Core–shell nanoparticles suppress metastasis and modify the tumour-supportive activity of cancer-associated fibroblasts

Abstract

Background: Although accumulating evidence suggests that the crosstalk between malignant cells and cancerassociated fibroblasts (CAFs) actively contributes to tumour growth and metastatic dissemination, therapeutic strategies targeting tumour stroma are still not common in the clinical practice. Metal-based nanomaterials have been shown to exert excellent cytotoxic and anti-cancerous activities, however, their effects on the reactive stroma have never been investigated in details. Thus, using feasible in vitro and in vivo systems to model tumour microenvironment, we tested whether the presence of gold, silver or gold-core silver-shell nanoparticles exerts anti-tumour and metastasis suppressing activities by influencing the tumour-supporting activity of stromal fibroblasts. Results: We found that the presence of gold-core silver-shell hybrid nanomaterials in the tumour microenvironment attenuated the tumour cell-promoting behaviour of CAFs, and this phenomenon led to a prominent attenuation of metastatic dissemination in vivo as well. Mechanistically, transcriptome analysis on tumour-promoting CAFs revealed that silver-based nanomaterials trigger expressional changes in genes related to cancer invasion and tumour metastasis. Conclusions: Here we report that metal nanoparticles can influence the cancer-promoting activity of tumour stroma by affecting the gene expressional and secretory profiles of stromal fibroblasts and thereby altering their intrinsic crosstalk with malignant cells. This potential of metal nanomaterials should be exploited in multimodal treatment approaches and translated into improved therapeutic outcomes.

Nanohydroxyapatite (nHAp) Doped with Iron Oxide Nanoparticles (IO), miR-21 and miR-124 Under Magnetic Field Conditions Modulates Osteoblast Viability, Reduces Inflammation and Inhibits the Growth of Osteoclast – A Novel Concept for Osteoporosis Treatment: Part 1

“… 9 We have shown previously that magnetic iron particles (IOs) promote the osteogenic activity of progenitor cells. 23 In the current study, nHAp/IO composite was used as a delivery platform for the controlled release of functional microRNAs, ie, miR-21 and miR-124. We have tested the influence of the obtained composite nHAp/IO@miR-21/124 on viability, morphology, growth pattern, metabolic activity, mitochondrial potential and mitochondrial network development in murine pre-osteoblasts and pre-osteoblasts cell lines.…”

“…We have recently shown that nHAp doped with IOs after exposition to the magnetic field promotes the expression of osteogenic markers in osteoblasts through integrin alpha-3 (INTa-3) activation, simultaneously inhibiting osteoclasts activity. 23 The nHAp/IOs composites reduced tartrate-resistant acid phosphatase activity (TRAP) and cathepsin K – two major regulators of osteoclasts metabolism. Moreover, we showed that nHAp doped with IOs could trigger apoptosis in osteoclasts via activation of BAX-p21-p53 and CASP-9 axis.…”

“…The combination of both nHAp and IOs under magnetic field condition influenced osteoblast precursors (MC3T3-E1), activating the expression of transcripts coding osteopontin (OPN), bone morphogenetic protein −2 (BMP-2), collagen type 1 (COL1A1) as well as alkaline phosphatase (ALP) – all factors crucial for bone regeneration and remodelling. 23 The combination of nHAp and IOs also brings additional advantages since IOs allow their trucking to use magnetic resonance imaging (MRI) and deliver particular agents, including genes, growth factors or miRNA. 24 , 25 …”

Application of Bionanomaterials in Tumor Immune Microenvironment Therapy

“…Besides the combination therapy of nanomaterials and chemotherapy, nanoparticles affect the gene expression and secretion of CAFs, thereby altering their intrinsic interactions with malignant cells and affecting the protumor activity of the TIME. It has been demonstrated that Au-Ag nanoparticles achieve remarkable metastasis-suppressing activity by directly inhibiting adenocarcinoma cell proliferation, as well as indirectly by affecting cancer-associated fibroblasts by reducing their cancer-promoting function and regulating their secretory profiles [ 68 ]. In addition, due to the off-target distribution of anticancer nanoparticles to CAFs, researchers have exploited nanoparticles that can genetically modify CAFs into cells producing secretable TNF-related apoptosis-inducing ligand (sTRAIL) efficiently in situ, leading to apoptosis in the adjacent tumor cells in mice [ 69 ].…”

Nanomedicine-based drug delivery towards tumor biological and immunological microenvironment

“…The peptide liposome FH-SSL-Nav exhibited increased cellular uptake and cytotoxicity in vitro , as well as improved antitumor efficacy in a Hep G2 tumor mouse model. A recent report 119 has shown that the tumor cell-promoting behavior of CAFs can be attenuated by gold-core silver-shell hybrid nanomaterials. In the in vivo study, the nanomaterial showed promising results in inhibiting tumor metastasis.…”