificity are continuously being addressed. On the other hand, several nano/microformulations are responsive to physical or chemical alterations and were successfully stimulated by tweaking the physical characteristics of the surrounding environment they are in. Some of them are termed as photodynamic, sonodynamic or thermodynamic therapeutic systems. In this regard, ultrasound and acoustic systems were extensively studied for its ability towards altering the properties of the systems to which they were applied on. In this review, we have detailed about the diagnostic and therapeutic applications of exosomes and ultrasound separately, consisting of their conventional applications, drawbacks, and developments for addressing the challenges. The information were categorized into various sections that provide complete overview of the isolation strategies and theranostic applications of exosomes in various diseases. Then the ultrasound-based disease diagnosis and therapy were elaborated, with special interest towards the use of ultrasound in enhancing the efficacy of nanomedicines and nanodrug delivery systems, Finally, we discussed about the ability of ultrasound in enhancing the diagnostic and therapeutic properties of exosomes, which could be the future of theranostics.

Keywords:  Acoustics; Exosomes; Extracellular vesicles; Theranostics; Ultrasound

DOI:  https://doi.org/10.1016/j.mtbio.2023.100556
J Immunother Cancer. 2023 Feb;pii: e006238. [Epub ahead of print]11(2):

MUC1-C is a master regulator of MICA/B NKG2D ligand and exosome secretion in human cancer cells.

Yoshihiro Morimoto, Nami Yamashita, Tatsuaki Daimon, Haruka Hirose, Shizuka Yamano, Naoki Haratake, Satoshi Ishikawa, Atrayee Bhattacharya, Atsushi Fushimi, Rehan Ahmad, Hidekazu Takahashi, Olga Dashevsky, Constantine Mitsiades, Donald Kufe.

   BACKGROUND: The MUC1-C protein evolved in mammals to protect barrier tissues from loss of homeostasis; however, MUC1-C promotes oncogenesis in association with chronic inflammation. Aberrant expression of MUC1-C in cancers has been linked to depletion and dysfunction of T cells in the tumor microenvironment. In contrast, there is no known involvement of MUC1-C in the regulation of natural killer (NK) cell function.
METHODS: Targeting MUC1-C genetically and pharmacologically in cancer cells was performed to assess effects on intracellular and cell surface expression of the MHC class I chain-related polypeptide A (MICA) and MICB ligands. The MICA/B promoters were analyzed for H3K27 and DNA methylation. Shedding of MICA/B was determined by ELISA. MUC1-C interactions with ERp5 and RAB27A were assessed by coimmunoprecipitation and direct binding studies. Exosomes were isolated for analysis of secretion. Purified NK cells were assayed for killing of cancer cell targets.
RESULTS: Our studies demonstrate that MUC1-C represses expression of the MICA and MICB ligands that activate the NK group 2D receptor. We show that the inflammatory MUC1-C→NF-κB pathway drives enhancer of zeste homolog 2-mediated and DNMT-mediated methylation of the MICA and MICB promoter regions. Targeting MUC1-C genetically and pharmacologically with the GO-203 inhibitor induced intracellular and cell surface MICA/B expression but not MICA/B cleavage. Mechanistically, MUC1-C regulates the ERp5 thiol oxidoreductase that is necessary for MICA/B protease digestion and shedding. In addition, MUC1-C interacts with the RAB27A protein, which is required for exosome formation and secretion. As a result, targeting MUC1-C markedly inhibited secretion of exosomes expressing MICA/B. In concert with these results, we show that targeting MUC1-C promotes NK cell-mediated killing.
CONCLUSIONS: These findings uncover pleotropic mechanisms by which MUC1-C confers evasion of cancer cells to NK cell recognition and destruction.

Keywords:  Gastrointestinal Neoplasms; Immunotherapy; Killer Cells, Natural; Tumor Escape; Tumor Microenvironment

DOI:  https://doi.org/10.1136/jitc-2022-006238
Drug Resist Updat. 2023 Jan 31. pii: S1368-7646(23)00019-5. [Epub ahead of print]68 100936

Loss of cancer-associated fibroblast-derived exosomal DACT3-AS1 promotes malignant transformation and ferroptosis-mediated oxaliplatin resistance in gastric cancer.

Xianlin Qu, Bing Liu, Longgang Wang, Luguang Liu, Weizhu Zhao, Changlei Liu, Jishuang Ding, Siwei Zhao, Botao Xu, Hang Yu, Xiang Zhang, Jie Chai.

   AIMS: Long non-coding RNAs (lncRNAs), as one of the components of exosomes derived from cancer-associated fibroblasts (CAFs), exhibit a crucial role in the pathogenesis and chemoresistance of gastric cancer (GC). Herein, we investigated the role and mechanism of a novel lncRNA disheveled binding antagonist of beta catenin3 antisense1 (DACT3-AS1) and its involvement in GC.
METHODS: DACT3-AS1 was identified by RNA-sequencing and verified by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The functional role of DACT3-AS1 in GC was evaluated using in vitro and in vivo experiments including Transwell assay, 5-Ethynyl-2'-deoxyuridine (EdU) assay, immunoblotting, and xenograft tumor mouse model. Dual-luciferase reporter assay was performed to assess the association between genes.
RESULTS: DACT3-AS1 was downregulated and involved in poor prognosis of patients with GC. The results from both in vitro and in vivo experiments showed that DACT3-AS1 suppressed cell proliferation, migration, and invasion through targeting miR-181a-5p/sirtuin 1 (SIRT1) axis. Additionally, DACT3-AS1 was transmitted from CAFs to GC cells mainly via exosomes. Exosomal DACT3-AS1 alleviated xenograft tumor growth. DACT3-AS1 conferred sensitivity of cancer cells to oxaliplatin through SIRT1-mediated ferroptosis both in vitro and in vivo.
CONCLUSIONS: CAFs-derived exosomal DACT3-AS1 is a suppressive regulator in malignant transformation and oxaliplatin resistance. DACT3-AS1 could be used for diagnosis and treatment of GC.

Keywords:  DACT3-AS1; Exosome; Ferroptosis; Gastric cancer; Oxaliplatin resistance

DOI:  https://doi.org/10.1016/j.drup.2023.100936