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

doi:10.18632/oncotarget.17216

Abstract

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.

Highlights

MSCs are pluripotent progenitor cells that contribute to the maintenance and regeneration of a variety of connective tissues, including bone and adipose tissue [1,2,3,4]
MSCs participate in prostate cancer (PCa) carcinogenesis and growth [8] and are recruited and activated into Carcinoma-Associated Fibroblasts (CAF) by molecules secreted by the Tumor Microenvironment (TME)[9]
Treatment with nanoparticles encapsulating Zoledronic acid (NZ) decreased in a dose dependent manner MSCs migration and, at the low concentrations, it was more active than Zoledronic Acid (ZA) (Figure 1B)

Summary

Introduction

MSCs are pluripotent progenitor cells that contribute to the maintenance and regeneration of a variety of connective tissues, including bone and adipose tissue [1,2,3,4]. MSCs recruited and “educated” by tumor cells, through direct and/or indirect interaction with tumor cells, can support tumor growth, promote angiogenesis, inhibit the development of an efficient antitumor response, induce drug resistance, invasion and even metastases [1,2,3,4,5,6,7]. MSCs participate in prostate cancer (PCa) carcinogenesis and growth [8] and are recruited and activated into Carcinoma-Associated Fibroblasts (CAF) by molecules secreted by the Tumor Microenvironment (TME)[9]. ZA exerts biological activity on MSCs differentiation [12] and inhibits the secretion by MSCs of cytokines involved in breast cancer cell migration [13] and in monocytes recruitment [14]. In PCa cellular models ZA impairs PCa-induced M2-macrophages polarization and prevents the M2 macrophages-mediated activation of normal fibroblasts [15]

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Results

Discussion

Conclusion