Force-feeding malignant mesothelioma stem-cell like with exosome-delivered miR-126 induces tumour cell killing

Our plain-English summary of Force-feeding malignant mesothelioma stem-cell like with exosome-delivered miR-126 induces tumour cell killing, by F. Monaco, L. De Conti, S. Vodret, et al (Translational Oncology, 2022).

The study

• Authors: F. Monaco, L. De Conti, S. Vodret, N. Zanotta, M. Comar, S. Manzotti, C. Rubini, L. Graciotti, G. Fulgenzi, M. Bovenzi, M. Baralle, M. Tomasetti, L. Santarelli
• Journal: Translational Oncology
• Published: 2022;20:101400
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive tumour resistant to treatments. It has been postulated that cancer stem cells (CSCs) persist in tumours causing relapse after multimodality treatment. In the present study, a novel miRNA-based therapy approach is proposed. MPM-derived spheroids have been treated with exosome-delivered miR-126 (exo-miR) and evaluated for their anticancer effect. The exo-miR treatment increased MPM stem-cell like stemness and inhibited cell proliferation. However, at a prolonged time, the up taken miR-126 was released by the cells themselves through exosomes; the inhibition of exosome release by an exosome release inhibitor GW4869 induced miR-126 intracellular accumulation leading to massive cell death and in vivo tumour growth arrest. Autophagy is involved in these processes; miR-126 accumulation induced a protective autophagy and the inhibition of this process by GW4869 generates a metabolic crisis that promotes necroptosis, which was associated with PARP-1 over-expression and cyt-c and AIF release. Here, for the first time, we proposed a therapy against CSCs, a heterogeneous cell population involved in cancer development and relapse.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

In plain English

This laboratory and animal study tested an experimental treatment approach for malignant pleural mesothelioma. It did not study asbestos exposure. The authors grew mesothelioma cell lines (MSTO-211H and MPP89) as spheroids, which are small 3-D clusters described as having cancer stem cell-like properties. They treated the spheroids with exosomes (tiny vesicles made by umbilical vein cells) loaded with a small RNA molecule, miR-126. On their own, these exosomes reduced spheroid growth, but over time the cells released the miR-126 again through their own exosomes. Pre-treatment with GW4869, a drug that blocks exosome release, raised miR-126 inside the spheroids, and the combination caused significant cell death. In ordinary flat-grown cells, the combination mostly slowed growth rather than killing cells. In NSG mice carrying MSTO-211H tumours under the skin, miR-126 exosomes injected directly into the tumours inhibited tumour growth by 27%, and by 70% with GW4869. The treatments did not affect body weight. The authors concluded that the combination killed the stem cell-like cells and inhibited tumour growth. They noted that a standardized protocol for large-scale production and isolation of clinical-grade exosomes is still lacking.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of mesothelioma cell lines and spheroids, plus a mouse xenograft experiment (human tumour cells grown in mice)
• Who was studied: The cell work used non-malignant mesothelial cells (Met-5A) and three mesothelioma cell lines: H28 (sarcomatoid), MSTO-211H (biphasic) and MPP89 (epithelial). Spheroids were made from MSTO-211H and MPP89. In the animal work, male NSG (NOD SCID gamma) mice had MSTO-211H cells injected under the skin of the back. They were then treated by injection into the tumour, in groups of 8 (control) or 10 (each treatment group).
• Exposure: No asbestos exposure was studied. The treatments were exosomes loaded with miR-126 (exo-miR) or with a scrambled control (exo-scr). These were given with or without the exosome-release inhibitor GW4869. In cells, the exosome dose was 20 µg/ml and the GW4869 dose was 20 µM. In mice, the exosome dose was 0.7 mg/Kg and the GW4869 dose was 1 mg/Kg, all injected into the tumour on days 10, 13 and 16.
• Main results:
  • In spheroids from both cell lines, uptake of the miR-126 exosomes was associated with significantly reduced growth.
  • Exo-miR treatment alone left less miR-126 inside the cells than in untreated cells. The authors attributed this to the cells secreting miR-126 through their own exosomes.
  • In flat-grown (adherent) mesothelioma cells, miR-126 accumulation mostly inhibited proliferation rather than causing cell death.
  • In mice, exo-miR injected into the tumours significantly inhibited tumour growth (27%), and more so when combined with GW4869 (70%).
  • In mice, tumours in the exo-miR and GW plus exo-scr groups tended to grow faster later on and ended larger than in the GW plus exo-miR group. This difference was not statistically significant.
  • The treatments did not affect the mice's body weight, and no sign of adverse effects was found in liver, lung and kidney tissue.
  • In tumours treated with GW4869 plus exo-miR, Ki67-positive cells (a marker of cell division) and VEGF expression were markedly reduced.
  • In spheroids, PARP-1 over-expression was found with GW4869. It increased further when GW4869 was combined with either type of exosome. No caspase activation was found.
  • Blocking PARP-1 with 3-ABA abolished the late apoptosis caused by the treatments but did not change the percentage of necrotic cells.
• The authors' conclusion: The authors concluded that GW4869 combined with miR-126-loaded exosomes killed cancer stem cell-like cells and inhibited tumour growth. They attributed this to miR-126 accumulating inside cells and to GW4869 blocking a protective autophagy response. They proposed this as a new miRNA-based therapy approach and reported that it was registered as a patent.
• Limitations the authors state:
  • There is no standardized protocol for large-scale production and isolation of clinical-grade exosomes.
  • The best choice of donor cells as the source of exosomes has not been clarified.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, STEM, Pleural Mesothelioma.

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