Dynamic transition of the blood-brain barrier in the development of non-small cell lung cancer brain metastases.

Hsin-Yi Weng,L. Tiffany Lyle,Alexandra M. Dieterly,Arvin H. Soepriatna,Michael K. Wendt,Aparna B. Shinde,Gozde Uzunalli,Chinyere M. Kemet,Craig J. Goergen

doi:10.18632/oncotarget.27274

Hsin-Yi Weng, L. Tiffany Lyle + Show 7 more

Open Access

https://doi.org/10.18632/oncotarget.27274

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Journal: Oncotarget	Publication Date: Oct 29, 2019
Citations: 35	License type: cc-by

Affiliation: Purdue University West Lafayette

Abstract

Invasion of the brain by non-small cell lung cancer (NSCLC) results in a shift of the blood-brain barrier (BBB) to the insufficiently characterized blood-tumor barrier (BTB). Effective drug delivery through the BTB is one of the greatest therapeutic obstacles in treating brain metastases. Using an experimental model, we defined key changes within the BTB and the BBB in the brain around the tumor (BAT) region over time. Brain-seeking NSCLC cells were delivered into the circulation of athymic-nude mice via intracardiac injection and developing brain metastases were evaluated over six-weeks. Components of the BBB and BTB were analyzed using immunofluorescence microscopy and compared using a mixed model of regression. Our results demonstrate a dynamic time-dependent BTB phenotype. Capillaries of the BAT and BTB were dilated with increased CD31 expression compared to controls. Expression of collagen IV, a pan-basement membrane component, was significantly decreased in the BTB compared to the BBB. There was also a significant increase in the desmin-positive pericyte subpopulation in the BTB compared to the BBB. The most striking changes were identified in astrocyte water channels with a 12.18-fold (p < 0.001) decrease in aquaporin-4 in the BTB; the BAT was unchanged. Analysis of NSCLC brain metastases from patient samples similarly demonstrated dilated capillaries and loss of both collagen IV and aquaporin-4. These data provide a comprehensive analysis of the BTB in NSCLC brain metastasis. Astrocytic endfeet, pericytes, and the basement membrane are potential therapeutic targets to improve efficacy of chemotherapeutic delivery into NSCLC brain metastases.

Highlights

In the United States, lung cancer is the leading cause of cancer-related deaths with a 19% five-year survival rate
This unique vascular barrier is composed of endothelial cells with distinct tight junctions, a parenchymal and endothelial basement membrane, pericytes embedded within the basement membrane, and polarized astrocyte endfeet [11]
We demonstrated the dynamic transition of the blood-brain barrier (BBB) to the blood-tumor barrier (BTB) in an experimental model of Non-small cell lung cancer (NSCLC) brain metastasis

Summary

Introduction

In the United States, lung cancer is the leading cause of cancer-related deaths with a 19% five-year survival rate. In 2019, 142,670 lung cancer patients are expected to die of lung cancer in the United States [1]. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer worldwide [2,3,4] and often metastasizes to bone, liver, and brain [5]. NSCLC brain metastases patients receive multimodal therapies including whole brain radiotherapy, stereotactic radiosurgery, surgical resection, immunotherapy and chemotherapy [7, 8]. NSCLC brain metastases shrink with chemotherapy; these metastases typically recur and are resistant to additional treatment [9, 10]

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