Dataset Information

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

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 cells-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" toward the metastatic messages from lung cancer cells and provided a potential therapeutic pathway for lung cancer metastasis to brain.

SUBMITTER: Gan DX

PROVIDER: S-EPMC7769850 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

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

Gan Dong-Xue DX Wang Yi-Bei YB He Ming-Yang MY Chen Zi-Yang ZY Qin Xiao-Xue XX Miao Zi-Wei ZW Chen Yu-Hua YH Li Bo B

Frontiers in cell and developmental biology 20201215

<h4>Objectives</h4>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.<h4>Materials and methods</h4>The animal models of retro-orbital and intra-ventricular injection were constructed to administrate lung cancer cells-derived exosomes. Cytokine array was used to screen the cytokines released from brain endothelium after internalization of lung cancer cells-derived exosom ...[more]

PMID: 33384994

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Project description:BackgroundDisseminated tumor cells (DTCs) in the bone marrow may exist in a dormant state for extended periods of time, maintaining the ability to proliferate upon activation, engraft at new sites, and form detectable metastases. However, understanding of the behavior and biology of dormant breast cancer cells in the bone marrow niche remains limited, as well as their potential involvement in tumor recurrence and metastasis. Therefore, the purpose of this study was to investigate the tumorigenicity and metastatic potential of dormant disseminated breast cancer cells (prior to activation) in the bone marrow.Methodology/principal findingsTotal bone marrow, isolated from mice previously injected with tumorspheres into the mammary fat pad, was injected into the mammary fat pad of NUDE mice. As a negative control, bone marrow isolated from non-injected mice was injected into the mammary fat pad of NUDE mice. The resultant tumors were analyzed by immunohistochemistry for expression of epithelial and mesenchymal markers. Mouse lungs, livers, and kidneys were analyzed by H+E staining to detect metastases. The injection of bone marrow isolated from mice previously injected with tumorspheres into the mammary fat pad, resulted in large tumor formation in the mammary fat pad 2 months post-injection. However, the injection of bone marrow isolated from non-injected mice did not result in tumor formation in the mammary fat pad. The DTC-derived tumors exhibited accelerated development of metastatic lesions within the lung, liver and kidney. The resultant tumors and the majority of metastatic lesions within the lung and liver exhibited a mesenchymal-like phenotype.Conclusions/significanceDormant DTCs within the bone marrow are highly malignant upon injection into the mammary fat pad, with the accelerated development of metastatic lesions within the lung, liver and kidney. These results suggest the acquisition of a more aggressive phenotype of DTCs during metastatic latency within the bone marrow microenvironment.

Dataset Information

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

Objectives

Materials and methods

Results

Conclusion

Publications

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

Similar Datasets

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