AUTHOR=Gan Dong-Xue , Wang Yi-Bei , He Ming-Yang , Chen Zi-Yang , Qin Xiao-Xue , Miao Zi-Wei , Chen Yu-Hua , Li Bo 

TITLE=Lung Cancer Cells-Controlled Dkk-1 Production in Brain Metastatic Cascade Drive Microglia to Acquire a Pro-tumorigenic Phenotype

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 8 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2020.591405

DOI=10.3389/fcell.2020.591405

ISSN=2296-634X

ABSTRACT=Objectives: Organotropism is primarily determined by tumor-derived exosomes. To date, the role of lung cancer cells-derived exosomes underlying the pre-metastatic niche formation is unclear. 
Materials and methods: The animal models of retro-orbital and intra-ventricular injection were constructed to administrate lung cancer cell-derived exosomes. Cytokine array was used to screen the cytokines released from brain endothelium after internalization of lung cancer cells-derived exosomes. The cellular co-culture system was established to mimic microglia-vascular niche contained lung cancer cells-derived exosomes. The levels of Dkk-1 and the activities of microglia were analyzed by qRT-PCR, western blot and immunofluorescence. In vivo selections of highly brain metastatic cells were performed to analyze the direct interaction of lung cancer cells with microglia.     
Results: Animal studies demonstrated that there was a suppressive signal transferred from brain endothelium to microglia after internalization of lung cancer cells-derived exosomes into brain endothelium, which caused an absolutely less M1 phenotypic microglia and a relatively more M2 phenotypic microglia. Further results indicated that lung cancer cells-derived exosomes induced a release of endogenous Dkk-1 from brain endothelium, which rendered microglia to acquire a pro-tumorigenic feature in pre-metastatic niche. Subsequently, the declines of Dkk-1 in metastatic lung cancer cells removed the suppression on microglia and enhanced microglial activation in metastatic niche.
Conclusion: Our findings shed a new light on the synergistic reaction of the different cells in “neurovascular units” towards the metastatic messages from lung cancer cells and provided a potential therapeutic pathway for lung cancer metastasis to brain.