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

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

来源：Cancer Research, 2010, 70(9): 3718-3729.

DOI：10.1158/0008-5472.CAN-09-1865

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.

• 出版日期2010-5-1