Research Papers:

Self-assembling nanoparticles encapsulating zoledronic acid inhibit mesenchymal stromal cells differentiation, migration and secretion of proangiogenic factors and their interactions with prostate cancer cells

Cinzia Borghese, Naike Casagrande, Eliana Pivetta, Alfonso Colombatti, Mariarosaria Boccellino, Evzen Amler, Nicola Normanno, Michele Caraglia, Giuseppe De Rosa and Donatella Aldinucci _

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Oncotarget. 2017; 8:42926-42938. https://doi.org/10.18632/oncotarget.17216

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Cinzia Borghese1,*, Naike Casagrande1,*, Eliana Pivetta1, Alfonso Colombatti1, Mariarosaria Boccellino2,3, Evzen Amler4,5, Nicola Normanno6, Michele Caraglia2,3, Giuseppe De Rosa7 and Donatella Aldinucci1

1Molecular Oncology Unit, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano, PN, Italy

2Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy

3Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA

4Indoor Environmental Quality, University Center for Energy Efficient Buildings, Czech Technical University in Prague, Buštěhrad, Czech Republic

5Laboratory of Tissue Engineering, Institute of Experimental Medicine, Czech Academy of Sciences, Prague, Czech Republic

6Cell Biology & Biotherapy Unit, Istituto Nazionale Tumori “Fondazione G Pascale”-IRCCS, Naples, Italy

7Department of Pharmacy, Federico II University of Naples, Naples, Italy

*These authors have contributed equally to this work

Correspondence to:

Donatella Aldinucci, email: [email protected]

Keywords: zoledronic acid, self-assembling nanoparticles, mesenchymal stromal cells, prostate cancer, tumor microenvironment

Received: January 21, 2017    Accepted: March 22, 2017    Published: April 19, 2017


Zoledronic Acid (ZA) rapidly concentrates into the bone and reduces skeletal-related events and pain in bone metastatic prostate cancer (PCa), but exerts only a limited or absent impact as anti-cancer activity. Recently, we developed self-assembling nanoparticles (NPS) encapsulating zoledronic acid (NZ) that allowed a higher intratumor delivery of the drug compared with free zoledronic acid (ZA) in in vivo cancer models of PCa. Increasing evidence suggests that Bone Marrow (BM) Mesenchymal stromal cells (BM-MSCs) are recruited into the stroma of developing tumors where they contribute to progression by enhancing tumor growth and metastasis.

We demonstrated that treatment with NZ decreased migration and differentiation into adipocytes and osteoblasts of MSCs and inhibited osteoclastogenesis. Treatment with NZ reduced the capability of MSCs to promote the migration and the clonogenic growth of the prostate cancer cell lines PC3 and DU145. The levels of Interleukin-6 and of the pro-angiogenic factors VEGF and FGF-2 were significantly reduced in MSC-CM derived from MSCs treated with NZ, and CCL5 secretion was almost totally abolished. Moreover, treatment of MSCs with supernatants from PC3 cells, leading to tumor-educated MSCs (TE-MSCs), increased the secretion of IL-6, CCL5, VEGF and FGF-2 by MSCs and increased their capability to increase PC3 cells clonogenic growth. Treatment with NZ decreased cytokine secretion and the pro-tumorigenic effects also of TE-MSCS. In conclusion, demonstrating that NZ is capable to inhibit the cross talk between MSCs and PCa, this study provides a novel insight to explain the powerful anticancer activity of NZ on PCa.

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