bims-exocan 2023-01-22 papers

bims-exocan

Biomed News

on Exosomes roles in cancer

Issue of 2023–01–22
ten papers selected by
Muhammad Rizwan, COMSATS University

The Contribution of Tumor Derived Exosomes to Cancer Cachexia.
High therapeutic efficacy of 5-Fluorouracil-loaded Exosomes against colon cancer cells.
Innovative model of surface-enhanced Raman spectroscopy for exosomes identification: An approach for the diagnosis of hepatocellular carcinoma.
Berberine Reverses the Tumorigenic Function of Colon Cancer Cell-Derived Exosomes.
Role of Exosomes and Their Potential as Biomarkers in Epstein-Barr Virus-Associated Gastric Cancer.
Advances in exosome analysis.
Role of circulating exosomal biomarkers and their diagnostic accuracy in pancreatic cancer.
Exosomal transfer of miR-195-5p restrains lung adenocarcinoma progression.
Visualization of Exosome Release and Uptake During Cell Migration Using the Live Imaging Reporter pHluorin_M153R-CD63.
Endosomal escape of nucleic acids from extracellular vesicles mediates functional therapeutic delivery.

Cells. 2023 Jan 12. pii: 292. [Epub ahead of print]12(2):

The Contribution of Tumor Derived Exosomes to Cancer Cachexia.

Christopher R Pitzer, Hector G Paez, Stephen E Alway.

  Cancer cachexia is defined as unintentional weight loss secondary to neoplasia and is associated with poor prognosis and outcomes. Cancer cachexia associated weight loss affects both lean tissue (i.e., skeletal muscle) and adipose tissue. Exosomes are extracellular vesicles that originate from multivesicular bodies that contain intentionally loaded biomolecular cargo. Exosome cargo includes proteins, lipids, mitochondrial components, and nucleic acids. The cargo carried in exosomes is thought to alter cell signaling when it enters into recipient cells. Virtually every cell type secretes exosomes and exosomes are known to be present in nearly every biofluid. Exosomes alter muscle and adipose tissue metabolism and biological processes, including macrophage polarization and apoptosis which contribute to the development of the cachexia phenotype. This has led to an interest in the role of tumor cell derived exosomes and their potential role as biomarkers of cancer cell development as well as their contribution to cachexia and disease progression. In this review, we highlight published findings that have studied the effects of tumor derived exosomes (and extracellular vesicles) and their cargo on the progression of cancer cachexia. We will focus on the direct effects of tumor derived exosomes and their cellular cross talk on skeletal muscle and adipose tissue, the primary sites of weight loss due to cancer cachexia.

Keywords:  adipocytes; adipose; cachexia; exosomes; extracellular vesicles; inflammation; metabolism; muscle

DOI:  https://doi.org/10.3390/cells12020292
Chem Biol Drug Des. 2023 Jan 18.

High therapeutic efficacy of 5-Fluorouracil-loaded Exosomes against colon cancer cells.

Rafia Shekh, Afza Ahmad, Rohit Kumar Tiwari, Mohd Saeed, Ratnakar Shukla, Wafa Safar Al-Thubiani, Irfan Ahmad Ansari, Mohd Ashfaque, Preeti Bajpai.

  The successful chemotherapeutic regime required for the clinical management of different cancers largely depends on the efficient drug delivery within the cancer cells. Exosomes have emerged as an enticing candidate for exploring their role as delivery vehicles. Exosomes are reported to be intrinsically nano-sized vesicles competent for efficient delivery across the cellular membrane. In the present study, we assessed the feasibility of an autologous exosome-based drug delivery platform for delivering 5-Fluorouracil (5-FU) against human colon cancer HCT116 cells. Autologous exosomes have shown probable tropism towards the tumour microenvironment, which makes them the most competitive vehicle for drug delivery. It was observed that the autologous exosomes loaded with 5-FU showed an enhanced rate of drug release under acidic conditions. The result of the cell viability assay showed that treatment of 5-FU-loaded exosomes (equivalent to 5 μg 5-FU) resulted in enhanced cytotoxic effect in HCT116 cells as compared to an equivalent amount of free 5-FU (5 μg), which elucidated the efficient delivery of the 5-FU by exosomes inside the cancer cells. Subsequently, 5-FU-loaded exosomes led to increased nuclear condensation and fragmentation along with increased ROS production. In addition, 5-FU-loaded exosomes caused enhanced dissipation of mitochondrial membrane potential and caspase-3 activation, resulting in increased apoptosis induction. Our study also revealed that 5-FU loaded exosomes upsurged the arrest in the cell cycle at the G0/G1 stage in HCT-116 cells and it was found to be associated with decreased CDK4 and Cyclin D1 expression concomitantly with the upregulation of CDK inhibitor, p21Cip1 expression. Thus, the findings from the present study highlight the advantages of autologous exosomes as a natural drug carrier which could efficiently deliver chemotherapeutic drugs to cancer cells.

Keywords:  5-Fluorouracil; Exosomes; HCT116; ROS; apoptosis; colon cancer; drug delivery

DOI:  https://doi.org/10.1111/cbdd.14205
Clin Chim Acta. 2023 Jan 13. pii: S0009-8981(23)00021-9. [Epub ahead of print]540 117228

Innovative model of surface-enhanced Raman spectroscopy for exosomes identification: An approach for the diagnosis of hepatocellular carcinoma.

Amr Elkady, Marwa Hassan, Mohamed F Hagag, Eman El-Ahwany, Osama M Helal, Mona Zoheiry, Mahmoud A Abdalla, Mohamed Elzallat.

   BACKGROUND: The current hepatocellular carcinoma (HCC) diagnostic approaches lack adequate sensitivity and specificity. So, this study was performed to develop an innovative model of surface-enhanced Raman spectroscopy (SERS) that can detect HCC patients by identifying the circulating tumor-derived exosomes.
METHODOLOGY: Sixty participants, including normal controls, hepatitis C virus (HCV)-infected patients, and HCV-associated HCC patients, had their whole blood samples and exosomes separated from these samples analyzed using Raman spectroscopy (RS). A revolutionary model of SERS, based on an innovative glass and nano-gold, was designed to directly identify exosomes. Its measurements were simulated by Comsol Multiphysics (5.6).
RESULTS: The RS examination of the whole blood samples revealed no Raman peaks. Yet, the isolated exosomes from these samples generated Raman peaks at 400 and 1000 cm-1 wavenumbers in the HCV group. A Raman shift was detected in HCC patients at 812, 852, and 878 cm-1 wavenumbers with intensity ratios of 120, 130, and 60, respectively. The RS had a sensitivity and specificity of 95 % and 100 %, respectively, for detecting HCC. However, the newly-designed SERS was able to identify the HCC-derived exosomes, at 812 and 878 cm-1 wavenumbers, with boosted intensity ratios of 9*106 and 4*106, respectively, in the whole blood samples.
CONCLUSION: The newly-developed SERS model has the potential to detect HCC patients through recognizing the tumor-derived exosomes non-invasively, with high accuracy, and without the need for laborious exosomal separation. Nonetheless, bringing this technology into the clinic demands the establishment of spectral databases and their validation using the current gold standards.

Keywords:  Exosome; Hepatitis C virus; Hepatocellular carcinoma; Nano-gold; Raman spectroscopy; Surface-enhanced Raman spectroscopy

DOI:  https://doi.org/10.1016/j.cca.2023.117228
Tohoku J Exp Med. 2023 Jan 13.

Berberine Reverses the Tumorigenic Function of Colon Cancer Cell-Derived Exosomes.

Qingyun Sun, Rongmei Shan, Tianmeng Qi, Ping Yang.

DOI: https://doi.org/10.1620/tjem.2022.J119
Cancers (Basel). 2023 Jan 12. pii: 469. [Epub ahead of print]15(2):

Role of Exosomes and Their Potential as Biomarkers in Epstein-Barr Virus-Associated Gastric Cancer.

Binnari Kim, Kyoung-Mee Kim.

  Exosomes are a subtype of extracellular vesicles ranging from 30 to 150 nm and comprising many cellular components, including DNA, RNA, proteins, and metabolites, encapsulated in a lipid bilayer. Exosomes are secreted by many cell types and play important roles in intercellular communication in cancer. Viruses can hijack the exosomal pathway to regulate viral propagation, cellular immunity, and the microenvironment. Cells infected with Epstein-Barr virus (EBV), one of the most common oncogenic viruses, have also been found to actively secrete exosomes, and studies on their roles in EBV-related malignancies are ongoing. In this review, we focus on the role of exosomes in EBV-associated gastric cancer and their clinical applicability in diagnosis and treatment.

Keywords:  EBV; biomarker; exosome; gastric cancer; immunotherapy

DOI:  https://doi.org/10.3390/cancers15020469
Adv Clin Chem. 2023 ;pii: S0065-2423(22)00070-1. [Epub ahead of print]112 69-117

Advances in exosome analysis.

Arnau Pallares-Rusiñol, Mireia Bernuz, Silio Lima Moura, Carolina Fernández-Senac, Rosanna Rossi, Mercè Martí, María Isabel Pividori.

  There is growing demand for novel biomarkers that detect early stage disease as well as monitor clinical management and therapeutic strategies. Exosome analysis could provide the next advance in attaining that goal. Exosomes are membrane encapsulated biologic nanometric-sized particles of endocytic origin which are released by all cell types. Unfortunately, exosomes are exceptionally challenging to characterize with current technologies. Exosomes are between 30 and 200nm in diameter, a size that makes them out of the sensitivity range to most cell-oriented sorting or analysis platforms, i.e., traditional flow cytometers. The most common methods for targeting exosomes to date typically involve purification followed by the characterization and the specific determination of their cargo. The whole procedure is time consuming, requiring thus skilled personnel as well as laboratory facilities and benchtop instrumentation. The most relevant methodology for exosome isolation, characterization and quantification is addressed in this chapter, including the most up-to-date approaches to explore the potential usefulness of exosomes as biomarkers in liquid biopsies and in advanced nanomedicine.

Keywords:  ELISA; Exosomes; Flow cytometry; Immunomagnetic separation; Liquid biopsy; NTA; Nanovesicles; PCR; Solid-phase preconcentration

DOI:  https://doi.org/10.1016/bs.acc.2022.09.002
JGH Open. 2023 Jan;7(1): 30-39

Role of circulating exosomal biomarkers and their diagnostic accuracy in pancreatic cancer.

Menazir Sha, Basir Kunduzi, Saied Froghi, Alberto Quaglia, Brian Davidson, Giuseppe K Fusai.

   Background and Aim: New biomarkers have the potential to facilitate early diagnosis of pancreatic cancer (PC). Circulating exosomes are cell-derived protein complexes containing RNA that can be used as indicators of cancer development. The aim of this review is to evaluate the current literature involving PC patient groups for highly accurate exosomal biomarkers.
Methods: The literature search followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eight-hundred and seventy-five studies were identified across various databases (Ovid MEDLINE, Embase, and Cochrane) published between 2009 and 2020. Nine studies fulfilled the inclusion criteria: human PC patients, diagnosis as outcome of interest, serum biomarker of exosomal content, reporting of diagnostic values, and disease progress. Area under the curve (AUC) of the exosomal biomarker was compared against that of CA19-9.
Results: Nine papers were reviewed for relevant outcomes based on the inclusion criteria. These studies involved 565 participants (331 PC, 234 controls; male/female ratio 1.21; mean age 64.1). Tumor staging was reported in all studies, with 45.6% of PC patients diagnosed with early-stage PC (T1-2). The mRNA panel (ARG1, CD63, CK18, Erbb3, GAPDH, H3F3A, KRAS, ODC1) and GPC 1 reported the highest performing sensitivity and specificity at 100% each. The microRNA panel (miR-10b, miR-21, miR-30c, miR-181a, and miR-let7a), mRNA panel (ARG1, CD63, CK18, Erbb3, GAPDH, H3F3A, KRAS, ODC1), and GPC 1 showed a perfect AUC of 1.0. Five studies compared the AUC of the exosomal biomarker against CA19-9, each being superior to that of CA19-9.
Conclusion: The potential of exosomal biomarkers remains promising in PC diagnosis. Standardization of future studies will allow for larger comparative analyses and overcoming contrasting findings.

Keywords:  cancer biomarker; exosomal biomarker; pancreatic cancer

DOI:  https://doi.org/10.1002/jgh3.12848
Exp Cell Res. 2023 Jan 16. pii: S0014-4827(23)00032-0. [Epub ahead of print] 113485

Exosomal transfer of miR-195-5p restrains lung adenocarcinoma progression.

Yongchun Zhou, Gaowei Wang, Jingjing Cai, Yaqian Du, Hongsheng Li, Lincan Duan, Guangqiang Zhao, Yunchao Huang.

  Exosome is an important way for tumor cells to communicate with other cells and plays an important role in tumor progression. Previous studies revealed that miR-195-5p acts as a tumor suppressor in lung cancer. However, the role and molecular mechanism of exosomal transferred miR-195-5p in lung adenocarcinoma (LAC) remains unknown. Here, we found that miR-195-5p expression in circulating exosomes of LAC patients was lower than that of healthy controls. Meanwhile, the expression of exosomal miR-195-5p from normal bronchial epithelial cell line BEAS-2B cells was significantly higher than that of lung cancer cell lines. The exosome labeling assay confirmed that BEAS-2B cells-derived exosomes could be captured by lung cancer cells. Furthermore, exosomal miR-195-5p derived from BEAS-2B cells remarkably inhibited the proliferation, migration, invasion of lung cancer cells, and tumor growth in vivo. In addition, exosomal miR-195-5p from BEAS-2B cells also suppressed the tube-forming ability of vascular endothelial cells. Moreover, we verified that miR-195-5p decreased apelin (APLN) expression to inactivate the Wnt signaling pathway, thereby inhibiting tumor invasiveness and angiogenesis. In conclusion, our research shows that exosomal miR-195-5p from normal bronchial epithelial cells hinders the progression of LAC, suggesting that regulation of exosomal miR-195-5p provides a novel strategy for LAC treatment.

Keywords:  Angiogenesis; Exosomes; Lung adenocarcinoma; miR-195-5p

DOI:  https://doi.org/10.1016/j.yexcr.2023.113485
Methods Mol Biol. 2023 ;2608 83-96

Visualization of Exosome Release and Uptake During Cell Migration Using the Live Imaging Reporter pHluorin_M153R-CD63.

Bong H Sung, Alissa M Weaver.

  Exosome secretion and uptake regulate cell migration through autocrine and paracrine mechanisms. Monitoring exosome secretion and uptake during cell migration is critical for investigation of these mechanisms. Exosomes can be visualized by direct labeling with fluorescent dyes or by tagging intrinsic markers with fluorescent proteins for live imaging. Due to several limitations of fluorescent dye-labeled exosomes, we created two bright genetically encoded reporters of exosome secretion, pHluorin_M153R-CD63 and pHluorin_M153R-CD63-mScarlet. Here, we describe how to visualize secretion and uptake of exosomes labeled with these pH-sensitive and pH-insensitive fluorescent protein-tagged exosomal markers during cell migration using time-lapse fluorescent microscopy.

Keywords:  Cell migration; Exosome labeling; Exosome secretion; Exosome uptake; Live cell imaging; Multivesicular body trafficking; Time-lapse fluorescent microscopy; pHluorin_M153R-CD63; pHluorin_M153R-CD63-mScarlet

DOI:  https://doi.org/10.1007/978-1-0716-2887-4_6
Pharmacol Res. 2023 Jan 16. pii: S1043-6618(23)00021-X. [Epub ahead of print]188 106665

Endosomal escape of nucleic acids from extracellular vesicles mediates functional therapeutic delivery.

Tuan Thach Pham, Huan Chen, Phuong Hoang Diem Nguyen, Migara Kavishka Jayasinghe, Anh Hong Le, Minh Tn Le.

  Extracellular vesicles hold great promise as a drug delivery platform for RNA-based therapeutics. However, there is a lack of experimental evidence for the intracellular trafficking of nucleic acid cargos, specifically, whether they are capable of escaping from the endolysosomal confinement in the recipient cells to be released into the cytosol and hence, interact with their cytoplasmic targets. Here, we demonstrated how red blood cell-derived extracellular vesicles (RBCEVs) release their therapeutic RNA/DNA cargos at specific intracellular compartments characteristic of late endosomes and lysosomes. The released cargos were functional and capable of knocking down genes of interest in recipient cells, resulting in tumor suppression in vitro and in an acute myeloid leukemia murine model without causing significant toxicity. Notably, surface functionalization of RBCEVs with an anti-human CXCR4 antibody facilitated their specific uptake by CXCR4+ leukemic cells, leading to enhanced gene silencing efficiency. Our results provide insights into the cellular uptake mechanisms and endosomal escape routes of nucleic acid cargos delivered by RBCEVs which have important implications for further improvements of the RBCEV-based delivery system.

Keywords:  Cancer; Drug delivery; Endosomal escape; Extracellular vesicles; RNA; Therapeutics

DOI:  https://doi.org/10.1016/j.phrs.2023.106665