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Breast Cancer Metastasis and Drug Resistance pp 211–226Cite as

Cellular and Molecular Mechanisms Involved in Breaching of the Blood–Brian Barrier by Circulating Breast Cancer Cells

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Abstract

Brain metastases are prevalent in lung, melanoma and breast cancers and are associated with high morbidity and mortality. Therefore, targeted treatments and preventative strategies of brain metastasis are needed. Brain metastases of breast cancer confer significant morbidity and appear to be increasing in incidence (~35 %) in subpopulations of metastatic breast cancer patients, particularly those with Her2+ or “triple-negative” breast cancer (TNBC). Current therapy for brain metastases of breast cancer involves radiation, surgery and chemotherapy. Unfortunately, both disease progression in brain and treatments cause significant patient morbidity, including cognitive defects. The main question is how are circulating breast tumor cells (CBTCs) able to penetrate the blood–brain barrier (BBB) and gain access to the brain parenchyma, forming brain metastases. The BBB is a dynamic and highly selective barrier due to existence of tight junctions and adherens junctions between adjacent brain microvascular endothelial cells (BMECs). Although, the disruption of the BBB by brain metastases of human triple-negative and basal-type breast cancer was observed, very little is known on the cellular and molecular mechanisms involved in the process of CBTC infiltration through the BBB. This review focuses on the BBB and BMECs as well as several biological determinants by which breast tumor cells infiltrate the BBB and activate BMECs, resulting in co-option and colonization of tumor cells in brain.

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Abbreviations

Ang:

Angiopoietin

Ang-2:

Angiopoietin-2

α-SMA:

Alpha smooth muscle actin

BBB:

Blood–brain barrier

BCM:

Breast cancer metastasis

BCM/brain:

Breast cancer metastasis in brain

BMECs:

Brain microvascular endothelial cells

BTB:

Blood–tumor barrier

CBTCs:

Circulating breast tumor cells

CNS:

Central nervous system

DMECs:

Dermal microvascular endothelial cells

EC:

Endothelial cells

ER− :

Estrogen receptor negative

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

HUVECs:

Human umbilical vein endothelial cells

HBMECs:

Human brain microvascular endothelial cells

IHC:

Immunohistochemistry

IF:

Immunostaining

LCM:

Laser capture microdissection

PR− :

Progesterone receptor negative

RT-PCR:

Reverse transcription polymerase chain reaction

TJs:

Tight junctions

TEER:

Trans-endothelial electrical resistance

TNBCs:

Triple negative and basal type breast cancer

VEGF:

Vascular endothelial growth factor

VEGFR-2:

Vascular endothelial growth factor receptor 2

WB:

Western blotting

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Acknowledgments

This research was supported in part by CA135226, DOD Idea Awards (HA), and BC102246, and BC-094909.

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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, Boston, MA, 02115, USA

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

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  1. Hava Karsenty Avraham
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Correspondence to Hava Karsenty Avraham .

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Editors and Affiliations

  1. School of Medicine, Karmanos Cancer Institute, Wayne State University, John R Street 4100, Detroit, 48201, Michigan, USA

    Aamir Ahmad

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Avraham, H.K., Jiang, S., Wang, L., Fu, Y., Avraham, S. (2013). Cellular and Molecular Mechanisms Involved in Breaching of the Blood–Brian Barrier by Circulating Breast Cancer Cells. In: Ahmad, A. (eds) Breast Cancer Metastasis and Drug Resistance. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5647-6_12

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