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.Electronic supplementary materialThe online version of this article (10.1186/s12943-019-0959-5) contains supplementary material, which is available to authorized users.

Bone marrow mesenchymal stem cells (BMSCs) are multipotent stromal cells that can differentiate into a variety of cell types. BMSCs are chemotactically guided towards the cancer cells and contribute to the formation of a cancer microenvironment. The homing of BMSCs was affected by various factors. Disseminated tumour cells (DTCs) in distant organs, especially in the bone marrow, are the source of cancer metastasis and cancer relapse. DTC survival is also determined by the microenvironment. Here we aim to elucidate how cancer-educated BMSCs promote the survival of cancer cells at primary tumour sites and distant sites. We highlight the dynamic change by identifying different gene expression signatures in intratumoral BMSCs and in BMSCs that move back in the bone marrow. Intratumoral BMSCs acquire high mobility and displayed immunosuppressive effects. Intratumoral BMSCs that ultimately home to the bone marrow exhibit a strong immunosuppressive function. Cancer-educated BMSCs promote the survival of lung cancer cells via expansion of MDSCs in bone marrow, primary tumour sites and metastatic sites. These Ly6G+ MDSCs suppress proliferation of T cells. CXCL5, nitric oxide and GM-CSF produced by cancer-educated BMSCs contribute to the formation of malignant microenvironments. Treatment with CXCL5 antibody, the iNOS inhibitor 1400w and GM-CSF antibody reduced MDSC expansion in the bone marrow, primary tumour sites and metastatic sites, and promoted the efficiency of PD-L1 antibody. Our study reveals that cancer-educated BMSCs are the component of the niche for primary lung cancer cells and DTCs, and that they can be the target for immunotherapy.

Tumorigenesis and progression of cancer are complex processes which transformed cells and stromal cells interact and co-evolve. Intrinsic and extrinsic factors cause the mutations of cells. The survival of transformed cells critically depends on the circumstances which they reside. The malignant transformed cancer cells reprogram the microenvironment locally and systemically. The formation of premetastatic niche in the secondary organs facilitates cancer cells survival in the distant organs. This review outlines the current understanding of the key roles of premalignant niche and premetastatic niche in cancer progression. We proposed that a niche facilitates survival of transformed cells is characteristics of senescence, stromal fibrosis and obese microenvironment. We also proposed the formation of premetastatic niche in secondary organs is critically influenced by primary cancer cells. Therefore, it suggested that strategies to target the niche can be promising approach to eradicate cancer cells.

EGFR-TKIs such as erlotinib and gefitinib have been introduced into the first-line treatment for patients having a mutation of deletion in exon 19 or L858R missense mutations in exon 21. Almost all patients who respond to EGFR-TKIs at first place eventually develop acquired resistance after several months of therapy. The secondary mutations and bypass signaling activation are involved in the generation of the resistance. Hypoxia in non-small cell lung cancer (NSCLC) is an important factor in treatment resistance including radiotherapy, chemotherapy and EGFR-TKI therapy. In this study, the effect of hypoxic cancer microenvironment in the bypass signaling activation was investigated. We found that bone marrowderived mesenchymal stem cells (BMSCs) residing in the hypoxic solid cancer microenvironment highly produced molecules associated with adipocytes including adipokine leptin and IGFBPs. Leptin could induce the resistance of lung cancer cells to erlotinib through activating IGF-1R signaling. IGFBP2 counteracted the activation role of IGF-1 and induced erlotinib resistance by activating IGF-1R signaling in an IGF-1 independent manner. IGFBP2 had synergistic effect with leptin to induce erlotinib resistance. Leptin and IGFBP2 may be predictive factors for acquired resistance for EGFR-TKIs.

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