Adipose-derived mesenchymal stem cells as stable source of tumor necrosis factor-related apoptosis-inducing ligand delivery for cancer therapy.
Adipose-derived mesenchymal stromal/stem cells (AD-MSC) may offer efficient tools for cell-based gene therapy approaches. In this study, we evaluated whether AD-MSC could deliver proapoptotic molecules for cancer treatment. Human AD-MSCs were isolated and transduced with a retroviral vector encoding full-length human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a proapoptotic ligand that induces apoptosis in a variety of human cancers but not normal tissues. Although several studies have documented the antitumor activity of recombinant human TRAIL, its use in vivo is limited by a short half-life in plasma due to a rapid clearance by the kidney. We found that these limitations can be overcome using stably transduced AD-MSC, which could serve as a constant source of TRAIL production. AD-MSC armed with TRAIL targeted a variety of tumor cell lines in vitro, including human cervical carcinoma, pancreatic cancer, colon cancer, and, in combination with bortezomib, TRAIL-resistant breast cancer cells. Killing activity was associated with activation of caspase-8 as expected. When injected i.v. or s.c. into mice, AD-MSC armed with TRAIL localized into tumors and mediated apoptosis without significant apparent toxicities to normal tissues. Collectively, our results provide preclinical support for a model of TRAIL-based cancer therapy relying on the use of adipose-derived mesenchymal progenitors as cellular vectors.
Grisendi
Giulia
G
Department of Oncology, Hematology and Respiratory Diseases, Plastic Surgery Unit, University-Hospital of Modena and Reggio Emilia, Modena, Italy.
Bussolari
Rita
R
Cafarelli
Luigi
L
Petak
Istvan
I
Rasini
Valeria
V
Veronesi
Elena
E
De Santis
Giorgio
G
Spano
Carlotta
C
Tagliazzucchi
Mara
M
Barti-Juhasz
Helga
H
Scarabelli
Laura
L
Bambi
Franco
F
Frassoldati
Antonio
A
Rossi
Giulio
G
Casali
Christian
C
Morandi
Uliano
U
Horwitz
Edwin M
EM
Paolucci
Paolo
P
Conte
Pierfranco
P
Dominici
Massimo
M
D017667:Adipocytes / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D053181:Caspase 8 / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology; D018920:Coculture Techniques; D004789:Enzyme Activation; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D011719:Pyrazines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D014161:Transduction, Genetic; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*
D001897:Boronic Acids; D011719:Pyrazines; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D000069286:Bortezomib; D053181:Caspase 8