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Genes that Mediate Metastasis across the Blood-Brain Barrier.

ABSTRACT: Brain metastasis is an important cause of mortality in patients with cancer and represents the majority of all intracranial tumors. A key step during the metastatic journey of the cancer cell to the brain is the invasion through the blood-brain barrier (BBB). Nevertheless, the molecular mechanisms that govern this process remain unknown. The BBB has been blamed for limiting the access of therapeutic drugs to the brain, which provides a safe haven for cancer cells in the brain and confers poor prognosis for the patient. Here, we explore the genes that control the transmigration of metastatic cancer cells across the BBB, offering new targets for the development of gene and cell therapies against brain metastases.

SUBMITTER: Fares J

PROVIDER: S-EPMC7392815 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Genes that Mediate Metastasis across the Blood-Brain Barrier.

Fares Jawad J Kanojia Deepak D Rashidi Aida A Ulasov Ilya I Lesniak Maciej S MS

Trends in cancer 20200513 8

Brain metastasis is an important cause of mortality in patients with cancer and represents the majority of all intracranial tumors. A key step during the metastatic journey of the cancer cell to the brain is the invasion through the blood-brain barrier (BBB). Nevertheless, the molecular mechanisms that govern this process remain unknown. The BBB has been blamed for limiting the access of therapeutic drugs to the brain, which provides a safe haven for cancer cells in the brain and confers poor pr ...[more]

PMID: 32417182

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Project description:BackgroundEffective chemotherapeutics for primary systemic tumors have limited access to brain metastases because of the blood-brain barrier (BBB). The aim of this study was to develop a strategy for specifically permeabilizing the BBB at sites of cerebral metastases.MethodsBALB/c mice were injected intracardially to induce brain metastases. After metastasis induction, either tumor necrosis factor (TNF) or lymphotoxin (LT) was administered intravenously, and 2 to 24 hours later gadolinium- diethylenetriaminepentaacetic acid, horseradish peroxidase, or radiolabeled trastuzumab ((111)In-BnDTPA-Tz) was injected intravenously. BBB permeability was assessed in vivo using gadolinium-enhanced T1-weighted magnetic resonance imaging and confirmed histochemically. Brain uptake of (111)In-BnDTPA-Tz was determined using in vivo single photon emission computed tomography/computed tomography. Endothelial expression of TNF receptors was determined immunohistochemically in both mouse and human brain tissue containing metastases. Group differences were analyzed with one-way analysis of variance followed by post hoc tests, Wilcoxon signed rank test, and Kruskal-Wallis with Dunn's multiple comparison test. All statistical tests were two-sided.ResultsLocalized expression of TNF receptor 1 (TNFR1) was evident on the vascular endothelium associated with brain metastases. Administration of TNF or LT permeabilized the BBB to exogenous tracers selectively at sites of brain metastasis, with peak effect at 6 hours. Metastasis-specific uptake ratio of (111)In-BnDTPA-Tz was also demonstrated after systemic TNF administration vs control (0.147±0.066 vs 0.001±0.001). Human brain metastases displayed a similar TNF receptor profile compared with the mouse model, with predominantly vascular TNFR1 expression.ConclusionsThese findings describe a new approach to selectively permeabilize the BBB at sites of brain metastases to aid in detection of micrometastases and facilitate tumor-specific access of chemotherapeutic agents. We hypothesize that this permeabilization works primarily though TNFR1 activation and has the potential for clinical translation.

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Genes that Mediate Metastasis across the Blood-Brain Barrier.

Publications

Genes that Mediate Metastasis across the Blood-Brain Barrier.

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