The Role of Brain Barriers in Brain Metastasis

Background Introduction

Brain metastases (BMs) are the most common intracranial tumors in adults, occurring 3 to 10 times more frequently than primary brain tumors. Despite multimodal treatments including surgical resection, radiotherapy, and chemotherapy, the prognosis for brain metastases remains poor, and treatment is challenging. Brain metastases predominantly originate from lung cancer (20-56%), breast cancer (5-20%), and melanoma (7-16%), but can also arise from other types of cancer. The process of brain metastasis involves multiple steps, including local invasion, entry into the bloodstream or lymphatic system, extravasation into normal tissue, and colonization of distant sites. Upon reaching the brain, circulating tumor cells (CTCs) must breach the blood-brain barrier (BBB).

The selective permeability of the BBB poses a significant challenge for therapeutic compounds, limiting the efficacy of treatments for brain metastases. Therefore, understanding the mechanisms of tumor cell interactions with the BBB is crucial for developing effective therapies. This review provides an in-depth analysis of brain barriers, including the BBB, blood-spinal cord barrier (BSCB), and blood-cerebrospinal fluid barrier (B-CSF barrier), focusing on their molecular and cellular components and their roles in brain metastasis. The review emphasizes the importance of this knowledge for identifying druggable targets to prevent or limit the formation of brain metastases.

Source of the Paper

This paper was co-authored by Nasim Izadi, Peter Solár, Klaudia Hašanová, Alemeh Zamani, and others, and published in the journal Fluids and Barriers of the CNS in 2025. The authors are affiliated with the Masaryk Memorial Cancer Institute and the Faculty of Medicine at Masaryk University in the Czech Republic. The paper is published under an open-access license, following the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Key Points

1. Structure and Function of Brain Barriers

Brain barriers are critical components of the central nervous system (CNS), primarily including the blood-brain barrier (BBB), blood-spinal cord barrier (BSCB), and blood-cerebrospinal fluid barrier (B-CSF barrier). These barriers regulate the exchange of nutrients, ions, drugs, and other substances between the blood and brain tissue, maintaining CNS homeostasis.

• Blood-Brain Barrier (BBB): The BBB is composed of brain endothelial cells, pericytes, and astrocytic end-feet, forming a highly selective barrier. Tight junctions (TJs) between endothelial cells restrict the movement of cells and molecules, allowing only small hydrophobic molecules to pass.
• Blood-Spinal Cord Barrier (BSCB): The BSCB is functionally equivalent to the BBB, protecting the spinal cord microenvironment. Compared to the BBB, the BSCB has higher permeability, partly due to lower expression levels of tight junction proteins and transporters.
• Blood-Cerebrospinal Fluid Barrier (B-CSF Barrier): Located in the choroid plexus (CP) of the brain ventricles, the B-CSF barrier is formed by epithelial cells connected by tight junctions, controlling the entry of substances into the cerebrospinal fluid (CSF).

2. Interaction Between Tumor Cells and Brain Barriers

Tumor cells breach brain barriers through various mechanisms, including the secretion of proteases and activation of signaling pathways that disrupt BBB integrity. The interaction between tumor cells and the BBB involves multiple molecular and cellular components, such as tight junction proteins, transporters, and the extracellular matrix (ECM).

• Tight Junction Proteins: The BBB’s tight junctions consist of transmembrane proteins (e.g., claudin and occludin) and cytoplasmic proteins (e.g., zonula occludens proteins, ZO). Tumor cells secrete proteases that degrade these proteins, increasing BBB permeability.
• Extracellular Matrix (ECM): Degradation of the ECM is a key step in tumor cell migration and invasion. Tumor cells secrete enzymes such as matrix metalloproteinases (MMPs) to degrade the ECM, facilitating their passage through the BBB.

3. Role of Exosomes in Brain Metastasis

Exosomes are small vesicles released by tumor cells, carrying proteins, lipids, and nucleic acids, and are involved in intercellular communication. Tumor-derived exosomes (TDEs) play a significant role in brain metastasis by altering the tumor microenvironment, promoting tumor cell migration, and facilitating invasion.

• Exosomes and BBB Disruption: TDEs carry microRNAs (e.g., miR-105 and miR-181c) that downregulate tight junction proteins (e.g., ZO-1) in the BBB, increasing its permeability and enabling tumor cells to enter the brain.
• Exosomes and Immune Microenvironment Regulation: TDEs modulate immune cell function to promote immune evasion by tumor cells. For example, TDEs carrying miR-503 can shift microglia from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype, suppressing the immune system’s ability to kill tumor cells.

4. Mechanisms of Brain Metastasis in Lung Cancer, Breast Cancer, and Melanoma

Different types of cancer exhibit distinct molecular mechanisms and signaling pathways in brain metastasis.

• Lung Cancer: Lung cancer is one of the most common causes of brain metastasis, particularly non-small cell lung cancer (NSCLC). Mutations in genes such as EGFR and KRAS play a significant role in lung cancer brain metastasis. EGFR mutations are strongly associated with the incidence of brain metastasis, especially in East Asian populations.
• Breast Cancer: The incidence of brain metastasis is higher in HER2-positive and triple-negative breast cancer (TNBC). HER2 overexpression promotes tumor cell migration and invasion by activating signaling pathways such as STAT3 and RAS-MAPK.
• Melanoma: Melanoma brain metastasis (MBM) has a high incidence and is closely related to the activation of the STAT3 signaling pathway. STAT3 promotes angiogenesis, cell invasion, and immune suppression, facilitating melanoma brain metastasis.

5. Challenges and Future Directions in Brain Metastasis Treatment

The treatment of brain metastasis faces multiple challenges, primarily due to the BBB’s restriction of therapeutic drug penetration into the brain. Future research directions include developing drugs that can cross the BBB, targeting molecular mechanisms of tumor cell-BBB interactions, and utilizing exosomes as diagnostic and therapeutic biomarkers.

Significance and Value of the Paper

This review comprehensively summarizes the role of brain barriers in brain metastasis, detailing the molecular mechanisms of tumor cell interactions with the BBB and proposing potential strategies for future treatments. By elucidating the complex mechanisms of brain metastasis, the paper provides a critical theoretical foundation for developing new therapeutic approaches, offering significant scientific and clinical value.

Highlights

• Comprehensiveness: The paper covers multiple components of brain barriers and their roles in brain metastasis, providing a holistic perspective.
• Innovation: This is the first systematic exploration of the role of exosomes in brain metastasis, revealing their critical role in BBB disruption and immune modulation.
• Application Value: The molecular mechanisms and potential therapeutic targets proposed in this paper offer new directions for future brain metastasis treatments.

Through this review, researchers and clinicians can gain a deeper understanding of the complex mechanisms of brain metastasis, laying the groundwork for developing more effective treatments.