Exploration of neurological tumour derivation across the Blood-Brain Barrier and development of Artemisinin and its derivatives as metastatic breast cancer therapies

Ji, Wenxiao 2025. Exploration of neurological tumour derivation across the Blood-Brain Barrier and development of Artemisinin and its derivatives as metastatic breast cancer therapies. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

This doctoral research thoroughly investigates the mechanisms underlying breast cancer metastasis to the brain, particularly focusing on the role and modulation of the blood-brain barrier (BBB) and the potential therapeutic application of Artemisinin and its derivatives. Brain metastasis remains a significant obstacle in breast cancer treatment due to the impermeable nature of the BBB, which substantially restricts the efficacy of existing therapeutic strategies. The study comprehensively explores the function of tight junction proteins, specifically claudin-8 (CLDN8), in regulating BBB permeability and the metastatic progression of breast cancer cells. To address this, extensive experimental methodologies were employed, including advanced molecular biology techniques such as quantitative real-time PCR, RNA sequencing for global gene expression profiling, Western blotting for protein expression validation, and immunofluorescence microscopy to assess protein localisation changes. Functional cellular assays, including invasion, migration, and adhesion assays, were rigorously performed to evaluate the biological impacts of CLDN8 expression changes. Additionally, BBB integrity assays involving transendothelial electrical resistance (TEER) measurements and paracellular permeability assays were utilized to precisely quantify barrier function. Key findings demonstrated that Artemisinin treatment markedly influences the expression levels and subcellular localization of tight junction proteins, especially causing a significant reduction in CLDN8 expression. This downregulation was associated with increased permeability of the BBB, facilitating improved penetration of therapeutic agents into the brain tissues. Further mechanistic investigations revealed critical interactions between CLDN8 and pivotal signalling pathways, notably the β-catenin pathway, providing insights into the molecular mechanisms driving Artemisinin's effects. Incorporation of clinical samples enhanced the translational value of this study, where analyses confirmed that decreased CLDN8 expression correlated with enhanced metastatic capability and poorer clinical outcomes in breast cancer patients. Complementary bioinformatic analyses utilizing patient data from The Cancer Genome Atlas (TCGA) provided additional validation, underscoring the prognostic significance of CLDN8 and other tight junction components in breast cancer metastasis to the brain. Ultimately, this comprehensive study significantly advances our understanding of the BBB's regulatory mechanisms in metastatic breast cancer and identifies Artemisinin and its derivatives as promising candidates for improving therapeutic outcomes. These results present a robust foundation for future clinical exploration, aiming to overcome current treatment barriers associated with breast cancer brain metastasis, thereby contributing valuable knowledge towards the development of more effective clinical strategies

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	21 October 2025
Last Modified:	21 Oct 2025 09:12
URI:	https://orca.cardiff.ac.uk/id/eprint/181781

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