Antitumor effects of TRAIL-expressing mesenchymal stromal cells in a mouse xenograft model of human mesothelioma

Our plain-English summary of Antitumor effects of TRAIL-expressing mesenchymal stromal cells in a mouse xenograft model of human mesothelioma, by M.J. Lathrop, E.K. Sage, S.L. Macura, et al (Cancer Gene Therapy, 2015).

The study

• Authors: M.J. Lathrop, E.K. Sage, S.L. Macura, E.M. Brooks, F. Cruz, N.R. Bonenfant, D. Sokocevic, M.B. MacPherson, S.L. Beuschel, C.W. Dunaway, A. Shukla, S.M. Janes, C. Steele, B.T. Mossman, D.J. Weiss
• Journal: Cancer Gene Therapy
• Published: 2015;22(1):44-54
• Cited by: 33 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma (MM) remains a highly deadly malignancy with poor treatment option. The MM cells further promote a highly inflammatory microenvironment, which contributes to tumor initiation, development, severity and propagation. We reasoned that the anti-inflammatory actions of mesenchymal stromal cells (MSCs) and further antitumor effects of MSCs engineered to overexpress tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein (MSC-TRAIL) would effectively inhibit mesothelioma growth. Using a mouse xenograft model of intraperitoneal human mesothelioma, native mouse (mMSCs) or human (hMSC) MSCs were administered either systemically (intravenously or intraperitoneally) at various times following tumor inoculation. Both mMSCs and hMSCs localized at the sites of MM tumor growth in vivo and decreased local inflammation. Further, a trend towards decrease in tumor burden was observed. Parallel studies of in vitro exposure of nine primary human mesothelioma cell lines to mMSCs or hMSCs demonstrated reduced tumor cell migration. MSC-TRAIL exposure induced apoptosis of TRAIL-sensitive MM cells in vitro, and both mouse and human MSC-TRAIL significantly reduced the inflammatory tumor environment in vivo. Moreover, human MSC-TRAIL administration significantly reduced peritoneal tumor burden in vivo and increased tumor cell apoptosis. These proof-of-concept studies suggest that TRAIL-expressing MSCs may be useful against malignant mesothelioma.

In plain English

This laboratory study, in cell cultures and mice, did not involve asbestos exposure. The authors tested whether mesenchymal stromal cells (MSCs, adult cells taken from bone marrow) could act against human mesothelioma, including MSCs engineered to make TRAIL, a protein that can trigger cell death. In lab dishes, mouse and human MSCs reduced movement of the four most mobile of 11 mesothelioma cell lines. MSCs did not change growth of four lines tested, invasion by any of the 11, or colony formation by HMESO cells. TRAIL-making MSCs increased mesothelioma cell death, though not significantly in every combination tested. In immune-deficient mice carrying human mesothelioma in the abdomen, human TRAIL-making MSCs significantly reduced tumor weight compared with saline; the authors describe a 25% reduction. Unmodified human MSCs gave only a trend toward smaller tumors, not statistically significant against saline, and the TRAIL group did not differ significantly from these MSC groups. Mouse TRAIL-making MSCs had no significant effect on tumor burden. The authors concluded the results suggest a potential role for MSCs, especially TRAIL-expressing human MSCs, in treating mesothelioma.

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 (in vitro) cell-culture experiments plus an animal experiment: mouse xenograft model in which human mesothelioma cells were injected into the abdominal cavity of immune-deficient (SCID) mice
• Who was studied: 11 human malignant mesothelioma cell lines (pleural and peritoneal) studied in vitro, and male 6-week-old Fox Chase SCID mice injected in the abdomen with the human mesothelioma cell line HMESO. Group sizes in the main human-MSC treatment experiment were 5 saline controls, 8 hMSC-Alone, 7 hMSC-Vector and 8 hMSC-TRAIL mice.
• Exposure: No asbestos or fiber exposure was studied. The treatment tested was mouse or human bone-marrow MSCs, unmodified or engineered to express human TRAIL. In the main treatment experiment, mice received 3 × 10^5 MSCs into the abdomen twice a week for 3 weeks, starting 21 days after tumor cells were injected; controls received saline.
• Main results:
  • In mice, human TRAIL-expressing MSCs significantly reduced total tumor weight compared with saline controls.
  • Unmodified human MSCs (hMSC-Alone) and empty-vector human MSCs (hMSC-Vector) produced only a trend toward reduced tumor burden in mice, which was not statistically significant compared with saline controls.
  • The tumor burden in mice given human TRAIL-expressing MSCs was not significantly different from that in mice given the human MSC comparison groups (Alone or Vector).
  • The authors describe the reduction in tumor burden in the HMESO mouse model as 25%.
  • Mouse TRAIL-expressing MSCs (clone 87) had no significant effect on tumor burden in mice.
  • Tumors from mice treated with unmodified human MSCs or with human TRAIL-expressing MSCs showed more dying (TUNEL-positive) cells than tumors from saline controls.
  • Human MSC treatment significantly lowered levels of multiple mouse and human inflammatory signaling molecules in the abdominal (peritoneal lavage) fluid of mice.
  • In lab dishes, mouse and human MSCs significantly reduced migration of the four most migratory mesothelioma cell lines (HMESO, H2373, CRL-5820 and CRL-5915).
  • In lab dishes, soluble factors from MSCs did not significantly change the growth rate of the pleural lines HMESO and H2373, and did not change proliferation of the peritoneal lines HAY and ORT.
  • All 11 cell lines invaded only weakly across a basement membrane, and MSC exposure had no effect on invasion.
  • When MSCs were plated together with HMESO cells, the size and shape of the colonies formed and the number of live cells were unchanged.
  • In lab dishes, both clones of mouse TRAIL-expressing MSCs significantly increased the percentage of apoptotic HMESO cells. Human TRAIL-expressing MSCs significantly increased apoptosis of YOU cells; for HMESO cells, the authors report the effect of human TRAIL-expressing MSCs only approached significance.
• The authors' conclusion: The authors concluded that the results suggest a potential role for MSCs, and in particular TRAIL-expressing human MSCs, in therapeutic approaches for malignant mesothelioma.
• Limitations the authors state:
  • Studying inflammatory pathways in immunocompromised SCID mice is limited, because these mice lack adaptive immunity.
  • The number of MSCs that reached the tumors was not measured.
  • The study had no treatment group given recombinant TRAIL alone.
  • The study had no comparison group given a control cell line that was not an MSC.

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: Mesothelioma, Malignant Mesothelioma, Necrosis, Apoptosis, Inflammation, Tumor Burden.

Related studies

• Systemic but not topical TRAIL-expressing mesenchymal stem cells reduce tumour growth in malignant mesothelioma — E.K. Sage, K.K. Kolluri, et al. (2014)
• Inflammation precedes the development of human malignant mesotheliomas in a SCID mouse xenograft model — J.M. Hillegass, A. Shukla, et al. (2010)
• Mesenchymal stem cells modulate lung injury — A.R. Brody, K.D. Salazar, et al. (2010)
• Paclitaxel-releasing mesenchymal stromal cells inhibit in vitro proliferation of human mesothelioma cells — F. Petrella, V. Coccè, et al. (2017)
• Microspheres targeted with a mesothelin antibody and loaded with doxorubicin reduce tumor volume of human mesotheliomas in xenografts — S.L. Macura, J.L. Steinbacher, et al. (2013)
• Downregulation of thymidylate synthase by RNAi molecules enhances the antitumor effect of pemetrexed in an orthotopic malignant mesothelioma xenograft mouse model — A.S. Abu Lila, C. Kato, et al. (2016)

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