Systemic but not topical TRAIL-expressing mesenchymal stem cells reduce tumour growth in malignant mesothelioma

Our plain-English summary of Systemic but not topical TRAIL-expressing mesenchymal stem cells reduce tumour growth in malignant mesothelioma, by E.K. Sage, K.K. Kolluri, K. McNulty, et al (Thorax, 2014).

The study

• Authors: E.K. Sage, K.K. Kolluri, K. McNulty, S. Lourenco Sda, T.L. Kalber, K.L. Ordidge, D. Davies, Y.C. Gary Lee, A. Giangreco, S.M. Janes
• Journal: Thorax
• Published: 2014;69(7):638-47
• Cited by: 53 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma is a rare but devastating cancer of the pleural lining with no effective treatment. The tumour is often diffusely spread throughout the chest cavity, making surgical resection difficult, while systemic chemotherapy offers limited benefit. Bone marrow-derived mesenchymal stem cells (MSCs) home to and incorporate into tumour stroma, making them good candidates to deliver anticancer therapies. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic molecule that selectively induces apoptosis in cancer cells, leaving healthy cells unaffected. We hypothesised that human MSCs expressing TRAIL (MSCTRAIL) would home to an in vivo model of malignant pleural mesothelioma and reduce tumour growth. Human MSCs transduced with a lentiviral vector encoding TRAIL were shown in vitro to kill multiple malignant mesothelioma cell lines as predicted by sensitivity to recombinant TRAIL (rTRAIL). In vivo MSC homing was delineated using dual fluorescence and bioluminescent imaging, and we observed that higher levels of MSC engraftment occur after intravenous delivery compared with intrapleural delivery of MSCs. Finally, we show that intravenous delivery of MSCTRAIL results in a reduction in malignant pleural mesothelioma tumour growth in vivo via an increase in tumour cell apoptosis.

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In plain English

This was a laboratory study in cells and mice, not a study of people or of asbestos exposure. The authors engineered human bone marrow mesenchymal stem cells (MSCs) to produce TRAIL, a molecule that triggers cancer cell death. They tested these cells against six human malignant pleural mesothelioma cell lines and against Met5A, a benign mesothelial cell line. Five of the six mesothelioma cell lines (83%) were sensitive to TRAIL. Met5A showed no significant increase in cell death. The authors then grew pleural tumours in female NOD/SCID mice using the MSTO-211H cell line. Labelled MSCs reached the tumours whether injected into a vein or into the chest cavity, but more of them reached tumours after injection into a vein. TRAIL-producing MSCs given into a vein significantly reduced tumour growth and lung weights compared with saline solution (PBS) or unmodified MSCs, and the treated tumours showed more cell death. Injection into the chest cavity gave no significant reduction. The authors concluded that delivery into a vein reduced tumour growth in this mouse model.

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: cell-culture (in vitro) experiments and an animal experiment in mice
• Who was studied: Six human malignant pleural mesothelioma cell lines (MSTO-211H, H28, H2052, ONE58, JU77, LO68) and the benign mesothelial cell line Met5A; in vivo, eight-week-old female NOD/SCID mice with pleural tumours grown from MSTO-211H cells. The number of mice is not given in the text.
• Exposure: No asbestos exposure was studied. The treatment studied was human bone marrow-derived MSCs engineered to express TRAIL (MSCTRAIL). In mice, 1×10^6 MSCTRAIL cells were given on days 5, 9, 12, 15 and 18, either into a vein or into the pleural space. The comparison groups received untransduced (unmodified) MSCs or PBS alone.
• Main results:
  • In cell culture, five of the six mesothelioma cell lines (83%) were sensitive to TRAIL.
  • H28 cells showed a significant increase in apoptosis and death with MSCTRAIL compared with recombinant TRAIL: 11.3 plus or minus 0.7% vs 3.6 plus or minus 0.1%, p=0.007.
  • In MSTO-211H cells, cell death was 42.6 plus or minus 4.2% with recombinant TRAIL vs 12.9 plus or minus 0.8% with inactivated MSCTRAIL (p less than 0.0001). It rose to over 58% with MSCTRAIL.
  • The benign mesothelial cell line Met5A showed no significant increase in apoptosis and death with recombinant TRAIL or MSCTRAIL.
  • In mice, MSCs did not appear outside the lungs, and the authors reported no evidence of toxicity.
  • In mice given MSCTRAIL into a vein, tumour growth was significantly reduced compared with the PBS and untransduced MSC groups (p less than 0.001, repeated measures ANOVA).
  • Lung weights were significantly reduced in mice treated with MSCTRAIL into a vein (printed as p<0.0391).
  • When MSCTRAIL was given into the pleural space, there was no significant reduction in tumour growth or lung weights compared with the PBS and untransduced MSC groups.
  • Tumour cell proliferation did not differ significantly between groups. Apoptosis (cell death) was significantly increased in tumours from the group given MSCTRAIL into a vein (printed as p<0.0053).
  • Labelled MSCs given into a vein gave a significantly higher signal at the tumours 24 h after injection than MSCs given into the pleural space (p=0.0125). The difference was maintained throughout imaging.
  • Flow cytometry of tumour samples showed a greater percentage of MSCs in tumours from mice given MSCs into a vein. The overall percentage of MSCs was low compared with tumour stromal cells and lung cells.
• The authors' conclusion: The authors concluded that MSCTRAIL given into a vein causes a reduction in tumour growth in an in vivo (mouse) model of malignant pleural mesothelioma.
• Limitations the authors state:
  • The authors noted that the number of MSCTRAIL cells injected appears high relative to the number of tumour cells inoculated. They argued that the ratio would be much lower once tumour cell doubling time is considered.
  • The authors noted that immunological reactions would need to be monitored in any phase I clinical trial using engineered MSCs.
  • The authors noted that there are currently no biomarkers to predict sensitivity to TRAIL.

Topics

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

Medical terms in this study, explained in our Lexicon: STEM, Malignant Mesothelioma, Pleural Mesothelioma, Surgical Resection, Chemotherapy, Necrosis, Apoptosis.

Related studies

• 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)
• Mesenchymal stem cells modulate lung injury — A.R. Brody, K.D. Salazar, et al. (2010)
• Cyclophosphamide chemotherapy sensitizes tumor cells to TRAIL-dependent CD8 T cell-mediated immune attack resulting in suppression of tumor growth — R.G. van der Most, A.J. Currie, et al. (2009)
• Sialic acid-binding lectin (leczyme) induces apoptosis to malignant mesothelioma and exerts synergistic antitumor effects with TRAIL — T. Tatsuta, M. Hosono, et al. (2014)
• Paclitaxel-releasing mesenchymal stromal cells inhibit in vitro proliferation of human mesothelioma cells — F. Petrella, V. Coccè, et al. (2017)
• Novel platinum agents and mesenchymal stromal cells for thoracic malignancies: state of the art and future perspectives — F. Petrella, I. Rimoldi, et al. (2018)

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