Brain microvascular endothelial cell exosome–mediated S100A16 up‐regulation confers small‐cell lung cancer cell survival in brain

Abstract

Small cell lung cancer (SCLC) is the most aggressive histologic subtype of lung cancer, with a strong predilection for early brain metastases. Despite efforts and advances in new therapeutics for SCLC, the prognosis of patients with SCLC with brain metastases is consistently poor. Therefore, a better understanding of the mechanisms of SCLC brain metastasis is important in improving current treatments. In this study, elevated S100A16 levels were associated with SCLC brain metastases, which was a possible secondary event arising from the brain metastatic microenvironment. Using an in vitro cell coculture system, we found that the coculturing of SCLC cells with human brain microvascular endothelial cells (HBMECs) led to an increased expression of S100A16 in SCLC cells. Conversely, treatment of HBMECs with GW4869, an inhibitor of exosome release, significantly blocked this effect in the cocultured SCLC cells. Alternatively, the results from Western blot analyses and immunofluorescence indicated that the HBMEC exosomes purified by ultracentrifugation also induced the elevation and translocation from the cytoplasm to the nucleus of S100A16 in the recipient SCLC cells. The inhibition experiments demonstrated that elevated S100A16 contributed a benefit of HBMEC exosomes for the survival of the recipient SCLC cells under stress. Moreover, the elevation of S100A16 in SCLC cells prevented the loss of mitochondrial membrane potential (Δψm) and enhanced resistance to apoptosis under stressful conditions, which were determined by Annexin V/propidium iodide and JC-1 assay. Further results showed that the S100A16-mediated protective effect was caused by the presence of an important element in Δψm, prohibitin (PHB)-1, a protein in the mitochondrial inner membrane. Conversely, the delivery of PHB-1 siRNAs into S100A16 overexpressing SCLC cells weakened these protective effects. Our findings suggest that elevated S100A16 plays an active role in facilitating the survival of SCLC cells through modulating the mitochondrial function, identifying S100A16 as an important potential target in SCLC brain metastasis.-Xu, Z.-H., Miao, Z.-W., Jiang, Q.-Z., Gan, D.-X., Wei, X.-G., Xue, X.-Z., Li, J.-Q., Zheng, F., Qin, X.-X., Fang, W.-G., Chen, Y.-H., Li. B. Brain microvascular endothelial cell exosome-mediated S100A16 up-regulation confers small cell lung cancer cell survival in brain.

<p>Cervical Cancer Cells-Secreted Exosomal microRNA-221-3p Promotes Invasion, Migration and Angiogenesis of Microvascular Endothelial Cells in Cervical Cancer by Down-Regulating MAPK10 Expression</p>

“…Microvascular endothelial cells (MVEC) arise from a lineage of endothelial cells of the large vessels 5. MVECs have gained focus due to its function in the anti-angiogenic therapy of cancer 6. Exosomal microRNAs (miRNAs) have been recognized as therapeutic targets and markers for the development of novel therapeutic interventions for cancer 7…”

Prohibitin Protects Against Cigarette Smoke Extract-Induced Cell Apoptosis in Cultured Human Pulmonary Microvascular Endothelial Cells

“…A previous study has demonstrated that prohibitin decrease the apoptosis of endothelial cells in response to glyLDL [19]. Another study has shown that high prohibitin tumor expression is associated with poorer overall survival in patients with non-small cell lung cancer (NSCLC) and systemic delivery of PHB1 siRNA drastic inhibit tumor growth [20]. These results suggest a pro-survival activity prohibitin.…”

Could Extracellular Vesicles Contribute to Generation or Awakening of “Sleepy” Metastatic Niches?

“…There is evidence that endothelial cell-derived EVs influence tumor cells and for example, human brain microvascular endothelial-derived exosomes are thought to favor lung cancer tumor cell survival and resistance to apoptosis by increasing the levels of S100A16 (Xu et al, 2019). In a model of glioma, CD9enriched EVs derived from endothelial cells also enhance glioma stem cell tumorigenesis by activating the BMX/STAT3 axis (Li D. et al, 2019).…”