Adipose-Derived Mesenchymal Stem Cells as Stable Source of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Delivery for Cancer Therapy

Cancer Research - Tập 70 Số 9 - Trang 3718-3729 - 2010
Giulia Grisendi1,2,3, Rita Bussolari1,2,3, Luigi Cafarelli1,2,3, István Peták1,2,3, Valeria Rasini1,2,3, Elena Veronesi1,2,3, Giorgio De Santis1,2,3, Carlotta Spano1,2,3, Mara Tagliazzucchi1,2,3, Helga Barti-Juhász1,2,3, Laura Scarabelli1,2,3, Franco Bambi1,2,3, Antonio Frassoldati1,2,3, Giulio Rossi1,2,3, Christian Casali1,2,3, Uliano Morandi1,2,3, Edwin M. Horwitz1,2,3, Paolo Paolucci1,2,3, Pierfranco Conté1,2,3, Massimo Dominici1,2,3
1Authors' Affiliations: 1Department of Oncology, Hematology and Respiratory Diseases, 2Plastic Surgery Unit, 3Department of Laboratory and Pathology, 4Department of Mother and Child, 5Department of Pathologic Anatomy and Forensic Medicine, Section of Pathology, and 6Chest Surgery Division, University-Hospital of Modena and Reggio Emilia, Modena, Italy; 7Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary; 8Blood Bank and Cellular Therapy Unit, Meyer Hospital, Firenze, Italy; and 9Division of Oncology/Blood and Marrow Transplantation, The Children's Hospital of Philadelphia and The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
2Blood Bank and Cellular Therapy Unit, Meyer Hospital, Firenze, Italy
3Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary

Tóm tắt

Abstract 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. Cancer Res; 70(9); 3718–29. ©2010 AACR.

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Cancer Research

Tập 70 Số 9

3718-3729

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