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.

Adipose-derived mesenchymal stem cells as stable source of tumor necrosis factor-related apoptosis-inducing ligand delivery for cancer therapy / Grisendi, Giulia; Bussolari, Rita; Cafarelli, Luigi; Petak, I.; Rasini, Valeria; Veronesi, Elena; De Santis, Giorgio; Spano, Maria Carlotta; Tagliazzucchi, M.; Barti Juhasz, H.; Scarabelli, Laura; Bambi, F.; Frassoldati, A.; Rossi, G.; Casali, Christian; Morandi, Uliano; Horwitz, E. M.; Paolucci, Paolo; Conte, P.; Dominici, Massimo. - In: CANCER RESEARCH. - ISSN 0008-5472. - STAMPA. - 70(2010), pp. 3718-3729. [10.1158/0008-5472.CAN-09-1865]

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

GRISENDI, Giulia;BUSSOLARI, Rita;CAFARELLI, Luigi;RASINI, Valeria;VERONESI, Elena;DE SANTIS, Giorgio;SPANO, Maria Carlotta;SCARABELLI, Laura;CASALI, Christian;MORANDI, Uliano;PAOLUCCI, Paolo;DOMINICI, Massimo
2010

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.
70
3718
3729
Adipose-derived mesenchymal stem cells as stable source of tumor necrosis factor-related apoptosis-inducing ligand delivery for cancer therapy / Grisendi, Giulia; Bussolari, Rita; Cafarelli, Luigi; Petak, I.; Rasini, Valeria; Veronesi, Elena; De Santis, Giorgio; Spano, Maria Carlotta; Tagliazzucchi, M.; Barti Juhasz, H.; Scarabelli, Laura; Bambi, F.; Frassoldati, A.; Rossi, G.; Casali, Christian; Morandi, Uliano; Horwitz, E. M.; Paolucci, Paolo; Conte, P.; Dominici, Massimo. - In: CANCER RESEARCH. - ISSN 0008-5472. - STAMPA. - 70(2010), pp. 3718-3729. [10.1158/0008-5472.CAN-09-1865]
Grisendi, Giulia; Bussolari, Rita; Cafarelli, Luigi; Petak, I.; Rasini, Valeria; Veronesi, Elena; De Santis, Giorgio; Spano, Maria Carlotta; Tagliazzucchi, M.; Barti Juhasz, H.; Scarabelli, Laura; Bambi, F.; Frassoldati, A.; Rossi, G.; Casali, Christian; Morandi, Uliano; Horwitz, E. M.; Paolucci, Paolo; Conte, P.; Dominici, Massimo
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/640282
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