bims-engexo 2024-12-15 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2024–12–15
nine papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Exosomes as carriers to stimulate an anti-cancer immune response in immunotherapy and as predictive markers.
Exosomes and SARS-CoV-2 infection.
Exosomes and tumor virus interlink: A complex side of cancer.
M1 macrophage-derived exosomes alleviate leukemia by causing mitochondrial dysfunction.
The significance of exosomal non-coding RNAs (ncRNAs) in the metastasis of colorectal cancer and development of therapy resistance.
Diversity of the Circulating Tumor Markers: Perspectives of a Multimodal Liquid Biopsy.
The imprinted Igf2-Igf2r axis is critical for exosome biogenesis during the early development of bovine placenta.
Pseudomonas aeruginosa- mediated cardiac dysfunction is driven by extracellular vesicles released during infection.
Tumor exosomal RNPEP promotes lung metastasis of liver cancer via inducing cancer-associated fibroblast activation.

Biochem Pharmacol. 2024 Dec 06. pii: S0006-2952(24)00700-7. [Epub ahead of print]232 116699

Exosomes as carriers to stimulate an anti-cancer immune response in immunotherapy and as predictive markers.

Lili Nie, Jingru Ma, Yang Yu, Ying Tao, Zhidu Song, Jian Li.

  During this era of rapid advancements in cancer immunotherapy, the application of cell-released small vesicles that activate the immune system is of considerable interest. Exosomes are cell-derived nanovesicles that show great promise for the immunological treatment of cancer because of their immunogenicity and molecular transfer capacity. Recent technological advancements have enabled the identification of functional functions that exosome cargoes perform in controlling immune responses. Exosomes are originated specifically from immune cells and tumor cells and they show unique composition patterns directly related to the immunotherapy against cancer. Exosomes can also deliver their cargo to particular cells, which can affect the phenotypic and immune-regulatory functions of those cells. Exosomes can influence the course of cancer and have therapeutic benefits by taking part in several cellular processes; as a result, they have the dual properties of activating and restraining cancer. Exosomes have tremendous potential for cancer immunotherapy; they may develop into the most powerful cancer vaccines and carriers of targeted antigens and drugs. Comprehending the potential applications of exosomes in immune therapy is significant for regulating cancer progression. This review offers an analysis of the function of exosomes in immunotherapy, specifically as carriers that function as diagnostic indicators for immunological activation and trigger an anti-cancer immune response. Moreover, it summarizes the fundamental mechanism and possible therapeutic applications of exosome-based immunotherapy for human cancer.

Keywords:  Cancer immunotherapy; Exosomes; Immune activation; Immune cell-derived exosomes; Nanovesicles; Tumor-derived exosomes

DOI:  https://doi.org/10.1016/j.bcp.2024.116699
Front Immunol. 2024 ;15 1467109

Exosomes and SARS-CoV-2 infection.

Liuying Li, Zixuan Yang, Jia Li.

  Exosomes, which are small extracellular vesicles, are of particular interest in studies on SARS-CoV-2 infection because of their crucial role in intercellular communication. These vesicles are released by several cell types and are rich in "cargo" such as proteins, lipids, and nucleic acids, which are vital for regulating immune response and viral pathogenesis. Exosomes have been reported to be involved in viral transmission, immune escape mechanisms, and illness development in SARS-CoV-2 infection. This review examines the current research on the contribution of exosomes to the interplay between the virus and host cells, highlighting their potential as diagnostic biomarkers and therapeutic targets in combating COVID-19.

Keywords:  COVID-19; SARS-CoV-2; exosomes; immunoregulation; interplay

DOI:  https://doi.org/10.3389/fimmu.2024.1467109
Pathol Res Pract. 2024 Nov 28. pii: S0344-0338(24)00658-7. [Epub ahead of print]266 155747

Exosomes and tumor virus interlink: A complex side of cancer.

Ibrahim S Topiwala, Aparna Ramachandran, Meghana Shakthi A, Ranjini Sengupta, Rajib Dhar, Arikketh Devi.

  Extracellular Vesicles (EVs) based cancer research reveals several complicated sides of cancer. EVs are classified as several subpopulations such as microvesicles, apoptotic bodies, and exosomes. In cancer, exosomes play a significant role as a cellular messenger in tumor development and progression. Tumor-derived exosomes (TEXs) are also a theranostic tool for cancer. Tumor virus-infected cell-derived EVs promote cancer development. Exosomes (a subpopulation of EVs) play a significant role in converting noninfecting cells to infected cells. It transports several biological active cargo (DNA, RNA, protein, and virions) towards the noninfected cells. This cellular transport enhances infection rates via reprogramming of noninfected cells. In this review, we explore tumor viruses, exosomes and tumor viruses interlink, the theranostic landscape of exosomes in tumor virus-associated cancer and the future orientation of exosomes-based virus oncology.

Keywords:  Cancer; Exosomes; Extracellular vesicles; Oncogenic virus

DOI:  https://doi.org/10.1016/j.prp.2024.155747
Ann Hematol. 2024 Dec 12.

M1 macrophage-derived exosomes alleviate leukemia by causing mitochondrial dysfunction.

Wenjuan Li, Rufei Ma, Xiaozhen Fan, Zheng Xiao.

  Acute myeloid leukemia (AML) is one type of blood cancer that initially has a high cure rate but frequently relapses and leading to death. Therefore, there is an urgent need for innovative AML treatments. The leukemia C1498 cells were co-cultured with M1 macrophage-derived exosomes (M1-exo), and the proliferation and apoptosis of C1498 cells were investigated using CCK-8 and flow cytometry, respectively. qPCR and Western blot were applied to determine the PGAM5 expression in M1-exo treated C1498 cells. The role of M1-exo-derived PGAM5 in mitochondria was examined via fluorescence staining. The anti-inflammatory effects of M1-exo-derived PGAM5 and M1-exo were evaluated by flow cytometry, HE staining, and immunohistochemistry in xenograft and nude mouse tumorigenic models. M1-exo exhibited a potent capability to attenuate C1498 cell proliferation, and induce cell apoptosis. In vivo experimentation demonstrated that administration of M1-exo led to a reduction in leukocyte count, alleviated inflammatory infiltration, decreased liver and spleen weights, and significantly diminished tumor size. PGAM5 was elevated in M1-exo, and knockdown of PGAM5 in C1498 cells and M1-exo enhanced proliferation and reduced apoptosis in C1498 cells. Concurrently, M1-exo-derived PGAM5 decreased mitochondrial membrane potential and increased calcium influx in vitro. In vivo, studies showed that knockdown of PGAM5 in M1-exo elevated liver and spleen weights, augmented tumor size, and intensified hepatic inflammatory infiltration. Our study reveals that M1-exo induces mitochondrial dysfunction against leukemia through PGAM5.

Keywords:  Exosomes; Leukemia; M1 macrophage; Mitochondria; PGAM5

DOI:  https://doi.org/10.1007/s00277-024-06138-4
Gene. 2024 Dec 04. pii: S0378-1119(24)01022-9. [Epub ahead of print]937 149141

The significance of exosomal non-coding RNAs (ncRNAs) in the metastasis of colorectal cancer and development of therapy resistance.

Omid Rahbar Farzam, Sahand Eslami, Ali Jafarizadeh, Sania Ghobadi Alamdari, Reza Dabbaghipour, Shima Alizadeh Nobari, Behzad Baradaran.

  Colorectal cancer (CRC) represents a common type of carcinoma with significant mortality rates globally. A primary factor contributing to the unfavorable treatment outcomes and reduced survival rates in CRC patients is the occurrence of metastasis. Various intricate molecular mechanisms are implicated in the metastatic process, leading to mortality among individuals with CRC. In the realm of intercellular communication, exosomes, which are a form of extracellular vesicle (EV), play an essential role. These vesicles act as conduits for information exchange between cells and originate from multiple sources. By fostering a microenvironment conducive to CRC progression, exosomes and EVs significantly influence the advancement of the disease. They contain a diverse array of molecules, including messenger RNAs (mRNAs), non-coding RNAs (ncRNAs), proteins, lipids, and transcription factors. Notably, ncRNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are prominently featured within exosomes. These ncRNAs have the capacity to regulate various critical molecules or signaling pathways, particularly those associated with tumor metastasis, thereby playing a crucial role in tumorigenesis. Their presence indicates a substantial potential to affect vital aspects of tumor progression, including proliferation, metastasis, and resistance to treatment. This research aims to categorize exosomal ncRNAs and examine their functions in colorectal cancer. Furthermore, it investigates the clinical applicability of novel biomarkers and therapeutic strategies in CRC. Abbreviations: ncRNAs, non-coding RNAs; CRC, Colorectal cancer; EV, extracellular vesicle; mRNAs, messenger RNAs; miRNAs, microRNAs; lncRNAs, long non-coding RNAs; circRNAs, circular RNAs; HOTTIP, HOXA transcript at the distal tip; NSCLC, non-small cell lung cancer; 5-FU, 5-fluorouracil; OX, Oxaliplatin; PDCD4, programmed cell death factor 4; Tregs, regulatory T cells; EMT, epithelial-mesenchymal transition; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3; USP2, ubiquitin carboxyl-terminal hydrolase 2; TNM, tumor node metastasis; TAMs, tumor-associated macrophages; RASA1, RAS p21 protein activator 1; PDCD4, programmed cell death 4; ZBTB2, zinc finger and BTB domain containing 2; SOCS1, suppressor of cytokine signaling 1; TUBB3, β-III tubulin; MSCs, mesenchymal stem cells.

Keywords:  Bioinformatics; Colorectal cancer; Drug resistance; Exosome; Metastasis; non-coding RNAs

DOI:  https://doi.org/10.1016/j.gene.2024.149141
Biochemistry (Mosc). 2024 Nov;89(11): 1985-1997

Diversity of the Circulating Tumor Markers: Perspectives of a Multimodal Liquid Biopsy.

Ekaterina S Kuligina, Grigoriy A Yanus, Evgeny N Imyanitov.

  Over the past decade, liquid biopsy (LB) has become a routine diagnostic test essential for the treatment of malignant tumors of various localizations. Its capabilities include early diagnosis, molecular genotyping, prognosis, prediction, and monitoring of tumor response. Typically, liquid biopsy involves the extraction of a single type of tumor-derived molecules or cellular elements from blood and subsequent molecular analysis. These elements may include circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), circulating tumor RNA (ctRNA), or contents of extracellular vesicles (exosomes). Despite the technical sophistication of molecular analysis methods for circulating biomarkers, this diagnostic approach has limited relevance. In a significant proportion of cancer patients (ranging from 10 to 50%, depending on the tumor type), none of these analytes can be detected and analyzed, even in the presence of large, progressing neoplastic foci in the body. It seems reasonable to suggest that heterogeneous fractions of the circulating tumor-specific biomarkers complement each other, thus simultaneous analysis of several fractions will not only increase sensitivity of the method but also more accurately characterize and predict the clinical situation. This review examines the possibilities and advantages of applying a combined multiparametric approach to liquid biopsy, which involves testing multiple circulating analytes in a single blood sample.

Keywords:  CTC; cancer; ctDNA; ctRNA; exosomes; liquid biopsy; predictive markers; prognostic markers; protein tumor markers

DOI:  https://doi.org/10.1134/S0006297924110129
J Reprod Dev. 2024 Dec 12.

The imprinted Igf2-Igf2r axis is critical for exosome biogenesis during the early development of bovine placenta.

Kunhua Zheng, Longfei Xiao, Naihan Yuan, Xihui Sheng, Xiaolong Qi, Yingqiu Wang, Chang Chen, Kaijun Guo, Lin Yang, Bingying Liu, Xiangguo Wang.

  Insulin-like growth factor 2 (IGF2) is essential for cell growth and differentiation and functions through the IGF2 receptor (IGF2R) to regulate embryonic and placental development. Exosomes that are synthesized and released from cells and play important roles in embryogenesis and placental development rely on the IGF2R for sorting and transport. However, the role of the imprinted Igf2-Igr2r axis and exosomes in the co-regulation of early placental development remains unknown. Cotyledon villi were collected from bovine placentas at different gestational ages, and the localization and expression of IGF2, IGF2R, and exosomal marker proteins were detected. Furthermore, the expression of exosomal marker factors was detected after the expression of IGF2R or IGF2 was inhibited through RNA interference or the addition of inhibitors, respectively. Our results demonstrated that IGF2, IGF2R, and the exosomal markers CD63, CD9, TSG101, and Rab11 are mainly located on the cell membrane of mononuclear trophoblast cells and binuclear trophoblast cells, which make up the cotyledon villi of the bovine placenta. The expressions of IGF2, IGF2R, and the exosomal marker proteins CD63, CD9, TSG101, and Rab11 showed a significant upward trend with increased gestation duration. Additionally, both Igf2r-knockdown and suppressing the expression of IGF2 with chromeceptin (IGF2 inhibitor) led to the downregulation of exosomal marker proteins in both bovine placental trophoblast cells (BTCs) and BTC-derived exosomes. Our study confirmed that the imprinted Igf2-Igf2r axis participates in the early development of cotyledon villi in the bovine placenta by manipulating exosome biogenesis, providing evidence for improving disorders during placental development.

Keywords:  Bovine; Exosomes; Insulin-like growth factor 2 (IGF2); Insulin-like growth factor 2 receptor (IGF2R); Placental trophoblast cells

DOI:  https://doi.org/10.1262/jrd.2024-081
bioRxiv. 2024 Nov 25. pii: 2024.11.22.624948. [Epub ahead of print]

Pseudomonas aeruginosa- mediated cardiac dysfunction is driven by extracellular vesicles released during infection.

Naresh Kumar, Sameer Salam Mattoo, Shridhar Sanghvi, Maneeth P Ellendula, Sahil Mahajan, Clara Planner, Joseph S Bednash, Mahmood Khan, Latha P Ganesan, Harpreet Singh, William P Lafuse, Daniel J Wozniak, Murugesan V S Rajaram.

Pseudomonas aeruginosa (P.a.) is a gram-negative, opportunistic bacterium abundantly present in the environment. Often P.a. infections cause severe pneumonia, if left untreated. Surprisingly, up to 30% of patients admitted to the hospital for community- acquired pneumonia develop adverse cardiovascular complications such as myocardial infarction, arrhythmia, left ventricular dysfunction, and heart failure. However, the underlying mechanism of infection-mediated cardiac dysfunction is not yet known. Recently, we demonstrated that P.a. infection of the lungs led to severe cardiac electrical abnormalities and left ventricular dysfunction with limited P.a. dissemination to the heart tissue. To understand the mechanism of cardiac dysfunction during P.a. infection, we utilized both in vitro and in vivo models. Our results revealed that inflammatory cytokines contribute but are not solely responsible for severe contractile dysfunction in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Instead, exposure of hiPSC-CMs with conditioned media from P.a. infected human monocyte-derived macrophages (hMDMs) was sufficient to cause severe contractile dysfunction and arrhythmia in hiPSC-CMs. Specifically, exosomes released from infected hMDMs and bacterial outer membrane vesicles (OMVs) are the major drivers of cardiomyocyte contractile dysfunction. By using LC-MS/MS, we identified bacterial proteins, including toxins that are packaged in the exosomes and OMVs, which are responsible for contractile dysfunction. Furthermore, we demonstrated that systemic delivery of bacterial OMVs to mice caused severe cardiac dysfunction, mimicking the natural bacterial infection. In summary, we conclude that OMVs released during infection enter circulation and drive cardiac dysfunction.

DOI: https://doi.org/10.1101/2024.11.22.624948
Cancer Sci. 2024 Dec 10.

Tumor exosomal RNPEP promotes lung metastasis of liver cancer via inducing cancer-associated fibroblast activation.

Yuankun Chen, Gaofeng Pan, Yijun Yang, Haifeng Wu, Minhua Weng, Qiuping Wu, Yufeng Gao, Wenting Li.

  Cancer-associated fibroblasts (CAFs) are essential players in the tumor microenvironment (TME) due to their roles in facilitating tumor progression and metastasis. It is worth noting that the high-metastatic hepatocellular carcinoma (HCC) cell-derived exosomes have exhibited the ability to transform normal fibroblasts into CAFs, which further fosters the lung metastasis of low-metastatic HCC cells. Yet, the mechanisms underlying this tumor exosome-induced metastatic niche formation are poorly explored. In this study, the secreted protein arginyl aminopeptidase (RNPEP) was highly expressed in the plasma of patients with HCC. In addition, high-metastatic HCC cells showed augmented RNPEP expression levels in their exosomes. These exosomes induced obvious CAF-like properties in the human fibroblast cell line MRC-5, as evidenced by the increased CAF marker expression, and enhanced migratory ability. More strikingly, the secretions from high-metastatic tumor exosome-educated MRC-5 cells increased tumor stemness and promoted epithelial-mesenchymal transition (EMT) in MHCC-97L cells, a low-metastatic HCC cell line. However, the knockdown of RNPEP in exosomes from high-metastatic HCC cells abated the changes described above. Animal studies in vivo highlighted the pro-tumor and pro-metastatic effects of exosomal RNPEP on MHCC-97L cells by inducing CAF activation. Furthermore, tumor-derived exosomal RNPEP induced the activation of NF-κB signaling in MRC-5 cells, a critical pathway associated with CAF activation. Collectively, these results provide novel insight into tumor-derived exosomal RNPEP for its crosstalk with CAFs during HCC lung metastasis.

Keywords:  RNPEP; cancer‐associated fibroblast activation; exosome; hepatocellular carcinoma (HCC); lung metastasis

DOI:  https://doi.org/10.1111/cas.16417