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Leukemic cells can impact the bone marrow niche to create a tumor-favorable microenvironment using their secreted factors. Little knowledge is available about immunosuppressive and tumor-promoting properties of chronic myeloid leukemia derived exosomes in bone marrow stromal components. We report here that K562-derived exosomes can affect the gene expression, cytokine secretion, nitric oxide (NO) production, and redox potential of bone marrow mesenchymal stem cells (BM-MSCs) and macrophages. Human BM-MSCs and mouse macrophages were treated with K562-derived exosomes. Our results demonstrated that the expression of the genes involved in hematopoietic developmental pathways and immune responses, including C-X-C motif chemokine 12 (Cxcl12), Dickkopf-related protein 1 (DKK1), wnt5a, interleukin 6 (IL-6), transforming growth factor-beta, and tumor necrosis factor-alpha (TNF-alpha), changed with respect to time and exosome concentration in BM-MSCs. The TNF-alpha level was higher in exosome-treated BM-MSCs compared with the control. Exosome treatment of BM-MSCs led to an increased production of NO and a decreased production of reactive oxygen species (ROS) in a time-and concentration-dependent manner. We have shown that K562-derived exosomes induce overexpression of IL-10 and TNF-alpha and downregulation of iNOS transcript levels in macrophages. The enzyme-linked immunosorbent assay results showed that TNF-alpha and IL-10 secretions increased in macrophages.Treatment of macrophages with purified exosomes led to reduced NO and ROS levels. These results suggest that K562-derived exosomes may alter the local bone marrow niche toward a leukemia-reinforcing microenvironment. They can modulate the inflammatory molecules (TNF-alpha and NO) and the redox potential of BM-MSCs and macrophages and direct the polarization of macrophages toward tumor-associated macrophages. K E Y W O R D S bone marrow mesenchymal stem cells (BM-MSC), chronic myeloid leukemia (CML)-derived exosomes, immunosuppression, macrophages, tumor microenvironment

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Crocus sativus L. (saffron) has been used as a spice and as a medicine for the past four thousand years. Recently, saffron has been well documented to possess anticancer effects on primary tumors. However studies of its antimetastatic potential are lacking. The present study is a comparative investigation of the antimetastatic effects of saffron carotenoids, crocin and crocetin, on triple negative metastatic breast cancer cells (4T1) and their effects on the Wnt/β-catenin pathway. It was found that treatment of 4T1 cells with crocin and crocetin resulted in the inhibition of viability in a dose-dependent manner. Scratch and Transwell chamber assays showed that the nontoxic doses of crocin and crocetin significantly inhibited migration, cell mobility, and invasion, also attenuating adhesion to extracellular matrix. Crocin downregulated mRNA expression of FZD7, NEDD9, VIM, and VEGF-α genes and upregulated E-CAD. Crocin and crocetin exhibited comparable anti-invasion properties on 4T1 cells. However, crocin and crocetin exerted more pronounced antimigration and antiadhesion potency, respectively. Furthermore, we showed that the antimetastatic effects of crocin can occur through interfering with the Wnt/β-catenin pathway.

No abstract