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Adenosine A2A receptor activation reduces brain metastasis via SDF-1/CXCR4 axis and protecting blood-brain barrier
Lei Chen1,2, Liangdong Li1,2, Changshuai Zhou1,2
1Department of Neurosurgery, Fudan University Shanghai Cancer Center, Shanghai, China.
Abstract:
Brain metastasis is a leading cause of death worldwide, but the mechanism involved remains unclear. Stromal cell-derived factor-1 (SDF-1)/C-X-C motif chemokine receptor 4 (CXCR4) signaling has been reported to induce the directed metastasis of cancers, and adenosine A2A receptor activation suppresses the SDF-1/CXCR4 interaction. However, whether A2A receptor activation implicates the SDF-1/CXCR4 signaling pathway and thus modulates brain metastasis remains unclear. In this study, Western blot was performed to evaluate the protein levels. Cell invasion and migration assays were used to estimate the metastasis ability of PC-9 cells. The viability of cells was demonstrated by lactate dehydrogenase and cell proliferation assays. And the findings in vitro were further identified in nude mice. Notably, adenosine A2A receptor activation inhibited the proliferation and viability of PC-9 cells and thus suppressed the brain metastasis. A2A receptor stimulation protected the function of blood-brain barrier (BBB). The suppression of brain metastasis and the protection of BBB by A2A receptor relied on SDF-1/CXCR4 signaling, and treatment using A2A receptor agonist and CXCR4 antagonist protected the nude mice from malignancy metastasis in vivo. Adenosine A2A receptor activation suppressed the brain metastasis by implicating the SDF-1/CXCR4 axis and protecting the BBB.
Insights
Adenosine A2A receptor activation suppresses brain metastasis by targeting the SDF-1/CXCR4 pathway. This action inhibits cancer cell proliferation and protects the blood-brain barrier, reducing cancer spread.
Area of Science:
- Oncology
- Neuroscience
- Pharmacology
Background:
- Brain metastasis is a major cause of cancer-related mortality, with unclear underlying mechanisms.
- Stromal cell-derived factor-1 (SDF-1) and C-X-C motif chemokine receptor 4 (CXCR4) signaling are implicated in cancer metastasis.
- Adenosine A2A receptor (A2AAR) activation is known to inhibit SDF-1/CXCR4 interactions, but its role in brain metastasis is not fully understood.
Purpose of the Study:
- To investigate whether A2AAR activation modulates brain metastasis via the SDF-1/CXCR4 signaling pathway.
- To assess the therapeutic potential of A2AAR agonists in preventing brain metastasis and maintaining blood-brain barrier integrity.
Main Methods:
- Western blot analysis to quantify protein levels.
- In vitro cell invasion, migration, proliferation, and viability assays (LDH assay).
- In vivo studies using nude mice models to evaluate metastasis and blood-brain barrier protection.
Main Results:
- A2AAR activation significantly inhibited PC-9 cell proliferation and viability.
- A2AAR stimulation suppressed brain metastasis and protected blood-brain barrier function in vivo.
- The observed effects were dependent on the SDF-1/CXCR4 signaling pathway, as confirmed by in vivo treatments with A2AAR agonists and CXCR4 antagonists.
Conclusions:
- Adenosine A2A receptor activation effectively suppresses brain metastasis by modulating the SDF-1/CXCR4 axis.
- A2AAR activation plays a protective role in maintaining blood-brain barrier integrity.
- Targeting the A2AAR represents a potential therapeutic strategy against brain metastasis.
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