bims-exocan 2023-07-16 papers

Issue of 2023–07–16
six papers selected by
Muhammad Rizwan, COMSATS University

Methods Mol Biol. 2023 ;2695 195-212

The Detection of Exosomal PD-L1 in Peripheral Blood.

Rui Wang, Yanjia Yang, Jiajun Huang, Yandan Yao.

Peripheral blood is a source for liquid biopsy, which can meet the requirements of pretreatment disease typing to determine precise targeted therapy and monitoring of posttreatment minimal residual disease monitoring. Compared with ctDNA and CTC, exosomes have a higher concentration, good biostability, biocompatibility, low immunogenicity, and low toxicity in peripheral blood. Tumors generally secrete a large amounts of exosomes, which have potential pathophysiological roles in tumor progression. With the continuous improvement of liquid biopsy technology, many researchers have found that exosomes are the key for tumor PD-L1 to exert its role, which may be the mechanism that leads to PD-L1 and/or PD-1 inhibitor therapy resistance. Namely, tumor-derived exosomes may mediate systemic immunosuppression against PD-1 or PD-L1 inhibitor therapy, endogenous tumor cell-derived exosomal PD-L1, and tumor microenvironment-derived exosomes. Induction of PD-L1 by exosomes may be a crucial mechanisms of exosome-mediated antitumor immune tolerance. This article reviews the relationship between the detection of peripheral blood exosomal PD-L1 and tumor progression and the mechanism of exosomal PD-L1 in tumor immunotherapy.

Keywords: Exosomes; Immunotherapy; Liquid biopsy; PD-L1; Tumor

DOI: https://doi.org/10.1007/978-1-0716-3346-5_13

J Cancer Res Clin Oncol. 2023 Jul 11.

Colorectal cancer-secreted exosomal circ_001422 plays a role in regulating KDR expression and activating mTOR signaling in endothelial cells by targeting miR-195-5p.

Iren Ghafouri, Katayoon Pakravan, Ehsan Razmara, Maryam Montazeri, Fatemeh Rouhollah, Sadegh Babashah.

BACKGROUND: As non-coding RNAs, exosomal circular RNAs (circRNAs) regulate colorectal cancer (CRC) progression, although the functional mechanisms by which such molecules affect the tumor microenvironment are still elusive. Herein, we aimed to explore the potential clinical significance of a signature of five serum-derived circRNAs in CRC and investigated the mechanisms underlying endothelial cell angiogenesis mediated by CRC-secreted exosomal circ_001422.
METHODS: The expression of a signature of five serum-derived circRNAs (circ_0004771, circ_0101802, circ_0082333, circ_0072309, and circ_001422) were measured by RT-qPCR, and their associations with tumor staging and lymph node metastasis were further evaluated in CRC patients. In silico analysis was used to show the relationship between circ_001422, miR-195-5p, and KDR, validated by dual-luciferase reporter and Western blotting assays. CRC cell-derived exosomes were isolated and characterized by scanning electron microscopy and Western blotting. Endothelial cell uptake of PKH26-labeled exosomes was demonstrated using a spectral confocal microscope. In vitro genetic strategies were used to exogenously alter the expression level of circ_001422 and miR-195-5p expression. Cell proliferation assay, transwell migration assay, and capillary tube formation assay were conducted to explore the role of CRC-secreted exosomal circ_001422 in endothelial cell function in vitro.
RESULTS: The expression levels of serum-derived circ_0004771, circ_0101802, circ_0082333, and circ_001422 were significantly higher in CRC and were positively correlated with the lymph node metastasis status. However, circ_0072309 showed a significant down-regulation in CRC than in healthy individuals. Furthermore, a higher expression level of circ_001422 in both cellular and exosomal fractions was found in HCT-116 CRC cells. We found that HCT-116 exosomes considerably enhanced proliferation and migration of endothelial cells through shuttling of circ_001422. We also observed that exosomes derived from HCT-116 cell, but not non-aggressive Caco-2 CRC cells, increased in vitro tubulogenesis of endothelial cells. Importantly, knockdown of circ_001422 impaired the capability of endothelial cells to form the capillary-like tube structures. CRC-secreted circ_001422 acted as an endogenous miR-195-5p sponge to inhibit miR-195-5p activity, which led to increased KDR expression and mTOR signaling activation in endothelial cells. Importantly, ectopic expression of miR-195-5p mimicked the effect of circ_001422 silencing on KDR/mTOR signaling in endothelial cells.
CONCLUSION: This study attributed a biomarker role for circ_001422 in CRC diagnosis and proposed a novel mechanism whereby circ_001422 up-regulates KDR through sponging miR-195-5p. These interactions may give rise to the activation of mTOR signaling and may be a possible clarification for the pro-angiogenesis effects of CRC-secreted exosomal circ_001422 on endothelial cells.

Keywords: Circ_001422; Colorectal cancer; Endothelial cell angiogenesis; Exosomes; miR-195-5p

DOI: https://doi.org/10.1007/s00432-023-05095-1

Curr Drug Deliv. 2023 Jul 12.

Engineered Exosomes for Drug Delivery in Cancer Therapy: A promising approach and application.

Peiwen Fu, Siqi Yin, Huiying Cheng, Wenrong Xu, Jiajia Jiang.

A significant amount of research effort is currently focused on investigating the role of exosomes in various cancers. These tiny vesicles, apart from acting as biomarkers, also play a crucial role in tumor formation and development. Several studies have demonstrated that exosomes can be a drug delivery vehicle for cancer therapy. In this paper, we highlight the key advantages of exosomes as a drug delivery candidate, with a particular focus on their low immunogenicity, natural targeting ability and suitable mechanical properties. Furthermore, we propose that the selection of appropriate exosomes and drug loading methods based on therapeutic goals and product heterogeneity is essential for preparing engineered exosomes. We comprehensively analyzed the superiorities of current drug-loading methods to improve the creation of designed exosomes. Moreover, we systematically review the applications of engineered exosomes in various therapies such as immunotherapy, gene therapy, protein therapy, chemotherapy, indicating that engineered exosomes have the potential to be reliable and, safe drug carriers that can address the unmet needs in cancer clinical practice.

Keywords: Anti-cancer; Drug delivery; Engineered exosomes; Extracellular vesicles; Gene therapy; circRNAs

DOI: https://doi.org/10.2174/1567201820666230712103942

Head Neck. 2023 Jul 14.

Hypoxia-induced tumor exosomes promote angiogenesis through miR-1825/TSC2/mTOR axis in oral squamous cell carcinoma.

Ozel Capik, Rasim Gumus, Omer Faruk Karatas.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is characterized by enhanced angiogenesis resulting in poor prognosis despite improvements in diagnostic/therapeutic techniques. Here, we aimed at investigating potential roles of miR-1825 enclosed in OSCC-derived exosomes on angiogenesis under hypoxic conditions.
METHODS: Effects of miR-1825 mimic/inhibitor as well as hypoxia-induced tumor derived exosomes on human umbilical vein endothelial cells (HUVECs) were evaluated using cell viability, migration/invasion, tube formation, and spheroid-based 3D angiogenesis assays.
RESULTS: Hypoxic conditions caused significant increase in miR-1825 levels in OSCC cells and hiTDEs. miR-1825 alone and within hiTDEs promoted endothelial cell viability, migration, invasion, and angiogenic potential, which is reversed via inhibition of miR-1825 expression. miR-1825 within hiTDEs altered the angiogenesis potential of HUVEC cells via deregulation of TSC2/mTOR axis.
CONCLUSIONS: We showed that hypoxia led to OSCC-derived exosome mediated transfer of miR-1825 to HUVECs and enhanced angiogenesis in OSCC in vitro.

Keywords: exosomes; hypoxia; miR-1825; microRNA; oral squamous cell carcinoma

DOI: https://doi.org/10.1002/hed.27460

Int J Biol Macromol. 2023 Jul 11. pii: S0141-8130(23)02689-2. [Epub ahead of print] 125794

Engineered multitargeting exosomes carrying miR-323a-3p for CRC therapy.

Yechun Pang, Xingshi Chen, Baiying Xu, Yuanzhou Zhang, Shunshun Liang, Jingying Hu, Rui Liu, Xiaoying Luo, YunFeng Wang.

Colorectal cancer (CRC) is in the forefront of malignancies for its high incidence and mortality. 5-Fluorouracil (5-FU) is one of the most widely used effective drugs for the treatment of CRC. However, there is an urgent need in reducing its systemic side effects and chemoresistance, in order to make 5-FU-based chemotherapy more effective in the treatment of CRC. In this study, engineered CRC cells were established to overexpress miR-323a-3p, which was a tumor suppressor that targeted both EGFR and TYMS. Then miR-323a-3p-loaded exosomes (miR-Exo) were obtained with suitable methods of collection and purification. We found that miR-Exo significantly inhibited CRC cell proliferation and induced apoptosis by the way of targeting EGFR directly in the cells, which eventually led to desirable tumor regression in the cell derived xenograft (CDX) and patient derived xenograft (PDX) tumor mice models. Moreover, we discovered that miR-323a-3p released from miR-Exo directly inhibited the upregulation of thymidylate synthase (TYMS) induced by 5-FU-resistence in CRC cells, resulting in the revival of tumor cytotoxicity from 5-FU. MiR-Exo could effectively induce the CRC cell apoptosis by targeting EGFR and TYMS, and enhance the therapeutic effects of 5-FU on CRC. Our work demonstrates the potency of miR-Exo for advanced CRC biotherapy.

Keywords: 5-fluorouracil (5-FU)-resistance; CRC therapy; EGFR; Exosomes; TYMS; miR-323a-3p

DOI: https://doi.org/10.1016/j.ijbiomac.2023.125794

Acta Pharm Sin B. 2023 Jun;13(6): 2645-2662

The suppression of cervical cancer ferroptosis by macrophages: The attenuation of ALOX15 in cancer cells by macrophages-derived exosomes.

Yanlin Luo, Yibing Chen, Huan Jin, Benxin Hou, Hongsheng Li, Xiang Li, Lingfeng Liu, Yuan Zhou, Yonghua Li, Yong Sang Song, Quentin Liu, Zhengzhi Zou.

Induction of cancer cell ferroptosis has been proposed as a potential treatment in several cancer types. Tumor-associated macrophages (TAMs) play a key role in promoting tumor malignant progression and therapy resistance. However, the roles and mechanisms of TAMs in regulating tumor ferroptosis is still unexplored and remains enigmatic. This study shows ferroptosis inducers has shown therapeutic outcomes in cervical cancer in vitro and in vivo. TAMs have been found to suppress cervical cancer cells ferroptosis. Mechanistically, macrophage-derived miRNA-660-5p packaged into exosomes are transported into cancer cells. In cancer cells, miRNA-660-5p attenuates ALOX15 expression to inhibit ferroptosis. Moreover, the upregulation of miRNA-660-5p in macrophages depends on autocrine IL4/IL13-activated STAT6 pathway. Importantly, in clinical cervical cancer cases, ALOX15 is negatively associated with macrophages infiltration, which also raises the possibility that macrophages reduce ALOX15 levels in cervical cancer. Moreover, both univariate and multivariate Cox analyses show ALOX15 expression is independent prognostic factor and positively associated with good prognosis in cervical cancer. Altogether, this study reveals the potential utility of targeting TAMs in ferroptosis-based treatment and ALOX15 as prognosis indicators for cervical cancer.

Keywords: ALOX15; Cervical cancer; Exosome; Ferroptosis; Macrophages infiltration; STAT6; Tumor-associated macrophage; miRNA-660-5p

DOI: https://doi.org/10.1016/j.apsb.2023.03.025