Curcumin-Loaded Nanoparticles Impair the Pro-Tumor Activity of Acid-Stressed MSC in an In Vitro Model of Osteosarcoma.

Gemma Di Di Pompo,Elena Bellotti,Sofia Avnet,Margherita Cortini,Roberto Palomba,Valentina Di Di Francesco,Nicola Baldini,Paolo Decuzzi

doi:10.3390/ijms22115760

Abstract

In the tumor microenvironment, mesenchymal stromal cells (MSCs) are key modulators of cancer cell behavior in response to several stimuli. Intratumoral acidosis is a metabolic trait of fast-growing tumors that can induce a pro-tumorigenic phenotype in MSCs through the activation of the NF-κB-mediated inflammatory pathway, driving tumor clonogenicity, invasion, and chemoresistance. Recent studies have indicated that curcumin, a natural ingredient extracted from Curcuma longa, acts as an NF-κB inhibitor with anti-inflammatory properties. In this work, highly proliferating osteosarcoma cells were used to study the ability of curcumin to reduce the supportive effect of MSCs when stimulated by acidosis. Due to the poor solubility of curcumin in biological fluids, we used spherical polymeric nanoparticles as carriers (SPN-curc) to optimize its uptake by MSCs. We showed that SPN-curc inhibited the release of inflammatory cytokines (IL6 and IL8) by acidity-stimulated MSCs at a higher extent than by free curcumin. SPN-curc treatment was also successful in blocking tumor stemness, migration, and invasion that were driven by the secretome of acid-stressed MSCs. Overall, these data encourage the use of lipid–polymeric nanoparticles encapsulating NF-κB inhibitors such as curcumin to treat cancers whose progression is stimulated by an activated mesenchymal stroma.

Highlights

Published: 28 May 2021The tumor microenvironment (TME) consists of several normal host cells in an extracellular matrix containing various solutes, and provides a milieu that enables cancer survival [1]
We have recently developed spherical polymeric nanoparticles (SPN) encapsulating curcumin (SPN-curc), and demonstrated their ability to effectively diminish the vascular deposition of circulating tumor cells (CTCs) from a highly metastatic breast cancer cell line [51], to prevent tumor growth in combination with conventional chemotherapeutic molecules [52], and to counteract amyloid-β fibrils-induced inflammation [53]
Since we previously demonstrated that extracellular acidosis activates the transcriptional inflammatory factor NF-κB complex [21], we verified whether curcumin effectively impairs the acid-induced secretion of NF-κB-mediated inflammatory cytokines in BM-mesenchymal stromal cells (MSCs)

Summary

Introduction

The tumor microenvironment (TME) consists of several normal host cells in an extracellular matrix containing various solutes, and provides a milieu that enables cancer survival [1] Under certain conditions, this heterogeneous and complex ecosystem may promote cancer aggressiveness and migration, and contribute to the failure of current anticancer therapies. MSCs are a heterogeneous class of self-renewing, multipotent progenitor cells that reside in the bone marrow, but can be found in other tissues [3] Their physiological functions include a tendency to migrate to sites of injury [4], to support the repair and regeneration of damaged tissues [5], and to modulate the immune response [6]. In the TME, MSCs interact with tumor cells and other reactive elements through several paracrine molecules in a complex crosstalk that facilitates tumor growth, metastasis, and resistance to therapy [7,8]

Objectives

Methods

Results

Conclusion