Abstract
BackgroundMetastasis is the main cause of lung cancer mortality. Bone marrow-derived mesenchymal stem cells (BMSCs) are a component of the cancer microenvironment and contribute to cancer progression. Intratumoral hypoxia affects both cancer and stromal cells. Exosomes are recognized as mediators of intercellular communication. Here, we aim to further elucidate the communication between BMSC-derived exosomes and cancer cells in the hypoxic niche.MethodsExosomal miRNA profiling was performed using a microRNA array. Lung cancer cells and an in vivo mouse syngeneic tumor model were used to evaluate the effects of select exosomal microRNAs. Hypoxic BMSC-derived plasma exosomal miRNAs were assessed for their capacity to discriminate between cancer patients and non-cancerous controls and between cancer patients with or without metastasis.ResultsWe demonstrate that exosomes derived from hypoxic BMSCs are taken by neighboring cancer cells and promote cancer cell invasion and EMT. Exosome-mediated transfer of select microRNAs, including miR-193a-3p, miR-210-3p and miR-5100, from BMSCs to epithelial cancer cells activates STAT3 signaling and increases the expression of mesenchymal related molecules. The diagnostic accuracy of individual microRNA showed that plasma exosomal miR-193a-3p can discriminate cancer patients from non-cancerous controls. A panel of these three plasma exosomal microRNAs showed a better diagnostic accuracy to discriminate lung cancer patients with or without metastasis than individual exosomal microRNA.ConclusionsExosome-mediated transfer of miR-193a-3p, miR-210-3p and miR-5100, could promote invasion of lung cancer cells by activating STAT3 signalling-induced EMT. These exosomal miRNAs may be promising noninvasive biomarkers for cancer progression.
Highlights
Metastasis is the main cause of lung cancer mortality
Identifying exosomal miRNAs secreted from hypoxic Bone marrow-derived mesenchymal stem cells (BMSCs) that improve the invasion of lung cancer cells It has long been known that hypoxia is the main feature of cancer microenvironments
Hematoxylin and eosin-stained sections showed more metastatic nodules in the lungs in the mixture-injection group (Fig. 1c). These results indicate that co-injection of BMSCs and Lewis lung carcinoma (LLC) into syngeneic mice leads to increased growth of the primary cancer and metastasis to lung
Summary
Metastasis is the main cause of lung cancer mortality. Bone marrow-derived mesenchymal stem cells (BMSCs) are a component of the cancer microenvironment and contribute to cancer progression. Intratumoral hypoxia affects both cancer and stromal cells. We aim to further elucidate the communication between BMSC-derived exosomes and cancer cells in the hypoxic niche. Lung cancer is the leading cause of cancer-related mortality. There is significant interest in roles of exosomal miRNAs in the development of cancer, especially in the non-invasive detection of cancer progression. Hypoxia is a feature of solid tumours [13].The rapid growth of cancer cells exceeds oxygen delivery, producing local hypoxia. Hypoxia enhances the release of exosomes containing CD63 and CD9 [15]. Stress can alter the content of exosomes [12]
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