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.
Highlights
There are more than 150,000 new cases of pancreatic ductal adenocarcinoma (PDAC) diagnosed every year between USA and Europe with an unacceptable 5-years survival rate of 5%1,2
The gene encoding for the soluble TRAIL was synthetized by linking different domains and cell modification was confirmed by the capacity to release soluble TRAIL
Others generated soluble TRAIL variants produced by E. coli, P. pastoris, the 293T cell line, by intra-tumor delivered adenoviral vector, by delivering of sTRAIL gene via nanoparticles targeting tumor stroma, by engineered human, rat and murine bone marrow Mesenchymal stromal/stem cells (MSC) and by transfected mesenchymal cells derived from pancreatic tissue[31,32,42,43,44,45,46,47,48,49,50,51]
Summary
There are more than 150,000 new cases of pancreatic ductal adenocarcinoma (PDAC) diagnosed every year between USA and Europe with an unacceptable 5-years survival rate of 5%1,2. PDAC is relatively resistant to traditional agents, including gemcitabine, 5-fluouracil, taxanes, and platin-derivatives[5], making the prognosis poor with median survival time reported to be between 5.7 and 11.1 months[6,7,8,9] This still dramatic scenario suggests the need of new approaches capable to take into account PDAC peculiarities. Together with more traditional PDAC targeting agents, strategies able to modify its microenvironment allowing a more performing intra tumor penetration of molecules are demanded The development of these novel tools aimed at a local deliver of highly active anti-PDAC agents targeting both tumor and his stroma may possibly change the natural history of this still deadly cancer. We conceived a novel TRAIL variant capable to be released as a soluble ligand by AD-MSC
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