Microcirculatory Disorders of Cerebral Blood Flow and the Hypoxic-Ischemic Microenvironment Related to Brain Metastasis Development

Background and Research Motivation

Brain metastasis (BM) is an increasing challenge in oncology due to its severe impact on neurological function, limited treatment options, and resulting poor prognosis. BM develops through the extravasation of circulating tumor cells (CTCs) across the blood-brain barrier (BBB). However, this extravasation process remains poorly understood. In this study, the authors propose a brain colonization process that mimics stroke-like microenvironment responses, dependent on the actions of angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF). The aim is to investigate the roles of these factors in the development of brain metastasis.

Source and Research Institutions

This study was jointly authored by Jenny Roesler, Daniel Spitzer, and others, from multiple institutions including the Clinical Neurology Department of Frankfurt University Hospital (Edinger Institute), the German Cancer Consortium (DKTK), and the Neurosurgical Department of Tianjin Huanhu Hospital in China. The article was published in 2024 in the journal “Neuro-Oncology”.

Research Process

Experimental Design and Procedures

1. Animal Models and Experimental Observation

   • A heart-brain metastasis model was used, with two-photon microscopy used through a cranial window to detect cerebral blood microcirculation. The formation of brain metastasis was observed through MRI, bioluminescence imaging (BLI), and post-mortem autopsy.
   • The experiments included Ang-2/VEGF targeted strategies and Ang-2 gain of function (GOF) mice to interfere with brain metastasis formation. The authors also analyzed vascular and stromal factors and clinical outcomes in brain metastasis patients.

2. Microcirculation and Local Hypoxic-Ischemic Response

   • In mouse models and human brain metastasis tissues, cancer cells caused vascular blockage, accompanied by significant cerebral blood microcirculatory disorders and localized stroke-like histological features.
   • By measuring blood flow velocity and using two-photon microscopy through a cranial window, the authors observed a significant reduction in red blood cell flow rate, confirming local hypoxia and ischemia.

3. Expression of Ang-2 and VEGF in Brain Colonization

   • The study found significant upregulation of Ang-2 expression in cerebral endothelial cells in both mouse and human brain metastasis models. Brain metastasis burden increased in Ang-2 GOF mice.
   • During early brain metastasis, hypoxia-induced Ang-2 and VEGF expression around blood vessels promoted cancer cell extravasation and brain colonization. Dual anti-Ang-2/VEGF treatment reduced the size and number of brain metastases.

Main Research Results

1. Cancer Cell-Induced Vascular Blockage and Changes in Cerebral Blood Microcirculation

   • The experiments demonstrated that cancer cell-induced vascular blockage significantly altered cerebral blood microcirculation, leading to local hypoxia and ischemia.
   • Unlike in normal animals, stroke-like pathology caused by cancer cell blockage in experimental animals partially overlapped with the sites of subsequent metastases, preliminarily suggesting a close relationship between early brain metastasis colonization and the hypoxic microenvironment.

2. Roles of Ang-2 and VEGF in Brain Metastasis

   • During brain metastasis formation, Ang-2 and VEGF play crucial regulatory roles in the microenvironment. Cerebral microvascular endothelial cells and tumor cells exhibit high expression of Ang-2 and VEGF, respectively, enhancing brain microvascular permeability and promoting tumor cell migration and colonization through vessel walls.
   • Specific experimental methods showed a significant increase in brain cancer cell extravasation and brain metastasis burden in Ang-2 GOF mice, indicating that Ang-2 plays a critical promoting role during early stages of brain metastasis.

3. Efficacy of Combined Anti-Ang-2 and Anti-VEGF Therapy

   • Combined anti-Ang-2 and anti-VEGF therapy significantly inhibited brain metastasis burden, particularly in mixed stromal tumors, effectively reducing the number and size of brain metastases by blocking the microenvironmental effects of Ang-2 and VEGF.

Research Conclusions and Significance

This study reveals the link between cerebral blood microcirculatory disorders and brain metastasis formation, indicating that cancer cell-induced vascular blockage accelerates tumor cell extravasation and colonization in the brain. Inhibiting the microenvironmental effects of Ang-2 and VEGF can prevent the growth of large metastatic tumors. The research opens new avenues for the early treatment of brain metastasis and suggests that combined anti-Ang-2 and anti-VEGF therapy might significantly improve therapeutic outcomes.

Research Highlights

1. New Findings

   • Discovery of cancer cell-induced vascular blockage leading to local hypoxia and ischemia responses, similar to stroke-like pathological changes, which play a role in brain metastasis formation.
   • Quantitative analysis shows the critical regulatory roles of Ang-2 and VEGF in brain metastasis formation and tumor extravasation.

2. New Methods

   • Blood flow velocity measurement with two-photon microscopy provides direct experimental data by observing cerebral blood flow changes in mouse models.
   • The application of combined anti-Ang-2 and anti-VEGF therapy in experimental mice demonstrates its potential efficacy in brain metastasis treatment.

3. Clinical Significance

   • The results indicate that early intervention strategies for brain metastasis should consider combined inhibition of Ang-2 and VEGF for better treatment outcomes. These new findings may further promote clinical translational research and the development of new therapeutic approaches.

Future Directions

Future studies should investigate the effects of radiation therapy on cancer cell extravasation and the proposed mechanisms. Additionally, exploring the pre-metastatic niche as a haven for metabolically aberrant tumor cells, and identifying high-risk patients prone to brain metastasis for preventive treatment are critical future research topics. Combined inhibition of Ang-2 and VEGF seems to help maintain metastatic tumor cells in a dormant state, thereby keeping patients clinically asymptomatic.

Summary

Brain metastasis is a complex biological process involving multiple microenvironmental changes. This study reveals the key roles of Ang-2 and VEGF in brain metastasis, proposes new therapeutic strategies, and points out future research directions, providing valuable reference materials for both basic and clinical research on brain metastasis.