bims-exocan 2022-12-11 papers

bims-exocan

Biomed News

on Exosomes roles in cancer

Issue of 2022–12–11
fourteen papers selected by
Muhammad Rizwan, COMSATS University

Non-small cell lung cancer-derived exosomes promote proliferation, phagocytosis, and secretion of microglia via exosomal microRNA in the metastatic microenvironment.
Exosomes in sarcoma: Prospects for clinical applications.
Dendritic cell derived exosomes loaded neoantigens for personalized cancer immunotherapies.
Exosomes-mediated tumor metastasis through reshaping tumor microenvironment and distant niche.
Tumor-derived exosomes elicit cancer-associated fibroblasts shaping inflammatory tumor microenvironment in head and neck squamous cell carcinoma.
Exosomal miR-628-5p from M1 polarized macrophages hinders m6A modification of circFUT8 to suppress hepatocellular carcinoma progression.
Exosome-transmitted circ_002136 promotes hepatocellular carcinoma progression by miR-19a-3p/RAB1A pathway.
Exploiting the potential of extracellular vesicles as delivery vehicles for the treatment of melanoma.
Cancer-derived exosomal miR-197-3p confers angiogenesis via targeting TIMP2/3 in lung adenocarcinoma metastasis.
Hypoxia-Induced miR-210 Promotes Endothelial Cell Permeability and Angiogenesis via Exosomes in Pancreatic Ductal Adenocarcinoma.
MIR4435-2HG in exosomes promotes gastric carcinogenesis by inducing M2 polarization in macrophages.
Monocytes educated by cancer-associated fibroblasts secrete exosomal miR-181a to activate AKT signaling in breast cancer cells.
Exosomal LINC00460/miR-503-5p/ANLN positive feedback loop aggravates pancreatic cancer progression through regulating T cell-mediated cytotoxicity and PD-1 checkpoint.
Exosomal circRNAs: Novel biomarkers and therapeutic targets for gastrointestinal tumors.

Transl Oncol. 2022 Dec 01. pii: S1936-5233(22)00253-4. [Epub ahead of print]27 101594

Non-small cell lung cancer-derived exosomes promote proliferation, phagocytosis, and secretion of microglia via exosomal microRNA in the metastatic microenvironment.

Peng Chen, Ying Li, Rui Liu, Yi Xie, Yu Jin, Minghuan Wang, Zhiyuan Yu, Wei Wang, Xiang Luo.

  Non-small cell lung cancer (NSCLC) is the most common tumor that metastasizes to the brain. It is now accepted that the successful colonization and growth of tumor cells are determined by the interaction between tumor cells and the tumor microenvironment (TME). Microglia, brain innate immune cells, have been reported to play a vital role in the establishment of brain metastases. As essential mediators of intercellular communications, tumor-derived exosomes have an important role in the pathogenesis and progression of cancer by transferring their cargos to specific recipient cells. The crosstalk between microglia and tumor-derived exosomes has been extensively described. However, it is still unclear whether metastatic NSCLC cells secret exosomes to microglia and regulate the microglial functions. Here, our results showed that microglia aggregated in the brain metastatic sites. Meanwhile, microglia could take up the exosomes derived from NSCLC cells, leading to alterations of microglial morphology and increased proliferation, phagocytosis, and release of inflammatory cytokines including interleukin-6, interleukin-8, and CXCL1. Further investigation indicated that miR1246 was the most enriched microRNA in NSCLC-derived exosomes and mediated the partial effects of exosomes on microglia. Notably, miR1246 was also upregulated in the plasmatic exosomes of NSCLC patients. These results offer a new insight into the impact of NSCLC-derived exosomes on microglia and provide a new potential biomarker for diagnosing NSCLC.

Keywords:  Brain metastases; Exosomes; Microglia; Non–small cell lung cancer; miR1246

DOI:  https://doi.org/10.1016/j.tranon.2022.101594
Crit Rev Oncol Hematol. 2022 Dec 05. pii: S1040-8428(22)00319-5. [Epub ahead of print] 103895

Exosomes in sarcoma: Prospects for clinical applications.

Huali Ye, Linyun Tan, Chongqi Tu, Li Min.

  Sarcoma is a group of rare and heterogeneous mesenchymal tumors, prone to late diagnosis and poor prognosis. Exosomes are cell-derived small extracellular vesicles found in most body fluids and contain nucleic acids, proteins, lipids, and other molecules. Qualitative and quantitative changes of exosomes and the contents are associated with sarcoma progression, exhibiting their potential as biomarkers. Exosomes possess the capacity of evading immune responses, bioactivity for trafficking, tumor tropism, and lesion residence. Thus, exosomes could be engineered as tumor-specific vehicles in drugs and RNA delivery systems. Exosomes might also serve as therapeutic targets in targeted therapy and immunotherapy and be involved in chemotherapy resistance. Here, we provide a comprehensive summary of exosome applications in liquid biopsy-based diagnosis and explore their implications in the delivery system, targeted therapy, and chemotherapy resistance of sarcoma. Moreover, challenges in exosome clinical applications are raised and some future research directions are proposed.

Keywords:  Biomarkers; Delivery vectors; Exosomes; Sarcoma; Therapeutic targets

DOI:  https://doi.org/10.1016/j.critrevonc.2022.103895
J Control Release. 2022 Dec 02. pii: S0168-3659(22)00807-0. [Epub ahead of print]

Dendritic cell derived exosomes loaded neoantigens for personalized cancer immunotherapies.

Ji Li, Jiajia Li, Yiwei Peng, Yitian Du, Zhenzhen Yang, Xianrong Qi.

  Despite the promising potential of cancer vaccine, their efficacy has been limited in clinical trials and improved methods are urgently needed. Here we designed a nanovaccine platform that contains dendritic cell derived exosomes carriers and patient-specific neoantigens for individualized immunotherapies. The nanovaccine exhibited convenient cargo loading and prolonged cargo transportation to the lymph nodes, followed by eliciting potent antigen specific broad-spectrum T-cell and B-cell-mediated immune responses with great biosafety and biocompatibility. Strikingly, delivery of neoantigen-exosome nanovaccine significantly prohibited tumor growth, prolonged survival, delayed tumor occurrences with long-term memory, eliminated the lung metastasis in the therapeutic, prophylactic and metastatic B16F10 melanoma as well as therapeutic MC-38 models, respectively. Additionally, exosome-based nanovaccine demonstrated synergistic antitumor response superior to liposomal formulation due to presence of exosomal proteins. Collectively, our research indicated improved strategies for cell free vaccines and suggested exosome-based nanoplatform for cancer immunotherapy and personalized nanotechnology. These findings represent a powerful pathway to generate individualized nanovaccine rapidly for clinical application.

Keywords:  Cancer immunotherapy; Dendritic cell derived exosomes; Neoantigen; Personalized nanovaccine

DOI:  https://doi.org/10.1016/j.jconrel.2022.11.053
J Control Release. 2022 Dec 06. pii: S0168-3659(22)00803-3. [Epub ahead of print]353 327-336

Exosomes-mediated tumor metastasis through reshaping tumor microenvironment and distant niche.

Xinyi Luo, Yang Li, Zhenglai Hua, Xiaoxia Xue, Xiangpeng Wang, Mingshi Pang, Cheng Xiao, Hongyan Zhao, Aiping Lyu, Yuanyan Liu.

  Tumor-derived exosomes (TDEs) are the particular communicator and messenger between tumor cells and other cells containing cancer-associated genetic materials and proteins. And TDEs who are also one of the important components consisting of the tumor microenvironment (TME) can reshape and interact with TME to promote tumor development and metastasis. Moreover, due to their long-distance transmission by body fluids, TDEs can facilitate the formation of pre-metastatic niche to support tumor colonization. We discuss the main characteristics and mechanism of TDE-mediated tumor metastasis by reshaping TME and pre-metastatic niche as well as the potential of TDEs for diagnosing tumor and predicting future metastatic development.

Keywords:  Metastasis; Pre-metastatic niche; Prediction; Tumor microenvironment; Tumor-derived exosomes

DOI:  https://doi.org/10.1016/j.jconrel.2022.11.050
Oral Oncol. 2022 Nov 30. pii: S1368-8375(22)00560-7. [Epub ahead of print]136 106270

Tumor-derived exosomes elicit cancer-associated fibroblasts shaping inflammatory tumor microenvironment in head and neck squamous cell carcinoma.

Ikko Mito, Hideyuki Takahashi, Reika Kawabata-Iwakawa, Momoka Horikawa, Shota Ida, Hiroe Tada, Toshiyuki Matsuyama, Kiyoshi Misawa, Shigeki Takeda, Kazuaki Chikamatsu.

   OBJECTIVES: Exosome-mediated reciprocal crosstalk between tumor and stromal cells plays a crucial role in tumor development and progression. This study investigated whether exosomes released from head and neck squamous cell carcinoma (HNSCC) tumor cells can convert normal fibroblasts into cancer-associated fibroblasts (CAF)-like cells and further analyzed the functional characterization of fibroblasts educated by tumor-derived exosomes.
MATERIALS AND METHODS: Exosomes secreted from HNSCC cell lines were isolated and normal fibroblasts were established from normal oropharyngeal mucosa. The effects of the exosomes on fibroblasts were examined by proliferation and migration assays, and exosome-educated fibroblasts were analyzed for the expression of eight genes (IL1B, IL6, CXCL8, TGFB1, ACTA2, FAP, CD274, and PDCD1LG2) by RT-qPCR. Moreover, T cells or CD14-positive cells were co-cultured with culture supernatants from exosome-educated fibroblasts. T-cell proliferation and macrophage polarization were examined using flow cytometry. Then, RNA sequencing (RNA-seq) of exosome-educated fibroblasts and the corresponding control fibroblasts was performed.
RESULTS: Tumor-derived exosomes enhanced fibroblast proliferation and migration. Moreover, gene expression analysis revealed upregulation of the gene expression of proinflammatory cytokines and immunoregulatory genes, and activated fibroblast marker genes. The culture supernatants of tumor-derived exosome-educated fibroblasts suppressed T cell proliferation and the induction of protumoral macrophages compared with those of control fibroblasts. Next, comprehensive RNA-seq analysis data revealed the activation of 11 signaling pathways, including IL-6- and IL-17-related signaling.
CONCLUSION: These results indicate that HNSCC tumor cells induce and/or differentiate into CAFs through exosome-based cell-to-cell communication to create an inflammatory tumor microenvironment.

Keywords:  Cancer-associated fibroblast; Exosome; Head and neck squamous cell carcinoma (HNSCC); Tumor microenvironment

DOI:  https://doi.org/10.1016/j.oraloncology.2022.106270
Cell Mol Biol Lett. 2022 Dec 06. 27(1): 106

Exosomal miR-628-5p from M1 polarized macrophages hinders m6A modification of circFUT8 to suppress hepatocellular carcinoma progression.

Liyan Wang, Xiaoyuan Yi, Xuhua Xiao, Qinghua Zheng, Lei Ma, Bin Li.

   BACKGROUND: Hepatocellular carcinoma (HCC) is the most common type of liver cancer. CircFUT8 has been shown to be upregulated in cancers, but its function in HCC remains unclear. Tumor-associated macrophages (TAMs) are one of the main components of the tumor microenvironment (TME), and M1 macrophages function as tumor suppressors in cancers. Exosomes exert an important role in the TME, and circRNAs can be modified by m6A. We investigated the function of circFUT8 in HCC and its interaction with exosomes, M1 macrophages, and m6A.
METHODS: CircFUT8 expression was detected in HCC cells, and its effects on HCC cell growth were verified through functional assays. Mechanism assays including RNA pull down, RNA-binding protein immunoprecipitation (RIP), and luciferase reporter assays were undertaken to verify how circFUT8 may interact with miR-628-5p, and how these molecules may modulate HCC cell malignancy via interacting with exosomes and macrophages.
RESULTS: CircFUT8 was upregulated in HCC cells and it accelerated HCC cell growth. Exosomes derived from M1 macrophages transferred miR-628-5p to HCC cells to inhibit human methyltransferase-like 14 (METTL14) expression. METTL14 promoted circFUT8 m6A modification and facilitated its nuclear export to the cytoplasm, where M1 macrophages regulated the circFUT8/miR-552-3p/CHMP4B pathway, thereby suppressing HCC progression.
CONCLUSION: M1 macrophages-derived exosomal miR-628-5p inhibited the m6A modification of circFUT8, inhibiting HCC development.

Keywords:  Exosomes; Hepatocellular carcinoma; M1 macrophages; circFUT8; m6A modification

DOI:  https://doi.org/10.1186/s11658-022-00406-9
BMC Cancer. 2022 Dec 07. 22(1): 1284

Exosome-transmitted circ_002136 promotes hepatocellular carcinoma progression by miR-19a-3p/RAB1A pathway.

Peng Yuan, Jinhua Song, Fei Wang, Baoan Chen.

   BACKGROUND: Circular RNAs (circRNAs) are enriched in exosomes and are extremely stable. Exosome-mediated intercellular transfer of specific biologically active circRNA molecules can drive the transformation of the tumor microenvironment and accelerate or inhibit the local spread and multifocal growth of hepatocellular carcinoma (HCC). In this study, we explored in depth about the biological roles of HCC cell-derived exosomes and exosome-transported circRNAs on HCC in vivo and in vitro.
METHODS: Exosomes extracted from HCC cells (Huh7 and HA22T) were characterized using transmission electron microscopy, nanoparticle size tracer analysis, and western blotting. Exosomes were observed for endocytosis using fluorescent labeling. The effects of HCC cell-derived exosomes and the circ_002136 they carried on cell growth, metastasis and apoptosis were determined by CCK-8 assay, transwell assay, flow cytometry analysis and TUNEL staining, respectively. The expressions of circ_002136, miR-19a-3p and RAB1A were detected by quantitative RT-PCR (qRT-PCR). Targeted binding between miR-19a-3p and circ_002136 or RAB1A was predicted and verified by bioinformatics analysis, dual-luciferase reporter and RNA pull-down experiments. The in vivo effect of circ_002136 was determined by constructing a xenograft tumor model.
RESULTS: The findings revealed that Huh7 and HA22T exosomes conferred enhanced viability as well as invasive ability to recipient HCC cells. Circ_002136 was shown for the first time to be differentially upregulated in HCC tissues and cells and transferred by HCC cell-derived exosomes. More importantly, selective silencing of circ_002136 depleted the malignant biological behaviors of HCC exosome-activated Huh7 and HA22T cells. Depletion of circ_002136 in vivo effectively retarded the growth of HCC xenograft tumors. Furthermore, a well-established circ_002136 ceRNA regulatory network was constructed, namely circ_002136 blocked miR-19a-3p expression, elevated RAB1A expression activity and stimulated HCC development. Finally, high levels of circ_002136 or RAB1A, as well as low levels of miR-19a-3p, negatively affected HCC patient survival.
CONCLUSION: The study on circ_002136 provides good data to support our insight into the mechanism of to-be-silenced circRNA as a therapeutic agent in the progression of HCC.

Keywords:  Exosome; Hepatocellular carcinoma; RAB1A; circ_002136; miR-19a-3p

DOI:  https://doi.org/10.1186/s12885-022-10367-z
Front Bioeng Biotechnol. 2022 ;10 1054324

Exploiting the potential of extracellular vesicles as delivery vehicles for the treatment of melanoma.

Chongchao Hou, Qiang Wu, Lizhou Xu, Rongwei Cui, Rongying Ou, Danyang Li, Yunsheng Xu.

  Melanoma, the most aggressive skin cancer that originated from genetic mutations in the melanocytes, is still a troublesome medical problem under the current therapeutic approaches, which include surgical resection, chemotherapy, photodynamic therapy, immunotherapy, biochemotherapy and targeted therapy. Nanotechnology has significantly contributed to the development of cancer treatment in the past few years, among which extracellular vesicles (EVs) are nanosized lipid bilayer vesicles secreted from almost all cells that play essential roles in many physiological and pathological processes. In terms of melanoma therapy, the unique physicochemical properties of EVs make them promising nanocarriers for drug transportation compared to other synthetic nanocarriers. Moreover, EVs can be further engineered to maximize their drug delivery potential. Herein, in this minireview, we gave a brief overview of EV-based drug delivery strategies for melanoma therapy, in which different therapeutics delivered via EVs were summarized. We also highlighted the current progress of the EV-based delivery platform for melanoma therapy in clinical trials. The obstacles to applying exosomes in clinical practice toward further translation of EVs melanoma therapy were also discussed at the end. In summary, EVs offer promising prospects for melanoma therapy, whilst the ways for unlocking EVs' full potential in melanoma therapies should be further investigated by solving relevant issues which hamper EVs-based melanoma therapy translation in the future.

Keywords:  chemotherapy; drug delivery; endogenous miRNAs; extracellular vesicle; immunotherapy; melanoma; photothermal therapy (PPT); radiotherapy

DOI:  https://doi.org/10.3389/fbioe.2022.1054324
Cell Death Dis. 2022 Dec 09. 13(12): 1032

Cancer-derived exosomal miR-197-3p confers angiogenesis via targeting TIMP2/3 in lung adenocarcinoma metastasis.

Rui-Min Chang, Yao Fu, Jun Zeng, Xiao-Yan Zhu, Yang Gao.

Cancer-derived exosomal miRNAs are implicated in tumorigenesis and development of lung adenocarcinoma (LUAD). The objective of this study is to unravel the biological function of exosomal miR-197-3p in LUAD metastasis. qRT-PCR showed that elevated miR-197-3p in LUAD tissues was positively correlated with LUAD metastasis. CCK-8, tube formation, transwell and wound healing assays revealed that exosomal miR-197-3p from LUAD cells promoted the proliferation, angiogenesis and migration of HUVECs in vitro. LUAD cells-derived exosomal miR-197-3p also facilitated tumor growth and angiogenesis in LUAD cells-derived tumor xenograft model. TIMP2 and TIMP3 were identified as target genes of miR-197-3p in HUVECs by bioinformatics analysis and luciferase reporter assay. Functional studies illustrated that exosomal miR-197-3p promoted angiogenesis and migration via targeting TIMP2 and TIMP3 in HUVECs. In vivo data further supported that exosomal miR-197-3p promoted lung metastasis via TIMP2/3-mediated angiogenesis. In conclusion, LUAD cells-derived exosomal miR-197-3p conferred angiogenesis via targeting TIMP2/3 in LUAD metastasis.

DOI: https://doi.org/10.1038/s41419-022-05420-5
Biochem Res Int. 2022 ;2022 7752277

Hypoxia-Induced miR-210 Promotes Endothelial Cell Permeability and Angiogenesis via Exosomes in Pancreatic Ductal Adenocarcinoma.

Guo Wu, Xiaojie Ding, Gang Quan, Jianwei Xiong, Qiang Li, Zhonghu Li, Yaqin Wang.

Background: Exosomes have been proven to play important diagnostic, regulatory, or communication roles in tumorigenesis, tumor progression, or metastasis; in recent studies, lots of molecules, including miRNAs, were found to be aberrantly expressed in tumor exosomes and were correlated with tumor development. However, studies about the expression, relationship, or control mechanisms of miRNAs in exosomes in pancreatic ductal adenocarcinoma (PDAC) are scarce and urgently needed. The aim of this article was to identify and investigate abnormally expressed miRNAs in PDAC exosomes in vivo and in vitro.
Methods: Microarray studies were used to detect aberrantly expressed miRNAs in PDAC exosomes, and miR-210 expression in cells or exosomes was further analyzed by qRT-PCR. Bioinformatics analyses, dual-luciferase assays, WB, and other assays were utilized to explore the miRNA molecular mechanisms. The living cell coculture model and immunofluorescence analysis were employed to image the communication between PDAC cells and endothelial cells. Other biological experiments in the study include a real-time intravital imaging system, EdU, transwell, xenograft models, and so on.
Results: miR-210 is significantly expressed in PDAC exosomes and malignant cells. High miR-210 significantly facilitated tumor angiogenesis, cell invasion, and proliferation in PDAC cells. Further mechanistic detection revealed that miR-210 negatively regulated EFNA3 expression and participated in the PI3K/AKT/VEGFA or Wnt/Β-catenin/RHOA pathways, thus promoting tumor angiogenesis and cellular permeability. PDAC cells promote endothelial angiogenesis or permeability via miR-210 transmission by tumor exosomes. Exosomal miR-210 promotes PDAC progression in vivo. Further detection of PDAC plasma exosomal miR-210 suggests that exosomal miR-210 expression was high and significantly associated with vascular invasion and TNM stage and was an independent risk factor for PDAC overall survival.
Conclusions: PDAC cell-secreted exosomes could promote angiogenesis and cellular permeability of neighboring endothelial angiogenesis or permeability via miR-210 transmission. Exosomal miR-210 may play important roles in tumor biology and may be a useful prognostic marker in PDAC.

DOI: https://doi.org/10.1155/2022/7752277
Front Oncol. 2022 ;12 1017745

MIR4435-2HG in exosomes promotes gastric carcinogenesis by inducing M2 polarization in macrophages.

Chaofeng Li, Zhengju Chen, Jinli Gao, Tao Tang, Lei Zhou, Guochao Zhang, Dongdong Zhang, Chao Shen, Lei Guo, Tao Fu.

  Gastric cancer (GC) is a cancer with a high mortality rate. lncRNAs play a role in regulating GC tumorigenesis. In this paper, we analyzed differentially expressed lncRNAs between GC and adjacent normal tissues using multiple bioinformatics tools to identify new potential targets in GC. Cell viability and migration ability were detected using the Cell Counting Kit-8 (CCK-8) and transwell assays, MIR4435-2HG was negatively correlated with the survival rate of GC patients, and by inhibiting the activity of MIR4435-2HG, the viability and migration ability of GC cells could be reduced. In addition, RT- qPCR and western blot to detect gene and protein level expression, transmission electron microscopy and nanoparticle tracking analysis (NTA) to study the efficiency of exosome isolation, and flow cytometry to observe cell differentiation were employed, delivery of MIR4435-2HG shRNA via MKN45 cell-derived exosomes significantly reversed the MKN45 exosome-induced M2 polarization in macrophages. Furthermore, the low expression of MIR4435-2HG in MKN45 cell-derived exosomes inhibited the Jagged1/Notch and JAK1/STAT3 pathways in macrophages; MIR4435-2HG downregulated exosomes were found to significantly inhibit GC tumor growth in vivo by establishing a mouse model. In short, MKN45 cell-derived exosomes deliver lncRNA MIR4435-2HG, which promotes gastric carcinogenesis by inducing macrophage M2 polarization.

Keywords:  GC; JAK1/STAT3; Jagged1/Notch; MIR4435-2HG; MKN45

DOI:  https://doi.org/10.3389/fonc.2022.1017745
J Transl Med. 2022 Dec 03. 20(1): 559

Monocytes educated by cancer-associated fibroblasts secrete exosomal miR-181a to activate AKT signaling in breast cancer cells.

Katayoon Pakravan, Majid Mossahebi-Mohammadi, Mohammad H Ghazimoradi, William C Cho, Majid Sadeghizadeh, Sadegh Babashah.

   BACKGROUND: Cancer-associated fibroblasts (CAFs), one of the major components of the tumor stroma, contribute to an immunosuppressive tumor microenvironment (TME) through the induction and functional polarization of protumoral macrophages. We have herein investigated the contribution of CAFs to monocyte recruitment and macrophage polarization. We also sought to identify a possible paracrine mechanism by which CAF-educated monocytes affect breast cancer (BC) cell progression.
METHODS: Monocytes were educated by primary CAFs and normal fibroblast (NF); the phenotypic alterations of CAF- or NF-educated monocytes were measured by flow cytometry. Exosomes isolated from the cultured conditioned media of the educated monocytes were characterized. An in vivo experiment using a subcutaneous transplantation tumor model in athymic nude mice was conducted to uncover the effect of exosomes derived from CAF- or NF-educated monocytes on breast tumor growth. Gain- and loss-of-function experiments were performed to explore the role of miR-181a in BC progression with the involvement of the AKT signaling pathway. Western blotting, enzyme-linked immunosorbent assay, RT-qPCR, flow cytometry staining, migration assay, immunohistochemical staining, and bioinformatics analysis were performed to reveal the underlying mechanisms.
RESULTS: We illustrated that primary CAFs recruited monocytes and established pro-tumoral M2 macrophages. CAF may also differentiate human monocyte THP-1 cells into anti-inflammatory M2 macrophages. Besides, we revealed that CAFs increased reactive oxygen species (ROS) generation in THP-1 monocytes, as differentiating into M2 macrophages requires a level of ROS for proper polarization. Importantly, T-cell proliferation was suppressed by CAF-educated monocytes and their exosomes, resulting in an immunosuppressive TME. Interestingly, CAF-activated, polarized monocytes lost their tumoricidal abilities, and their derived exosomes promoted BC cell proliferation and migration. In turn, CAF-educated monocyte exosomes exhibited a significant promoting effect on BC tumorigenicity in vivo. Of clinical significance, we observed that up-regulation of circulating miR-181a in BC was positively correlated with tumor aggressiveness and found a high level of this miRNA in CAF-educated monocytes and their exosomes. We further clarified that the pro-oncogenic effect of CAF-educated monocytes may depend in part on the exosomal transfer of miR-181a through modulating the PTEN/Akt signaling axis in BC cells.
CONCLUSIONS: Our findings established a connection between tumor stromal communication and tumor progression and demonstrated an inductive function for CAF-educated monocytes in BC cell progression. We also proposed a supporting model in which exosomal transfer of miR-181a from CAF-educated monocytes activates AKT signaling by regulating PTEN in BC cells.

Keywords:  AKT signaling; Breast cancer; Cancer-associated fibroblasts; Exosomes; Immunosuppressive tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1186/s12967-022-03780-2
Cancer Cell Int. 2022 Dec 08. 22(1): 390

Exosomal LINC00460/miR-503-5p/ANLN positive feedback loop aggravates pancreatic cancer progression through regulating T cell-mediated cytotoxicity and PD-1 checkpoint.

Jun Yao, Ruoyu Gao, Minghan Luo, Defeng Li, Liliangzi Guo, Zichao Yu, Feng Xiong, Cheng Wei, Benhua Wu, Zhenglei Xu, Dingguo Zhang, Jianyao Wang, Lisheng Wang.

   BACKGROUND: Long non-coding RNA (lncRNA) LINC00460 is an onco-lncRNA in a variety of cancers, including pancreatic cancer (PC). This study is aimed to investigate the regulatory mechanisms of LINC00460 in PC.
METHODS: The tumor and adjacent normal tissues were collected from 73 PC patients. The expression of LINC00460, miR-503-5p, and ANLN was detected using qRT-PCR. We then analyzed the proliferation, migration, invasion, and apoptosis/cell cycle of PC cells by performing the MTT/EdU, transwell, and flow cytometry assays, respectively. The xenograft tumor model were utilized to confirm the effect of LINC00460 knockdown on PC through anti-PD-1 therapy in vivo, and the sensitivity of PANC-1 cells to the cytotoxicity of CD8+ T cells in vitro. Western blotting was used to determine the protein levels. A co-culture model was utilized to explore the effects of exosomes on macrophages.
RESULTS: LINC00460 was up-regulated in PC tissues and cells. LINC00460 knockdown suppressed cell proliferation, migration, and invasion, facilitated cell apoptosis and G0/G1 phase arrest, and inhibited the tumor growth through anti-PD-1 therapy. Both miR-503-5p down-regulation and ANLN up-regulation reversed the effects of LINC00460 knockdown on inhibiting the proliferation, migration and invasion, and on promoting the apoptosis, G0/G1 phase arrest, and the sensitivity of PC cells to the cytotoxicity of CD8+ T cells. Exosomes were uptaken by the ambient PC cells. PANC-1 cells-derived exosomal LINC00460-induced M2 macrophage polarization accelerates the cell migration and invasion.
CONCLUSIONS: LINC00460 silencing attenuates the development of PC by regulating the miR-503-5p/ANLN axis and exosomal LINC00460-induced M2 macrophage polarization accelerates the migration and invasion of PANC-1 cells, thus LINC00460 may act as a possible therapeutic target for treating PC.

Keywords:  ANLN; Exosomes; LINC00460; M2 polarization; Pancreatic cancer; miR-503-5p

DOI:  https://doi.org/10.1186/s12935-022-02741-5
Biomed Pharmacother. 2022 Nov 30. pii: S0753-3322(22)01442-1. [Epub ahead of print]157 114053

Exosomal circRNAs: Novel biomarkers and therapeutic targets for gastrointestinal tumors.

Dongli Wang, Rong Li, Jiajia Jiang, Hui Qian, Wenrong Xu.

  Despite the high prevalence of gastrointestinal tumors, early diagnosis and treatment of these tumors is limited by the lack of effective and specific biomarkers and therapeutic targets. Exosomes carry active molecules to mediate cell-to-cell communication, especially in the tumor microenvironment, and are promising biomarkers and therapeutic targets for cancer. Circular RNAs (circRNAs) are stably enriched in exosomes and show a unique circular structure, high stability, conservation, and tissue specificity. Exosomal circRNAs play important roles in regulating cell proliferation, metastasis, angiogenesis, metabolism, and the immune microenvironment of gastrointestinal tumors and exhibit great potential as tumor biomarkers and anti-tumor targets or tools. This review briefly introduces the characteristics and functions of circRNAs and exosomes, and systematically describes the biological roles and mechanisms of exosomal circRNAs in gastrointestinal tumors. This article also summarizes the detection methodology of exosomal circRNAs and discusses their clinical significance as biomarkers and targets for gastrointestinal tumors.

Keywords:  Biomarker; CircRNA; Exosome; Gastrointestinal tumors; Therapeutic target

DOI:  https://doi.org/10.1016/j.biopha.2022.114053