title: Pre-activated human mesenchymal stromal cells in combination with doxorubicin synergistically enhance tumor-suppressive activity in mice.
abstract: OBJECTIVE
  Previously, we showed that human mesenchymal stromal cells (hMSCs) were activated to express tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) upon TNF-α stimulation, induced cell death in triple-negative breast cancer (TNBC) MDA-MB-231 cells (MDA), and RNA released from apoptotic MDA further increased TRAIL expression in hMSCs. This feed-forward stimulation increased apoptosis in MDA cells. Here, we tested whether TRAIL-expressing hMSCs, in combination with a sub-toxic-dose of a chemotherapy drug doxorubicin, would overcome TRAIL resistance and create synergistic effects on targeting metastatic TNBC.
  
  
  METHODS
  To optimize conditions for the combination treatment, we (i) selected an optimal condition to activate hMSCs for TRAIL expression, (ii) selected an optimal dose of doxorubicin treatment, (iii) examined underlying mechanisms in vitro and (iv) tested the efficacy of the optimized conditions in a xenograft mouse model of human breast cancer lung metastasis.
  
  
  RESULTS
  The results showed that DNA fragments from apoptotic MDA triggered hMSCs to increase further TRAIL expression in an absent in melanoma 2 (AIM2)-dependent manner, and thus higher TRAIL-expressing hMSCs stimulated with synthetic DNA, poly(deoxyadenylic-deoxythymidylic) acid [poly(dA:dT)], more effectively suppressed tumor progression in vivo. Furthermore, activated hMSCs increased apoptosis in MDA cells when combined with a sub-toxic dose of doxorubicin, which was mediated by up-regulating TRAIL and Fas-related pathways. When we combined the optimized conditions, pre-activated hMSCs with poly (dA:dT) synergistically reduced tumor burden even with minimal doxorubicin treatment in a xenograft mouse model of human breast cancer lung metastasis.
  
  
  CONCLUSIONS
  These results suggest that the treatment of hMSCs with a sub-toxic dose of doxorubicin can overcome TRAIL resistance and be a potential novel therapy for TNBC metastasis treatment.
authors.affiliation: Institute for Regenerative Medicine, College of Medicine, Texas A&M University Health Science Center, Temple, Texas, USA.
authors.forename: Nara
authors.initials: N
authors.lastname: Yoon
authors.affiliation: Institute for Regenerative Medicine, College of Medicine, Texas A&M University Health Science Center, Temple, Texas, USA.
authors.forename: Min Sung
authors.initials: MS
authors.lastname: Park
authors.affiliation: Institute for Regenerative Medicine, College of Medicine, Texas A&M University Health Science Center, Temple, Texas, USA.
authors.forename: Grantham C
authors.initials: GC
authors.lastname: Peltier
authors.affiliation: Institute for Regenerative Medicine, College of Medicine, Texas A&M University Health Science Center, Temple, Texas, USA. Electronic address: rlee@medicine.tamhsc.edu.
authors.forename: Ryang Hwa
authors.initials: RH
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000235:genetics; D053938:DNA Fragmentation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D011067:Poly dA-dT / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C540422:Aim2 protein, mouse; D004268:DNA-Binding Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D011067:Poly dA-dT; D004317:Doxorubicin; C510592:Ifih1 protein, mouse; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1
keywords: IFIH1; Poly (I:C); bone marrow; multipotent stromal cells