Soluble TRAIL Armed Human MSC As Gene Therapy For Pancreatic Cancer

• Type of Material: Article
• Authors: Carlotta Spano, University-Hospital of Modena and Reggio Emilia; Giulia Grisendi, University-Hospital of Modena and Reggio Emilia; Giulia Golinelli, University-Hospital of Modena and Reggio Emilia; Filippo Rossignoli, University-Hospital of Modena and Reggio Emilia; Malvina Prapa, University-Hospital of Modena and Reggio Emilia; Marco Bestagno, International Centre for Genetic Engineering and Biotechnology; Olivia Candini, University-Hospital of Modena and Reggio Emilia; Tiziana Petrachi, Technopole of Mirandola TPM; Aessandra Recchia, University of Modena and Reggio Emilia; Francesca Miselli, University of Modena and Reggio Emilia; Giulia Rovesti, University-Hospital of Modena and Reggio Emilia; Giulia Orsi, University-Hospital of Modena and Reggio Emilia; Antonino Maiorana, University of Modena and Reggio Emilia; Paola Manni, University of Modena and Reggio Emilia; Elena Veronesi, University-Hospital of Modena and Reggio Emilia; Maria Serena Piccinno, Technopole of Mirandola TPM; Alba Murgia, University-Hospital of Modena and Reggio Emilia; Massimo Pinelli, University-Hospital of Modena and Reggio Emilia; Edwin Horwitz, Emory University; Stefano Cascinu, University-Hospital of Modena and Reggio Emilia; Pierfranco Conte, University of Padua; Massimo Dominici, University-Hospital of Modena and Reggio Emilia
• Language: English
• Date: 2019-02-11
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2019, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-018-37433-6
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 9
• Issue: 1
• Start Page: 1788
• End Page: 1788
• Grant/Funding Information: This work was supported in parts by: Associazione Italiana Ricerca Cancro (AIRC) IG 2012 Grant #12755 (MD;CS;GG); AIRC IG 2015 Grant# 17326 (MD,CS,MP,FR) Ministero Italiano Istruzione Università e Ricerca PRIN 2008WECX78 (MD), the Associazione ASEOP (MD) and Project “Dipartimenti Eccellenti MIUR 2017” (MD).
• Keywords: TNF-FAMILY; Science & Technology - Other Topics; TRIMERIC TRAIL; Multidisciplinary Sciences; APO2L/TRAIL; MESENCHYMAL STEM-CELLS; Science & Technology; VEGF EXPRESSION; RECEPTOR; CRYSTAL-STRUCTURE; TUMORS IN-VIVO; APOPTOSIS-INDUCING LIGAND; DELIVERY
• Research Categories: Health Sciences, Oncology; Health Sciences, Public Health; Biology, Genetics

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is still one of the most aggressive adult cancers with an unacceptable prognosis. For this reason novel therapies accounting for PDAC peculiarities, such as the relevant stromal reaction, are urgently needed. Here adipose mesenchymal stromal/stem cells (AD-MSC) have been armed to constantly release a soluble trimeric and multimeric variant of the known anti-cancer TNF-related apoptosis-inducing ligand (sTRAIL). This cancer gene therapy strategy was in vitro challenged demonstrating that sTRAIL was thermally stable and able to induce apoptosis in the PDAC lines BxPC-3, MIA PaCa-2 and against primary PDAC cells. sTRAIL released by AD-MSC relocated into the tumor stroma was able to significantly counteract tumor growth in vivo with a significant reduction in tumor size, in cytokeratin-7+ cells and by an anti-angiogenic effect. In parallel, histology on PDAC specimens form patients (n = 19) was performed to investigate the levels of TRAIL DR4, DR5 and OPG receptors generating promising insights on the possible clinical translation of our approach. These results indicate that adipose MSC can very efficiently vehicle a novel TRAIL variant opening unexplored opportunities for PDAC treatment.