Adipose-derived mesenchymal stem cells as stable source of tumor necrosis factor-related apoptosis-inducing ligand delivery for cancer therapy

Giulia Grisendi, Rita Bussolari, Luigi Cafarelli, Istvan Petak, Valeria Rasini, Elena Veronesi, Giorgio De Santis, Carlotta Spano, Mara Tagliazzucchi, Helga Barti-Juhasz, Laura Scarabelli, Franco Bambi, Antonio Frassoldati, Giulio Rossi, Christian Casali, Uliano Morandi, Edwin M. Horwitz, Paolo Paolucci, Pierfranco Conte, Massimo Dominici

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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.

Original languageEnglish
Pages (from-to)3718-3729
Number of pages12
JournalCancer Research
Volume70
Issue number9
DOIs
Publication statusPublished - May 1 2010

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Grisendi, G., Bussolari, R., Cafarelli, L., Petak, I., Rasini, V., Veronesi, E., De Santis, G., Spano, C., Tagliazzucchi, M., Barti-Juhasz, H., Scarabelli, L., Bambi, F., Frassoldati, A., Rossi, G., Casali, C., Morandi, U., Horwitz, E. M., Paolucci, P., Conte, P., & Dominici, M. (2010). Adipose-derived mesenchymal stem cells as stable source of tumor necrosis factor-related apoptosis-inducing ligand delivery for cancer therapy. Cancer Research, 70(9), 3718-3729. https://doi.org/10.1158/0008-5472.CAN-09-1865