Exosomes released by oxidative stress-induced mesenchymal stem cells promote murine mammary tumor progression through activating the STAT3 signaling pathway.

Mesenchymal stem cells (MSCs) may play a pivotal role in shaping the tumor microenvironment (TME), influencing tumor growth. Nonetheless, conflicting evidence exists regarding the distinct impacts of MSCs on tumor progression, with some studies suggesting promotion while others indicate suppression of tumor cell growth. Considering that oxidative stress is implicated in the dynamic interaction between components of the TME and tumor cells, we investigated the contribution of exosomes released by hydrogen peroxide (H2O2)-treated MSCs to murine mammary tumor growth and progression. Additionally, we aimed to identify the underlying mechanism through which MSC-derived exosomes affect breast tumor growth and angiogenesis. Our findings demonstrated that exosomes released by H2O2-treated, stress-induced MSCs (St-MSC Exo) promoted breast cancer cell progression by inducing the expression of vascular endothelial growth factor (VEGF) and markers associated with epithelial-to-mesenchymal transition. Further clarification revealed that the promoting effect of St-MSC Exo on VEGF expression may, in part, depend on activating STAT3 signaling in BC cells. In contrast, exosomes derived from untreated MSCs retarded JAK1/STAT3 phosphorylation and reduced VEGF expression. Additionally, our observations revealed that the activation of the transcription factor NF-κB in BC cells, stimulated with St-MSC Exo, occurs concurrently with an increase in intracellular ROS production. Moreover, we observed that the increase in VEGF secretion into the conditioned media of 4T1 BC, mediated by St-MSC Exo, positively influenced endothelial cell proliferation, migration, and vascular behavior in vitro. In turn, our in vivo studies confirmed that St-MSC Exo, but not exosomes derived from untreated MSCs, exhibited a significant promoting effect on breast tumorigenicity. Collectively, our findings provide new insights into how MSCs may contribute to modulating the TME. We propose a novel mechanism through which exosomes derived from oxidative stress-induced MSCs may contribute to tumor progression and angiogenesis.

Circular RNAs play roles in regulatory networks of cell signaling pathways in human cancers.

AIMS: Circular RNAs (circRNAs) are endogenous covalently closed non-coding RNAs produced by reverse splicing of linear RNA. These molecules are highly expressed in mammalian cells and show cell/tissue-specific expression patterns. They are also significantly dysregulated in various cancers and function as oncogenes or tumor suppressors. Emerging evidence reveals that circRNAs contribute to cancer progression via modulating different cell signaling pathways. Nevertheless, the functional significance of circRNAs in cell signaling pathways regulation is still largely elusive. Considering this, shedding light on the multi-pathway effects of circRNAs may improve our understanding of targeted cancer therapy. Here, we discuss how circRNAs regulate the major cell signaling pathways in human cancers. MATERIALS AND METHODS: We adopted a systematic search in PubMed using the following MeSH terms: circRNAs, non-coding RNAs, lncRNAs, exosomal circRNAs, cancer, and cell signaling. KEY FINDINGS: We discussed different roles of circRNAs during tumorigenesis in which circRNAs affect tumor development through activating or inactivating certain cell signaling pathways via molecular interactions using various signaling pathways. We also discussed how crosstalk between circRNAs and lncRNAs modulate tumorigenesis and provides a resource for the identification of cancer therapeutic targets. SIGNIFICANCE: We here elucidated how circRNAs can modulate different cell signaling pathways and play roles in cancer. This can broaden our horizons toward introducing promising prognostic, diagnostic, and therapeutic targets.