title: Stem Cell Implants for Cancer Therapy: TRAIL-Expressing Mesenchymal Stem Cells Target Cancer Cells In Situ.
abstract: OBJECTIVE
  Tumor-specific delivery of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), an apoptosis-inducing peptide, at effective doses remains challenging. Herein we demonstrate the utility of a scaffold-based delivery system for sustained therapeutic cell release that capitalizes on the tumor-homing properties of mesenchymal stem cells (MSCs) and their ability to express genetically-introduced therapeutic genes.
  
  
  METHODS
  Implants were formed from porous, biocompatible silk scaffolds seeded with full length TRAIL-expressing MSCs (FLT-MSCs). under a doxycycline inducible promoter. In vitro studies with FLT-MSCs demonstrated TRAIL expression and antitumor effects on breast cancer cells. Next, FLT-MSCs were administered to mice using three administration routes (mammary fat pad co-injections, tail vein injections, and subcutaneous implantation on scaffolds).
  
  
  RESULTS
  In vitro cell-specific bioluminescent imaging measured tumor cell specific growth in the presence of stromal cells and demonstrated FLT-MSC inhibition of breast cancer growth. FLT-MSC implants successfully decreased bone and lung metastasis, whereas liver metastasis decreased only with tail vein and co-injection administration routes. Average tumor burden was decreased when doxycycline was used to induce TRAIL expression for co-injection and scaffold groups, as compared to controls with no induced TRAIL expression.
  
  
  CONCLUSIONS
  This implant-based therapeutic delivery system is an effective and completely novel method of anticancer therapy and holds great potential for clinical applications.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA. ; Department of Medicine, Harvard Medical School, Boston, USA. ; Department of Biomedical Engineering, Tufts University, Medford, USA.
authors.forename: Michaela R
authors.initials: MR
authors.lastname: Reagan
authors.forename: F Philipp
authors.initials: FP
authors.lastname: Seib
authors.forename: Douglas W
authors.initials: DW
authors.lastname: McMillin
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Sage
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
authors.forename: Sam M
authors.initials: SM
authors.lastname: Janes
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
authors.forename: David L
authors.initials: DL
authors.lastname: Kaplan
keywords: Breast neoplasms; Mesenchymal stem cells; TNF-related apoptosis-inducing ligand; Tissue engineering; Tissue therapy