Inhibition of Human Malignant Pleural Mesothelioma Growth by Mesenchymal Stromal Cells

Our plain-English summary of Inhibition of Human Malignant Pleural Mesothelioma Growth by Mesenchymal Stromal Cells, by V. Coccè, S. La Monica, M. Bonelli, et al (Cells, 2021).

The study

• Authors: V. Coccè, S. La Monica, M. Bonelli, G. Alessandri, R. Alfieri, C.A. Lagrasta, D. Madeddu, C. Frati, L. Flammini, D. Lisini, A. Marcianti, E. Parati, F. Paino, A. Giannì, G. Farronato, A. Falco, L. Spaggiari, F. Petrella, A. Pessina
• Journal: Cells
• Published: 2021;10(6)
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant Pleural Mesothelioma (MPM) is an aggressive tumor that has a significant incidence related to asbestos exposure with no effective therapy and poor prognosis. The role of mesenchymal stromal cells (MSCs) in cancer is controversial due to their opposite effects on tumor growth and in particular, only a few data are reported on MSCs and MPM.

Methods: We investigated the in vitro efficacy of adipose tissue-derived MSCs, their lysates and secretome against different MPM cell lines. After large-scale production of MSCs in a bioreactor, their efficacy was also evaluated on a human MPM xenograft in mice.

Results: MSCs, their lysate and secretome inhibited MPM cell proliferation in vitro with S or G0/G1 arrest of the cell cycle, respectively. MSC lysate induced cell death by apoptosis. The efficacy of MSC was confirmed in vivo by a significant inhibition of tumor growth, similar to that produced by systemic administration of paclitaxel. Interestingly, no tumor progression was observed after the last MSC treatment, while tumors started to grow again after stopping chemotherapeutic treatment.

Conclusions: These data demonstrated for the first time that MSCs, both through paracrine and cell-to-cell interaction mechanisms, induced a significant inhibition of human mesothelioma growth. Since the prognosis for MPM patients is poor and the options of care are limited to chemotherapy, MSCs could provide a potential new therapeutic approach for this malignancy.

In plain English

This laboratory study tested whether mesenchymal stromal cells (MSCs) could slow human malignant pleural mesothelioma growth. The MSCs came from fat tissue of healthy cosmetic-surgery volunteers. The study did not examine asbestos exposure or patients. In dishes, MSC extracts (lysates), the fluid MSCs had grown in (conditioned medium), and MSCs themselves all slowed growth of three mesothelioma cell lines. In one line, MSTO-211H, lysate and conditioned medium both caused cell death, but apoptosis (programmed cell death) was documented only with lysate. Mice with human mesothelioma tumors under the skin got four weekly injections: vehicle without active drug (7 mice), MSCs beside the tumor (7), or paclitaxel chemotherapy (8). The authors reported that MSCs reduced tumor volume similarly to paclitaxel. At day 22, average tumor volume was 325 cubic millimetres with paclitaxel and 898 with MSCs. After treatment stopped, paclitaxel-treated tumors regrew, reaching 817 cubic millimetres by day 35; control tumors reached 1893. The authors reported no relapses in MSC-treated mice. The authors concluded that MSCs could have a role in controlling tumor growth. They noted that studies of the MSC secretome in dishes have limitations.

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: in vitro experiments on human mesothelioma cell lines plus an animal experiment (human mesothelioma xenograft in mice)
• Who was studied: Three human malignant pleural mesothelioma cell lines: MSTO-211H (biphasic), NCI-H2452 (epithelioid) and NCI-H2052 (sarcomatoid). Also 6-week-old Balb/c-Nude female mice given MSTO-211H tumors under the skin and randomized into control (n = 7), paclitaxel (n = 8) and MSC (n = 7) groups. MSCs came from adipose tissue of healthy volunteer donors aged 18 to 66 having aesthetic plastic surgery.
• Exposure: No asbestos exposure was studied. In the dish experiments, tumor cells were treated with adipose tissue-derived MSCs, their cell lysates and their conditioned medium (secretome). In the mice, treatments were given once a week. One group had 5 million MSCs injected under the skin near the tumor. One group had paclitaxel 20 mg/kg given into the abdomen. The control group had vehicle alone. Treatment was given at days 0, 7, 14 and 21, then stopped for two weeks.
• Main results:
  • In the three mesothelioma cell lines, both the MSC lysates and the MSC conditioned medium significantly inhibited cell proliferation.
  • In MSTO-211H cells, the MSC lysate blocked the S phase of the cell cycle after 24 hours. The conditioned medium caused a G0/G1 arrest after 48 hours.
  • In MSTO-211H cells, cell death occurred with both the MSC lysate and the MSC conditioned medium, but apoptosis was documented only with the lysate. This analysis was done in MSTO-211H only, and compared the lysate with the conditioned medium.
  • In direct co-culture, fluorescent MSCs significantly impaired proliferation of all three mesothelioma cell lines.
  • In mice at day 35, mean tumor volume in the paclitaxel group was 817 ± 228 mm3, against 1893 ± 93 mm3 in untreated (control) mice (p < 0.0001).
  • Local MSC treatment significantly reduced tumor volume, to a degree the authors described as similar to systemic paclitaxel.
  • At day 22, mean tumor volume was 325 ± 78 mm3 in paclitaxel-treated mice and 898 ± 90 mm3 in MSC-treated mice (p < 0.001).
  • After treatment stopped, tumors in paclitaxel-treated mice grew again, from 325 ± 78 mm3 to 817 ± 228 mm3 (p < 0.05). No relapses were observed in MSC-treated mice.
  • Tissue analysis at day 35 showed a significant decrease (p < 0.02) in the fraction of tissue occupied by tumor cells after paclitaxel or MSCs. There were no relevant variations in necrotic or fibrotic tissue.
  • CD31 staining, a marker of blood vessels, in MSC-treated tumors was similar to that in untreated tumors.
  • During the 35 days, the mice showed no signs of toxicity, and no animal died.
• The authors' conclusion: The authors concluded that their data support the hypothesis that MSCs could have a role in controlling mesothelioma tumor growth, and could be considered a possible therapeutic tool.
• Limitations the authors state:
  • The authors noted that in vitro studies of the MSC secretome have limitations, because MSC function depends on the tissue they work in and on cell-to-cell interaction.
  • The secretome analysis did not identify any specific molecule responsible for the anti-tumor activity.
  • Whether this approach could serve as therapy for human MPM was not tested and remains to be investigated.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Asbestos Exposure, Prognosis, Apoptosis, Mesothelioma, Chemotherapy.

Related studies

• Paclitaxel-releasing mesenchymal stromal cells inhibit in vitro proliferation of human mesothelioma cells — F. Petrella, V. Coccè, et al. (2017)
• Antitumor effects of TRAIL-expressing mesenchymal stromal cells in a mouse xenograft model of human mesothelioma — M.J. Lathrop, E.K. Sage, et al. (2015)
• Phase I Clinical Trial on Pleural Mesothelioma Using Neoadjuvant Local Administration of Paclitaxel-Loaded Mesenchymal Stromal Cells (PACLIMES Trial): Study Rationale and Design — G.M. Stella, D. Lisini, et al. (2024)
• Uptake-release by MSCs of a cationic platinum(II) complex active in vitro on human malignant cancer cell lines — I. Rimoldi, V. Coccè, et al. (2018)
• The flavonoid resveratrol suppresses growth of human malignant pleural mesothelioma cells through direct inhibition of specificity protein 1 — K.A. Lee, Y.J. Lee, et al. (2012)
• In vitro and in vivo therapeutic efficacy of the PPAR-γ agonist troglitazone in combination with cisplatin against malignant pleural mesothelioma cell growth — N. Hamaguchi, H. Hamada, et al. (2010)

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