bims-exocan 2022-10-02 papers

bims-exocan

Biomed News

on Exosomes roles in cancer

Issue of 2022–10–02
24 papers selected by
Muhammad Rizwan, COMSATS University

Exosome secretion from hypoxic cancer cells reshapes the tumor microenvironment and mediates drug resistance.
The roles of small extracellular vesicles in cancer and immune regulation and translational potential in cancer therapy.
Effective Separation of Cancer-Derived Exosomes in Biological Samples for Liquid Biopsy: Classic Strategies and Innovative Development.
Exosomal miR-452-5p Induce M2 Macrophage Polarization to Accelerate Hepatocellular Carcinoma Progression by Targeting TIMP3.
Exosomes: Promising biomarkers and targets for cancer.
Exosomal noncoding RNAs in colorectal cancer: An overview of functions, challenges, opportunities, and clinical applications.
Tumor-derived exosomal HOTAIRM1 regulates SPON2 in CAFs to promote progression of lung adenocarcinoma.
Comparative evaluation of long non-coding RNA-based biomarkers in the urinary sediment and urinary exosomes for non-invasive diagnosis of bladder cancer.
Exosomes in bone remodeling and breast cancer bone metastasis.
Extracellular vesicles as central regulators of blood vessel function in cancer.
Exosomal telomerase transcripts reprogram the microRNA transcriptome profile of fibroblasts and partially contribute to CAF formation.
Cancer as an infective disease: The role of EVs in tumorigenesis.
Phenformin suppresses angiogenesis through the regulation of exosomal microRNA-1246 and microRNA-205 levels derived from oral squamous cell carcinoma cells.
Role of extracellular vesicles secretion in paclitaxel resistance of prostate cancer cells.
The prognostic and predictive values of differential expression of exosomal receptor tyrosine kinases and associated with the PI3K/AKT/mTOR signaling in breast cancer patients undergoing neoadjuvant chemotherapy.
The Study of Exosomes-Encapsulated mPEG-PLGA Polymer Drug-Loaded Particles for Targeted Therapy of Liver Cancer.
Exosomal AP000439.2 from clear cell renal cell carcinoma induces M2 macrophage polarization to promote tumor progression through activation of STAT3.
MSC-Derived Exosomes Suppress Colorectal Cancer Cell Proliferation and Metastasis via miR-100/mTOR/miR-143 Pathway.
Clinical impact of bile-derived exosomal miRNAs as novel diagnostic and prognostic biomarkers for biliary tract cancers.
Alcohol-related diseases and liver metastasis: Role of cell-free network communication.
[Research Advances of Immunotherapy of Exosome PD-L1  in Non-small Cell Lung Cancer].
Tumor-associated macrophage-derived exosomes promote EGFR-TKI resistance in non-small cell lung cancer by regulating the AKT, ERK1/2 and STAT3 signaling pathways.
Responsive role of nanomedicine in the tumor microenvironment and cancer drug resistance.
The immunosuppressive tumor microenvironment in hepatocellular carcinoma-current situation and outlook.

Cancer Drug Resist. 2022 ;5(3): 577-594

Exosome secretion from hypoxic cancer cells reshapes the tumor microenvironment and mediates drug resistance.

Kenneth K W To, William C S Cho.

  Hypoxia is a common phenomenon in solid tumors as the poorly organized tumor vasculature cannot fulfill the increasing oxygen demand of rapidly expanding tumors. Under hypoxia, tumor cells reshape their microenvironment to sustain survival, promote metastasis, and develop resistance to therapy. Exosomes are extracellular vesicles secreted by most eukaryotic cells, including tumor cells. They are enriched with a selective collection of nucleic acids and proteins from the originating cells to mediate cell-to-cell communication. Accumulating evidence suggests that exosomes derived from tumor cells play critical roles in modulating the tumor microenvironment (TME). Hypoxia is known to stimulate the secretion of exosomes from tumor cells, thereby promoting intercellular communication of hypoxic tumors with the surrounding stromal tissues. Exosome-mediated signaling pathways under hypoxic conditions have been reported to cause angiogenesis, invasion, metastasis, drug resistance, and immune escape. Recently, the programmed cell death ligand-1 (PD-L1) has been reported to reside as a transmembrane protein in tumor exosomes. Exosomal PD-L1 was shown to suppress T cell effector function in the TME and cause drug resistance to immune checkpoint therapy. This review provides an update about the pivotal role of tumor-derived exosomes in drug resistance to chemotherapy and immunotherapy, particularly under hypoxic conditions. Emerging strategies that target the exosomes in the hypoxic TME to enhance the antitumor efficacy are discussed.

Keywords:  Hypoxia; drug resistance; exosome; immunotherapy; non-coding RNA; tumor microenvironment

DOI:  https://doi.org/10.20517/cdr.2022.38
J Exp Clin Cancer Res. 2022 Sep 27. 41(1): 286

The roles of small extracellular vesicles in cancer and immune regulation and translational potential in cancer therapy.

Kewen Qian, Wenyan Fu, Tian Li, Jian Zhao, Changhai Lei, Shi Hu.

  Extracellular vesicles (EVs) facilitate the extracellular transfer of proteins, lipids, and nucleic acids and mediate intercellular communication among multiple cells in the tumour environment. Small extracellular vesicles (sEVs) are defined as EVs range in diameter from approximately 50 to 150 nm. Tumour-derived sEVs (TDsEVs) and immune cell-derived sEVs have significant immunological activities and participate in cancer progression and immune responses. Cancer-specific molecules have been identified on TDsEVs and can function as biomarkers for cancer diagnosis and prognosis, as well as allergens for TDsEVs-based vaccination. Various monocytes, including but not limited to dendritic cells (DCs), B cells, T cells, natural killer (NK) cells, macrophages, and myeloid-derived suppressor cells (MDSCs), secrete sEVs that regulate immune responses in the complex immune network with either protumour or antitumour effects. After engineered modification, sEVs from immune cells and other donor cells can provide improved targeting and biological effects. Combined with their naïve characteristics, these engineered sEVs hold great potential as drug carriers. When used in a variety of cancer therapies, they can adjunctly enhance the safety and antitumor efficacy of multiple therapeutics. In summary, both naïve sEVs in the tumour environment and engineered sEVs with effector cargoes are regarded as showing promising potential for use in cancer diagnostics and therapeutics.

Keywords:  Cancer diagnosis; Cancer therapy; Exosomes; Extracellular vesicles; Genetic engineering; Liquid biopsy; Targeted delivery

DOI:  https://doi.org/10.1186/s13046-022-02492-1
Glob Chall. 2022 Sep;6(9): 2100131

Effective Separation of Cancer-Derived Exosomes in Biological Samples for Liquid Biopsy: Classic Strategies and Innovative Development.

Yujiao Xie, Xiawei Xu, Jie Lin, Yanping Xu, Jing Wang, Yong Ren, Aiguo Wu.

  Liquid biopsy has remarkably facilitated clinical diagnosis and surveillance of cancer via employing a non-invasive way to detect cancer-derived components, such as circulating tumor DNA and circulating tumor cells from biological fluid samples. The cancer-derived exosomes, which are nano-sized vesicles secreted by cancer cells have been investigated in liquid biopsy as their important roles in intracellular communication and disease development have been revealed. Given the challenges posed by the complicated humoral microenvironment, which contains a variety of different cells and macromolecular substances in addition to the exosomes, it has attracted a large amount of attention to effectively isolate exosomes from collected samples. In this review, the authors aim to analyze classic strategies for separation of cancer-derived exosomes, giving an extensive discussion of advantages and limitations of these methods. Furthermore, the innovative multi-strategy methods to realize efficient isolation of cancer-derived exosomes in practical applications are also presented. Additionally, the possible development trends of exosome separation in to the future is discussed in this review.

Keywords:  cancers; cancer‐derived exosomes; liquid biopsies; separation methods

DOI:  https://doi.org/10.1002/gch2.202100131
J Immunol Res. 2022 ;2022 1032106

Exosomal miR-452-5p Induce M2 Macrophage Polarization to Accelerate Hepatocellular Carcinoma Progression by Targeting TIMP3.

Hu Zongqiang, Chen Jiapeng, Zhao Yingpeng, Yan Chuntao, Wang Yiting, Zhu Jiashun, Li Li.

Background: Hepatocellular carcinoma (HCC) cell-derived exosomes have shown effects on inducing M2 macrophage polarization and promoting HCC progression. MiR-452-5p was reported by recent studies to promote malignancy progression as an exosomal microRNA that secreted by HCC cells, of which the underlying mechanism remains unclear. Here, we further explored how miR-452-5p functions in HCC.
Methods: MiR-452-5p expressions in HCC cells was examined by in situ hybridization. Next, HCC cell lines were transfected with the mimics or the inhibitor of miR-452-5p. Transfected cells' biological behavior were analyzed by CCK-8, flow cytometry, and Transwell assay. Then, exosomes were purified from miR-452-5p inhibited or overexpressed HCC cells and cocultured with macrophages to examine the role of miR-452-5p in macrophage polarization. To examine the role of exosomal miR-452-5p on macrophage polarization and tumor growth. We also performed the dual-luciferase assay to explore the targeting relationship between miR-452-5p and TIMP3.
Results: The upregulation of miR-452-5p was identified in HCC. The effects of HCC cell-derived exosomes on accelerating HCC migration and invasion and inducing M2 macrophage polarization were confirmed, which were further enhanced after overexpressing miR-452-5p but neutralized after silencing miR-452-5p. In addition, in vivo experiments demonstrated the effect of miR-452-5p on accelerating HCC growth and metastasis. Also, we identified that TIMP3 overexpression inhibited the promoted cell invasion and migration by HCC cell-derived exosomes.
Conclusion: Exosomal miR-452-5p secreted from HCC cells could induce polarization of M2 macrophage and therefore stimulating HCC progression by targeting TIMP3. Thus, miR-452-5p might be a potential biomarker for HCC prognosis.

DOI: https://doi.org/10.1155/2022/1032106
World J Gastrointest Oncol. 2022 Aug 15. 14(8): 1594-1596

Exosomes: Promising biomarkers and targets for cancer.

Zhen Fang, Yi-Xuan Ding, Fei Li.

  The review article entitled "Exosomes as potential diagnosis and treatment for liver cancer " recently published in World Journal of Gastrointestinal Oncology 2022; 14: 334-347 concluded that exosomes can be used as effective biomarkers or therapeutic biotargets in liver cancer. Exosomes are a hot spot in the field of tumor diagnosis and treatment research. We had also previously published a review on exosomes and tumors. In this letter to the editor, we summarize the clinical application prospects and current challenges of exosomes.

Keywords:  Biomarkers; Cancer; Diagnosis; Exosomes; Therapy

DOI:  https://doi.org/10.4251/wjgo.v14.i8.1594
Pathol Res Pract. 2022 Sep 17. pii: S0344-0338(22)00377-6. [Epub ahead of print]238 154133

Exosomal noncoding RNAs in colorectal cancer: An overview of functions, challenges, opportunities, and clinical applications.

Melika Amelimojarad, Mandana AmeliMojarad, Ehsan Nazemalhosseini-Mojarad.

  Colorectal cancer (CRC) is the third most threatening malignancy worldwide. Colorectal tumors transfer information with their tumor microenvironment (TME) and communicate together which can be detected through exosome transmission. Exosomes are important regulators made by different types of cells in all body fluids containing RNA, DNA, metabolites, and proteins. Recently, Exosome-derived noncoding RNAs (ncRNAs) applications have gained great consideration based on their potential role in the different pathological processes. Therefore, in this review, we summarized the recent discoveries on exosomal ncRNAs function in CRC initiation and development, and drug resistance to provide a novel insight into exosomal ncRNAs' clinical application and their potential to be biomarkers for CRC patients.

Keywords:  Clinical application; Colorectal cancer; Exosome; NcRNAs

DOI:  https://doi.org/10.1016/j.prp.2022.154133
Discov Oncol. 2022 Sep 24. 13(1): 92

Tumor-derived exosomal HOTAIRM1 regulates SPON2 in CAFs to promote progression of lung adenocarcinoma.

Zhipeng Chen, Chengyu Bian, Jingjing Huang, Xiang Li, Liang Chen, Xueying Xie, Yang Xia, Rong Yin, Jun Wang.

   OBJECTIVE: SPON2 is one of the extracellular matrix proteins, which is closely related to the progression of a variety of tumors including non-small cell lung cancer (NSCLC), but its upstream regulation mechanism remains unclear. Our research aims to find the specific regulatory pathway of SPON2 by exploring the potential crosstalk between tumor cells and cancer-associated fibroblasts (CAFs) in tumor microenvironment (TME) of NSCLC.
METHODS: We analyzed T1 lung adenocarcinoma samples from TCGA and screened extracellular matrix proteins that indicate poor prognosis. Expression level of SPON2 was verified by qPCR in clinical samples. The exosomes of NSCLC cell supernatant were extracted and identified by nanoparticle tracking analysis (NTA) and transmission electron microscope, western blots. The exosomes and CAFs were co-cultured, and cell migration and Matrigel invasion assay were used to evaluate the effect of CAFs on the migration and invasion of NSCLC cells. The interaction between LncRNA and miRNA was verified by Targetscan prediction, luciferase reporter assay, and RNA binding protein immunoprecipitation (RIP).
RESULTS: We found that the expression of SPON2 was up-regulated in clinical T1a stage NSCLC patients. The expression of lnc HOTAIRM1 (HOTAIRM1) in exosomes secreted by NSCLC tissues increased. After exosomal HOTAIRM1 entered CAFs, HOTAIRM1 can adsorb miR-328-5p to up-regulate the expression of SPON2 in CAFs. Up-regulation of SPON2 in CAFs could promote the migration and invasion of NSCLC cells.
CONCLUSION: Tumor-derived exosomal HOTAIRM1 can transfer into CAFs and competitively adsorb miR-328-5p, and regulate the SPON2 expression of CAFs cells, ultimately promote the progression of NSCLC. The discovery of this regulatory pathway can provide a new potential therapeutic target for the diagnosis and treatment of NSCLC.

Keywords:  CAFs; Exosomes; Lung adenocarcinoma; SPON2; Tumour microenvironment

DOI:  https://doi.org/10.1007/s12672-022-00553-7
Mol Omics. 2022 Sep 27.

Comparative evaluation of long non-coding RNA-based biomarkers in the urinary sediment and urinary exosomes for non-invasive diagnosis of bladder cancer.

Tongtong Qiu, Mei Xue, Xu Li, Fangyuan Li, Shanshan Liu, Chenyu Yao, Wei Chen.

Bladder cancer (BC) frequently causes a heavy disease burden for patients because of its easy recurrence. There is still a lack of convenient and effective methods to diagnose or monitor BC in the clinic. Emerging evidence suggests that long non-coding RNAs (lncRNAs) in urine are promising biomarkers for BC diagnosis. This study aimed to evaluate the performance of lncRNAs in urine for BC diagnosis. Seven lncRNAs (UCA1, H19, MALAT1, TUG1, GAS5, RMRP, and LINC01517) were selected as candidates by analyzing The Cancer Genome Atlas database or the literature. Expression of the candidate lncRNAs in the urinary sediment and exosomes was determined in a training cohort (n = 42) and an independent validation cohort (n = 56). Compared with normal controls, the patients with BC had a higher expression of RMRP, UCA1 and MALAT1 in the urinary exosomes and a higher expression of MALAT1 in the urinary sediment. Compared with MALAT1 in the urinary sediment, RMRP, UCA1, and MALAT1 in urinary exosomes exhibited higher combined diagnostic performance for BC diagnosis. Furthermore, higher RMRP expression in urinary exosomes was correlated with advanced tumor stages. A lncRNA panel consisting of urinary exosomal RMRP, UCA1 and MALAT1 was used to establish the support vector machine (SVM) model. An area under receiver operating characteristic (ROC) curve of the lncRNA panel predicted by the SVM model was 0.875 (sensitivity = 80.0% and specificity = 81.4%). Therefore, the lncRNA panel consisting of three urinary exosomal RMRP, UCA1 and MALAT1 has the potential to be biomarkers for BC diagnosis.

DOI: https://doi.org/10.1039/d2mo00107a
Prog Biophys Mol Biol. 2022 Sep 22. pii: S0079-6107(22)00099-2. [Epub ahead of print]

Exosomes in bone remodeling and breast cancer bone metastasis.

Lakshana Sadu, R Hari Krishnan, R L Akshaya, Udipt Ranjan Das, Sneha Satishkumar, N Selvamurugan.

  Exosomes are endosome-derived microvesicles that carry cell-specific biological cargo, such as proteins, lipids, and noncoding RNAs (ncRNAs). They play a key role in bone remodeling by enabling the maintenance of a balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Recent evidence indicates that exosomes disrupt bone remodeling that occurs during breast cancer (BC) progression. The bone is a preferred site for BC metastasis owing to its abundant osseous reserves. In this review, we aimed to highlight the roles of exosomes derived from bone cells and breast tumor in bone remodeling and BC bone metastasis (BCBM). We also briefly outline the mechanisms of action of ncRNAs and proteins carried by exosomes secreted by bone and BCBM. Furthermore, this review highlights the potential of utilizing exosomes as biomarkers or delivery vehicles for the diagnosis and treatment of BCBM.

Keywords:  Bone remodeling; Breast cancer; Exosome; Metastasis; Osteoblast; Osteoclast

DOI:  https://doi.org/10.1016/j.pbiomolbio.2022.09.008
Sci Signal. 2022 Sep 27. 15(753): eaaz4742

Extracellular vesicles as central regulators of blood vessel function in cancer.

Fernanda G Kugeratski, Alice Santi, Sara Zanivan.

Blood vessels deliver oxygen and nutrients that sustain tumor growth and enable the dissemination of cancer cells to distant sites and the recruitment of intratumoral immune cells. In addition, the structural and functional abnormalities of the tumor vasculature foster the development of an aggressive tumor microenvironment and impair the efficacy of existing cancer therapies. Extracellular vesicles (EVs) have emerged as major players of tumor progression, and a growing body of evidence has demonstrated that EVs derived from cancer cells trigger multiple responses in endothelial cells that alter blood vessel function in tumors. EV-mediated signaling in endothelial cells can occur through the transfer of functional cargos such as miRNAs, lncRNAs, cirRNAs, and proteins. Moreover, membrane-bound proteins in EVs can elicit receptor-mediated signaling in endothelial cells. Together, these mechanisms reprogram endothelial cells and contribute to the sustained exacerbated angiogenic signaling typical of tumors, which, in turn, influences cancer progression. Targeting these angiogenesis-promoting EV-dependent mechanisms may offer additional strategies to normalize tumor vasculature. Here, we discuss the current knowledge pertaining to the contribution of cancer cell-derived EVs in mechanisms regulating blood vessel functions in tumors. Moreover, we discuss the translational opportunities in targeting the dysfunctional tumor vasculature using EVs and highlight the open questions in the field of EV biology that can be addressed using mass spectrometry-based proteomics analysis.

DOI: https://doi.org/10.1126/scisignal.aaz4742
Sci Rep. 2022 Sep 30. 12(1): 16415

Exosomal telomerase transcripts reprogram the microRNA transcriptome profile of fibroblasts and partially contribute to CAF formation.

Daniela Likonen, Maria Pinchasi, Einat Beery, Zinab Sarsor, Lorenzo Federico Signorini, Asia Gervits, Roded Sharan, Meir Lahav, Pia Raanani, Orit Uziel.

It is now well accepted that cancer cells change their microenvironment from normal to tumor-supportive state to provide sustained tumor growth, metastasis and drug resistance. These processes are partially carried out by exosomes, nano-sized vesicles secreted from cells, shuttled from donor to recipient cells containing a cargo of nucleic acids, proteins and lipids. By transferring biologically active molecules, cancer-derived exosomes may transform microenvironmental cells to become tumor supportive. Telomerase activity is regarded as a hallmark of cancer. We have recently shown that the transcript of human telomerase reverse transcriptase (hTERT), is packaged in cancer cells derived- exosomes. Following the engulfment of the hTERT transcript into fibroblasts, it is translated into a fully active enzyme [after assembly with its RNA component (hTERC) subunit]. Telomerase activity in the recipient, otherwise telomerase negative cells, provides them with a survival advantage. Here we show that exosomal telomerase might play a role in modifying normal fibroblasts into cancer associated fibroblasts (CAFs) by upregulating [Formula: see text]SMA and Vimentin, two CAF markers. We also show that telomerase activity changes the transcriptome of microRNA in these fibroblasts. By ectopically expressing microRNA 342, one of the top identified microRNAs, we show that it may mediate the proliferative phenotype that these cells acquire upon taking-up exosomal hTERT, providing them with a survival advantage.

DOI: https://doi.org/10.1038/s41598-022-20186-8
Mol Oncol. 2022 Sep 27.

Cancer as an infective disease: The role of EVs in tumorigenesis.

Lucia Robado de Lope, Estela Sánchez-Herrero, Roberto Serna-Blasco, Mariano Provencio, Atocha Romero.

  Cancer is conventionally considered an evolutionary disease where tumor cells adapt to the environment and evolve, eventually leading to the formation of metastasis through the seeding and growth of metastasis-initiating cells in distant organs. Tumor cell and tumor-stroma communication via soluble factors and extracellular vesicles (EVs) is essential for the success of the metastatic process. As the field of EVs advances, growing data support a role of tumor-derived EVs not only in modifying the microenvironment to facilitate tumor progression, but also in inducing changes in cells outside the primary tumor that may lead to a malignant transformation. Thus, an alternative hypothesis has emerged suggesting the conceptualization of cancer as an "infective" disease. Still, tackling EVs as a possible cancer treatment has not been widely explored. A major understanding is needed to unveil possible additional contributions of EVs in progression and metastasis, which may be essential for the development of novel approaches to treat cancer patients. Here, we review the contribution of EVs to cancer progression and the possible implication of these factors in the oncogenic transformation of indolent cells.

Keywords:  Cancer; extracellular vesicles; metastasis; oncogenic transformation

DOI:  https://doi.org/10.1002/1878-0261.13316
Front Oncol. 2022 ;12 943477

Phenformin suppresses angiogenesis through the regulation of exosomal microRNA-1246 and microRNA-205 levels derived from oral squamous cell carcinoma cells.

Dexuan Zhuang, Shuangshuang Wang, Guanyi Liu, Panpan Liu, Huiting Deng, Jianfeng Sun, Chang Liu, Xue Leng, Qun Zhang, Fuxiang Bai, Jun Mi, Xunwei Wu.

  Exosomes secreted by cancer cells are important components in the tumor microenvironment, enabling cancer cells to communicate with each other and with noncancerous cells to play important roles in tumor progression and metastasis. Phenformin, a biguanide antidiabetic drug, has been reported to have a strong antitumor function in multiple types of cancer cells, however little research has been reported about whether phenformin can regulate the secretion of exosomes by cancer cells to regulate the tumor microenvironment and contribute to its antitumor function. Here we found that exosomes (Phen-Exo) derived from phenformin-treated oral squamous cell carcinoma (OSCC) cells significantly suppress the proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro. The inhibition of angiogenesis by Phen-Exo was verified in vivo by matrigel plug angiogenesis assays and by chick chorioallantoic membrane assays. Mechanistically, we discovered that the expression of microRNA-1246 (miR-1246) and microRNA-205 (miR-205) was significantly increased in exosomes secreted by OSCC cells treated with phenformin, while high expression levels of miR-1246 or miR-205 in vascular endothelial cells inhibited their angiogenic effects and decreased expression of the angiogenic factor VEGFA. In conclusion, these results reveal that phenformin can inhibit angiogenesis by regulating the levels of miR-1246 and miR-205 in exosomes secreted by OSCC cells, suggesting that phenformin has the potential to alter the tumor microenvironment to antagonize the growth of OSCCs, which provides a theoretical basis for developing new strategies to treat OSCCs in the future.

Keywords:  angiogenesis; exosomes; miR-1246; miR-205; oral squamous cell carcinoma cells

DOI:  https://doi.org/10.3389/fonc.2022.943477
Cancer Drug Resist. 2022 ;5(3): 612-624

Role of extracellular vesicles secretion in paclitaxel resistance of prostate cancer cells.

Ashish Kumar, Pawan Kumar, Mitu Sharma, Susy Kim, Sangeeta Singh, Steven J Kridel, Gagan Deep.

  Aim: The development of chemotherapy resistance is the major obstacle in the treatment of advanced prostate cancer (PCa). Extracellular vesicles (EVs) secretion plays a significant role among different mechanisms contributing to chemoresistance. Hence, inhibition of EVs release may increase the efficacy of chemotherapeutic drugs against PCa. Methods: Paclitaxel (PTX) resistant PCa cells (PC3-R and DU145-R) were treated with GW4869, a known exosome biogenesis inhibitor. EVs were isolated from the conditioned media by ExoQuick-based precipitation method and characterized for concentration and size distribution by nanoparticle tracking analysis. The effect of GW4869 treatment on the survival and growth of PCa cells was assessed by MTT, and colony formation assays in vitro, and ectopic PC3-R xenografts in male athymic nude mice in vivo. The effect of other EV biogenesis inhibitors, imipramine and dimethyl amiloride (DMA), treatment was also analyzed on the survival of PC3-R cells. Results: GW4869 (10-20 µM) treatment of PTX resistant PCa cells significantly reduced the release of small EVs (50-100 nm size range) while increasing the release of larger EVs (> 150 nm in size), and inhibited their clonogenicity. Moreover, GW4869 (5-20 µM) treatment (24-72h) significantly inhibited the survival of PC3-R cells in a dose-dependent manner. We observed a similar growth inhibition with both imipramine (5-20 µg/mL) and DMA (5-20 µg/mL) treatment in PC3-R cells. Furthermore, GW4869 treatment (IP) in mice bearing PC3-R xenografts significantly reduced the tumor weight (65% reduction, P = 0.017) compared to the vehicle-treated control mice without causing any noticeable toxicity. Conclusion: Inhibiting the release of EVs could sensitize the resistant PCa cells to chemotherapy.

Keywords:  GW4869; Prostate cancer; chemoresistance; extracellular vesicles; paclitaxel

DOI:  https://doi.org/10.20517/cdr.2022.26
Clin Transl Oncol. 2022 Oct 01.

The prognostic and predictive values of differential expression of exosomal receptor tyrosine kinases and associated with the PI3K/AKT/mTOR signaling in breast cancer patients undergoing neoadjuvant chemotherapy.

Gamze Guney Eskiler, Nur Kazan, Ayten Haciefendi, Asuman Deveci Ozkan, Kayhan Ozdemir, Mirac Ozen, Havva Belma Kocer, Fahri Yilmaz, Suleyman Kaleli, Elvan Sahin, Cemil Bilir.

   PURPOSE: Cancer cell-derived exosomes are the mediator of the tumor microenvironment and the molecular content of exosomes presents a promising prognostic or predictive marker in tumor progression and the treatment response of cancer patients. The aim of this study was to identify the expression levels of receptor tyrosine kinases (RTKs) and AKT1 and mTOR before and after neoadjuvant chemotherapy (NACT) in the exosomes of BC patients compared with healthy females.
METHODS: After isolating exosomes in the serum of 25 BC patients and characterization by flow cytometry, the mRNA levels of FGFR2, FGFR3, PDGFRB, AKT1 and mTOR in the exosomes were analyzed by RT-PCR.
RESULTS: Our preliminary findings showed that FGFR2, PDGFRB, AKT1 and mTOR levels were significantly upregulated in BC patients before NACT compared with the healthy group (p < 0.05). Furthermore, the mRNA levels PDGFRB and AKT1 were significantly down-regulated after NACT compared with control. PDGFRB expression level could predict pathological non-response and significantly correlated with tumor size after NACT.
CONCLUSION: Therefore, especially FGFR2, PDGFRB and AKT1 could be a therapeutic target as a prognostic marker, whereas PDGFRB may be a promising predictive indicator of therapy response in BC patients. However, the prognostic or predictive role of RTKs and PI3K/AKT/mTOR signaling in the exosomes should be further investigated in a large patient population.

Keywords:  Breast cancer; Exosomes; PI3K/AKT/mTOR signaling; Receptor tyrosine kinases

DOI:  https://doi.org/10.1007/s12094-022-02959-9
J Oncol. 2022 ;2022 4234116

The Study of Exosomes-Encapsulated mPEG-PLGA Polymer Drug-Loaded Particles for Targeted Therapy of Liver Cancer.

Jiantao Mo, Xuanbo Da, Qiaoxin Li, Jingjing Huang, Le Lu, Hongwei Lu.

The emergence of targeted drugs brings hope to patients with advanced liver cancer. However, due to the complex and diverse environment in the human body, the overall response rate of targeted drugs is not high. Therefore, how to efficiently deliver targeted drugs to tumor sites is a major challenge for current research. The project intends to construct mPEG-PLGA nanoparticles loaded with Sora and encapsulate them with exosomes for targeted therapy of hepatocellular carcinoma. mPEG-PLGA drug-loaded nanoparticles were prepared by the dialysis method and characterized by TEM and DLS. The obtained nanoparticles were incubated with the exosomes of liver cancer cells, and the exosomes-encapsulated drug-loaded nanoparticles (Exo-Sora-NPs) were obtained under pulsed ultrasound conditions, and they were characterized by Western blot, transmission electron microscopy (TEM), and dynamic light scattering (DLS). The toxic effect of Exo-Sora-NPs on liver cancer cells was detected by the CCK-8 experiment. The uptake efficiency of nanoparticles by liver cancer cells was detected by a confocal microscope. The accumulation and infiltration depth of nanomedicine in liver cancer tissues were observed by confocal microscope on frozen sections of liver cancer tissue after the H22 liver cancer subcutaneous tumor transplantation model was constructed. The tumor size, body weight, pathology, and serology analysis of mice were measured after administration. The mPEG-PLGA polymer drug-loaded particles encapsulated by exosomes have high targeting ability and biosafety. To a certain extent, they can target the drug to the tumor site with a smaller systemic response and have a highly effective killing effect on the tumor. Nanodrug-loaded particles encapsulated by exosomes have great potential as drug carriers.

DOI: https://doi.org/10.1155/2022/4234116
Cell Commun Signal. 2022 09 24. 20(1): 152

Exosomal AP000439.2 from clear cell renal cell carcinoma induces M2 macrophage polarization to promote tumor progression through activation of STAT3.

Tianyi Shen, Suqin Miao, Yulin Zhou, Xiaoming Yi, Song Xue, Bowen Du, Chaopeng Tang, Le Qu, Dian Fu, Ruipeng Jia, Haowei He.

   BACKGROUND: Tumorigenic phenotype of M2 tumor-associated macrophages promote tumor progression in response to exosomes cues imposed by tumor cells. However, the effect and underlying mechanisms of clear cell renal cell carcinoma (ccRCC)-derived exosomes (ccRCC-exo) on instructing macrophages phenotype remains unclear.
METHODS: Macrophages were cocultured with ccRCC-exo and then evaluate the polarization of macrophages and migration of ccRCC cells. The effect and mechanism of lncRNA AP000439.2 overexpressed or deleted exosomes on macrophages M2 polarization were examined. Xenograft tumor mice model was used for in vivo validation.
RESULTS: The ccRCC-exo significantly activated macrophages to M2 phenotype presented by increased expression of transforming growth factor-beta (TGF-β) and interleukin 10 (IL-10) at mRNA and protein levels, and these M2 macrophages in turn facilitating the migration of ccRCC cells. LncRNA AP000439.2 was highly enriched in the ccRCC-exo. Overexpression of exosomal AP000439.2 promoted M2 macrophage polarization whereas AP000439.2-deficient exosome had the opposite effects. Nuclear-localized AP000439.2 directly interacted with signal transducer and activator of transcription 3 (STAT3) proteins and phosphorylated STAT3 in macrophages. RNA-Seq results showed overexpression of AP000439.2 activated NF-κB signaling pathway. Silencing of STAT3 suppressed overexpression of AP000439.2-induced up-regulation of TGF-β and IL-10 expression, and p65 phosphorylation. AP000439.2-deleted exosome inhibited tumor growth in vivo.
CONCLUSION: Exosomes from ccRCC deliver AP000439.2 to promote M2 macrophage polarization via STAT3, thus enhancing ccRCC progression, indicating exosomal AP000439.2 might be a novel therapeutic target in ccRCC. Video Abstract.

Keywords:  Clear cell renal cell carcinoma; Exosomes; Macrophage; NF-κB signaling pathway; STAT3; lncRNA AP000439.2

DOI:  https://doi.org/10.1186/s12964-022-00957-6
Int J Pharm. 2022 Sep 21. pii: S0378-5173(22)00768-2. [Epub ahead of print] 122214

MSC-Derived Exosomes Suppress Colorectal Cancer Cell Proliferation and Metastasis via miR-100/mTOR/miR-143 Pathway.

Babak Jahangiri, Mohammad Khalaj-Kondori, Elahe Asadollahi, Leyli Purrafee Dizaj, Majid Sadeghizadeh.

  Exosomes derived from mesenchymal stem cells (MSCs) are mostly responsible for the therapeutic effects of MSCs. To show the therapeutic effects of the human bone marrow MSC-derived exosomes (MSC-Exos) on colorectal cancer and explore the molecular cross-talks between them, CRC cells were treated with the MSC-Exos. We found that MSC-Exos were enriched with miR-100 and miR-143, which effectively downregulated mTOR, Cyclin D1, K-RAS, HK2 while upregulated p-27 expression. All these effects were reversed by concurrent treatment with MSC-Exos and antagomiR-100, confirming that they were caused by exosomal transfer of miR-100 into recipient CRC cells. Moreover, exosomal miR-100 promoted endogenous miR-143 expression. The flow cytometry, MTT and trypan blue assays revealed that MSC-Exos could efficiently suppress proliferation and induce apoptosis of the CRC cells. Furthermore, wound healing, transwell migration and invasion assays confirmed their inhibitory effects on the migration and invasiveness of SW480 cells. We further confirmed these effects by analyzing the expression levels of epithelial to mesenchymal transition (EMT) factors and metastasis-related genes. Results showed that MSC-Exos significantly suppressed the expression of MMP2 and MMP9 (metastasis-related genes), SNAIL and TWIST (EMT-inducing transcription factors), Vimentin and N-cadherin (mesenchymal cell markers), whereas E-cadherin (epithelial cell marker) was remarkably up-regulated. Collectively, our data indicated that MSC-Exos could suppress proliferation, migration, invasion and metastasis while inducing the apoptosis of the CRC cells via miR-100/mTOR/miR-143 axis. Our findings highlight that MSC-Exo treatment as well as miR-100 restoration might be considered as potential therapeutic strategies for CRC.

Keywords:  Colorectal cancer; Exosomes; Mesenchymal stem cells; mTOR; miR-100; microRNAs

DOI:  https://doi.org/10.1016/j.ijpharm.2022.122214
Cancer Sci. 2022 Sep 28.

Clinical impact of bile-derived exosomal miRNAs as novel diagnostic and prognostic biomarkers for biliary tract cancers.

Michihiro Yoshida, Hiroshi Yukawa, Kazuki Hayashi, Itaru Naitoh, Katsuyuki Miyabe, Yasuki Hori, Makoto Natsume, Naruomi Jinno, Akihisa Kato, Kenta Kachi, Go Asano, Hidenori Sahashi, Tadashi Toyohara, Kayoko Kuno, Yusuke Kito, Hiromu Kondo, Atsuyuki Hirano, Fumihiro Okumura, Kaiki Anbe, Yoshinobu Baba, Hiromi Kataoka, Yasuhito Tanaka.

  Sampling of bile juice during endoscopic retrograde cholangiopancreatography (ERCP) has potential benefit of being amenable to the identification of novel biomarkers in liquid biopsy. This study demonstrated a global investigation for exosomal miRNAs in bile to identify potential biomarkers for biliary tract cancers (BTCs). Eighty-eight bile samples collected during ERCP (45 BTC and 43 non-cancer control samples) were enrolled in this study. Eleven BTC samples and 9 control samples were assigned as the discovery set. Exosomes in bile and serum samples were collected using a glass membrane column with size-controlled macro-porous glass (MPG), and exosomal miRNA expression profiles were evaluated using comprehensive miRNA microarray analysis (3D-Gene). For validation, exosomal miRNA in the bile samples of 34 BTCs and 34 controls were comprehensively evaluated using 3D-Gene. In the discovery set, eight exosomal miRNAs in bile were identified as significant aberrant expression markers, while no miRNA with aberrant expression in serum was identified. In a comparison of the discovery and validation sets, miR-451a and miR-3619-3p were identified as reproducible up-regulated markers, and the combination of the two bile miRNAs showed an excellent area under the curve (0.819) value for diagnosing BTCs. In addition, high miR-3619-3p expression in bile reflects poorer prognosis of BTCs (hazard ratio=2.89). MPG-extracted exosomal miRNAs in bile aspirated during ERCP provide a convenient new approach for diagnosing biliary diseases. Bile-derived miRNA analysis with miR-451a and miR-3619-3p represents a potentially valuable diagnostic strategy for identifying BTCs as well as a predictive indicator of BTC prognosis.

Keywords:  bile; biliary tract cancer; exosome; liquid biopsy; miRNA

DOI:  https://doi.org/10.1111/cas.15597
World J Gastroenterol. 2022 Aug 14. 28(30): 4231-4234

Alcohol-related diseases and liver metastasis: Role of cell-free network communication.

Manuel Muro, Aurelia Collados-Ros, Isabel Legaz.

  Alcohol intake is a risk factor for cancer development and metastatic disease progression. Extracellular vesicle (EV)-mediated interorgan communication is assumed to be significant in boosting tumorigenic pathways and disease progression. Recent research indicates that exosomes have a variety of roles in the development of cancer during pathophysiological conditions. The involvement of EV signaling during cancer progression in the alcohol environment is unknown. Therefore, understanding communication networks and the role of EVs as biomarkers can contribute significantly to developing strategies to address the serious public health problems associated with alcohol consumption and cancer.

Keywords:  Alcohol-associated liver disease; Cancer; Exosomes; Liver metastasis

DOI:  https://doi.org/10.3748/wjg.v28.i30.4231
Zhongguo Fei Ai Za Zhi. 2022 Sep 20. 25(9): 689-695

[Research Advances of Immunotherapy of Exosome PD-L1  in Non-small Cell Lung Cancer].

Na Wang, Xia Song.

  Cancer immunotherapy is increasingly popular in the field of cancer treatment, and related research is emerging. For patients with non-small cell lung cancer (NSCLC), in recent years, immune checkpoint inhibitors (ICIs) represented by programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) immunosuppressants, have become one of the most promising treatments for malignant tumors. Immune checkpoint blockade therapy includes anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) mAb, anti-PD-1 mAb and anti-PD-L1 mAb, with the best-known number of PD-L1 immunotherapy. At present, ICIs have achieved very good therapeutic results in clinical treatment, but with less effective efficiency, so we hope to obtain higher therapeutic efficiency. In recent years, exosomal PD-L1 has played an important role in the progress of immunotherapy for NSCLC. This paper reviews the effects of tumor exosomal PD-L1 protein on the tumor microenvironment, the effect prediction of immunotherapy, and as novel therapeutic strategies for immunotherapy in NSCLC. .

Keywords:  Exosome; Immunotherapy; Lung neoplasms; PD-L1

DOI:  https://doi.org/10.3779/j.issn.1009-3419.2022.102.33
Oncol Lett. 2022 Oct;24(4): 356

Tumor-associated macrophage-derived exosomes promote EGFR-TKI resistance in non-small cell lung cancer by regulating the AKT, ERK1/2 and STAT3 signaling pathways.

Shiyang Yuan, Wenjun Chen, Jian Yang, Yuanhai Zheng, Wen Ye, Hui Xie, Lie Dong, Junping Xie.

  The evolutionary properties of organisms lead to the issue of targeted drug resistance. Numerous clinical trials have shown that tumor-associated macrophages (TAMs) in patients with lung cancer adversely affect the clinical efficacy of epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, the mechanism by which TAMs influence the tumor cell response to TKIs remains unclear. The aim of the present study was to investigate the influence of TAM-derived exosomes on the sensitivity of PC9 and HCC827 lung adenocarcinoma cells to the EGFR inhibitor gefitinib. Multiple cytokines were used to induce the differentiation of THP-1 human leukemia monocytes into macrophages in vitro. The obtained cells were identified as TAMs by cytomorphology and flow cytometry. Exosomes were extracted from the TAM culture supernatants and identified using electron microscopy and nanoparticle tracking analysis. Flow cytometry was used to examine the apoptosis of lung adenocarcinoma cells when treated with gefitinib and/or TAM-derived exosomes. In addition, western blotting was used to detect the expression of the key proteins of the AKT, ERK1/2 and STAT3 signaling pathways. TAM-derived exosomes were successfully obtained. The TAM-derived exosomes were shown to affect the proliferation and apoptosis of lung adenocarcinoma cells. Furthermore, the killing effect of gefitinib on the tumor cells was attenuated. The mechanism underlying the effects of the TAM-derived exosomes may be associated with reactivation of the AKT, ERK1/2 and STAT3 signaling pathways. In conclusion, the findings indicate that TAM-derived exosomes promote resistance to gefitinib in non-small cell lung cancer (NSCLC), and the mechanism may be associated with reactivation of the AKT, ERK1/2 and STAT3 signaling pathways. This study may serve as a reference in the exploration of alternative strategies for NSCLC following the development of resistance to EGFR-targeted drugs.

Keywords:  gefitinib; macrophages; non-small cell lung cancer; resistance; tumor microenvironment

DOI:  https://doi.org/10.3892/ol.2022.13476
Curr Med Chem. 2022 09 22.

Responsive role of nanomedicine in the tumor microenvironment and cancer drug resistance.

Pratikshya Sa, Sanjeeb K Sahoo, Fahima Dilnawaz.

  Cancer remains a major worldwide health challenge. Current studies emphasize the tumor microenvironment that plays a vital role in tumor proliferation, invasion, metastasis, and drug resistance. The tumor microenvironment supports the cancer cell to evade conventional treatment such as surgery, radiotherapy, and chemotherapy. Moreover, the components of tumor microenvironments have a major contribution to developing therapy resistance in solid tumors. Therefore, targeting the tumor microenvironment can be a novel approach to achieving advancement in cancer nanomedicine. The recent progress in understanding TME and developing TME-responsive nanoparticles offers a great advantage in treating cancer drug resistance. These nanoparticles developed in response to TME stimuli such as low pH, redox, and hypoxia improve nanomedicine's pharmacokinetic and therapeutic efficacy. This review discusses the various components of the tumor microenvironment responsible for drug resistance and nanomedicine's role in overcoming it.

Keywords:  cancer drug resistance; delivery systems; drug; nanomedicine; pharmacokinetics; tumor microenvironment

DOI:  https://doi.org/10.2174/0929867329666220922111336
Mol Immunol. 2022 Sep 27. pii: S0161-5890(22)00432-1. [Epub ahead of print]151 218-230

The immunosuppressive tumor microenvironment in hepatocellular carcinoma-current situation and outlook.

Zhou Zhou, Yuhao Hu, Yixuan Wu, Qianyi Qi, Jianxin Wang, Lin Chen, Feng Wang.

  Hepatocellular carcinoma (HCC) is one of the most severe malignant tumors that threaten human health, and its incidence is still on the rise recently. In spite of the current emerging treatment strategies, the overall prognosis of liver cancer remains worrying. Currently, immunotherapy has become a new research-active spot. The emergence of immune checkpoints and targeted immune cell therapy can significantly improve the prognosis of HCC. To a large extent, the effect of this immunotherapy depends on the tumor immune microenvironment (TME), an intricate system in which cancer cells and other non-cancer cells display various interactions. Understanding the immunosuppressive situation of these cells, along with the malignant behavior of cancer cells, can assist us to design new therapeutic approaches against tumors. Therefore, it is necessary to clarify the TME of HCC for further improvement of clinical treatment. This review discussed the functions of several immunosuppressive cells and exosomes in the latest research progress of HCC, including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) and tumor-associated neutrophils (TANs) interacted actively to facilitate tumor progression. It further describes the treatment methods targeting them and the potential that needs to be explored in the future.

Keywords:  Exosomes; Hepatocellular carcinoma; Immunosuppressive cells; Immunotherapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.molimm.2022.09.010