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VEGF-Mediated Effects on Brain Microvascular Endothelial Tight Junctions and Transmigration of Breast Cancer Cells Across the Blood-Brain Barrier

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Tight Junctions in Cancer Metastasis

Part of the book series: Cancer Metastasis - Biology and Treatment ((CMBT,volume 19))

Abstract

Breast cancer spreads to the bones, lungs, brain and liver. While the mechanisms of breast metastasis to bones and lungs have been studied and characterized, there is little information about the molecular basis for metastasis to the brain. The disruption of the blood brain barrier (BBB) by brain metastases of triple-negative and basal-type breast cancers, but not of Her2/neu positive breast cancer, was reported recently. To metastasize to the brain, breast cancer cells must attach to brain microvascular endothelial cells (BMECs) and invade the BBB. Structurally, the BBB is a barrier comprised mainly of BMECs. BBB function is maintained by the tight junctions protein complexes (TJs) between adjacent BMECs which is comprised mainly of zonula occudens-1 and -2 (ZO-1 and -2), occludin, claudins, junctional adhesion molecules, actin and cingulin. Very little is known about extravasation of breast cancer cells across the BBB and their effects on TJs expression and function as well as their interactions with BMECs.

Here, we focused on VEGF as a mediator for breast cancer cell extravasation across the BBB and the function of VEGF on TJs expression and activation of BMECs. Our results showed that breast cells with high homing capacity to the brain secrete high levels of VEGF but no Angiopoietin-2. VEGF induced significant changes in the localization and distribution of ZO-1 and claudin-5 in BMECs as well as alterations in BMEC permeability and integrity, resulting in transmigration of tumor cells across the BBB. Further, VEGF acts as an important biological determinant in remodeling and cytoskeletal reorganization in BMECs, leading to formation of brain microvasculature niche for colonization of breast cancer in brain. Thus, therapies targeted to TJs in the BBB in conjunction with anti-antiangiogenic therapies may hold significant promise for the treatment and prevention of breast cancer metastasis to the brain.

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Abbreviations

BBB:

Blood-brain barrier

BMEC:

Brain microvascular endothelial cells

CNS:

Central nervous system

EC:

Endothelial cells

FAs:

Focal adhesion sites

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

HBMECs:

Human brain microvascular endothelial cells

HUVECs:

Human umbilical vein endothelial cells

IHC:

Immunohistochemistry

IF:

Immunostaining

TEER:

Trans-endothelial electrical resistance

TJs:

Tight junctions

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

WB:

Western blotting

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Authors and Affiliations

  1. The Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Research North, 99 Brookline Avenue, Room 330F, Boston, MA, 02215, USA

    Shalom Avraham, Shuxian Jiang, Lili Wang, Yigong Fu & Hava Karsenty Avraham

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  1. Shalom Avraham
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  2. Shuxian Jiang
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  3. Lili Wang
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  4. Yigong Fu
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  5. Hava Karsenty Avraham
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Correspondence to Hava Karsenty Avraham .

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Editors and Affiliations

  1. Cardiff University, Institute of Cancer & Genetics, Heath Park, Cardiff, CF14 4XN, West Glamorgan, United Kingdom

    Tracey A. Martin

  2. Cardiff University, Institute of Cancer & Genetics, Heath Park, Cardiff, CF4 4XN, United Kingdom

    Wen G. Jiang

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Avraham, S., Jiang, S., Wang, L., Fu, Y., Avraham, H.K. (2013). VEGF-Mediated Effects on Brain Microvascular Endothelial Tight Junctions and Transmigration of Breast Cancer Cells Across the Blood-Brain Barrier. In: Martin, T., Jiang, W. (eds) Tight Junctions in Cancer Metastasis. Cancer Metastasis - Biology and Treatment, vol 19. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6028-8_10

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