In vitro and in vivo discrepancy in inducing apoptosis by mesenchymal stromal cells delivering membrane-bound tumor necrosis factor-related apoptosis inducing ligand in osteosarcoma pre-clinical models

Cytotherapy. 2018 Aug;20(8):1037-1045. doi: 10.1016/j.jcyt.2018.06.013. Epub 2018 Aug 6.

Abstract

Background: Osteosarcoma (OS) is the most frequent pediatric malignant bone tumor. OS patients have not seen any major therapeutic progress in the last 30 years, in particular in the case of metastatic disease, which requires new therapeutic strategies. The pro-apoptotic cytokine Tumor necrosis factor (TNF)-Related Apoptosis Inducing Ligand (TRAIL) can selectively kill tumor cells while sparing normal cells, making it a promising therapeutic tool in several types of cancer. However, many OS cell lines appear resistant to recombinant human (rh)TRAIL-induced apoptosis. We, therefore, hypothesized that TRAIL presentation at the membrane level of carrier cells might overcome this resistance and trigger apoptosis.

Methods: To address this, human adipose mesenchymal stromal cells (MSCs) transfected in a stable manner to express membrane-bound full-length human TRAIL (mbTRAIL) were co-cultured with several human OS cell lines.

Results: This induced apoptosis by cell-to-cell contact even in cell lines initially resistant to rhTRAIL. In contrast, mbTRAIL delivered by MSCs was not able to counteract tumor progression in this OS orthotopic model.

Discussion: This was partly due to the fact that MSCs showed a potential to support tumor development. Moreover, the expression of mbTRAIL did not show caspase activation in adjacent tumor cells.

Keywords: Tumor necrosis factor (TNF)–Related Apoptosis Inducing Ligand; mesenchymal stromal cells; osteosarcoma.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer / methods
  • Animals
  • Apoptosis* / drug effects
  • Apoptosis* / genetics
  • Bone Neoplasms / genetics
  • Bone Neoplasms / pathology
  • Bone Neoplasms / therapy*
  • Cells, Cultured
  • Genetic Therapy / methods
  • Humans
  • In Vitro Techniques
  • Mesenchymal Stem Cell Transplantation* / methods
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism*
  • Mice
  • Mice, Nude
  • Osteosarcoma / genetics
  • Osteosarcoma / pathology
  • Osteosarcoma / therapy*
  • TNF-Related Apoptosis-Inducing Ligand / genetics
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*
  • Transfection
  • Xenograft Model Antitumor Assays

Substances

  • TNF-Related Apoptosis-Inducing Ligand