scholarly journals Circulating MicroRNAs and Blood-Brain-Barrier Function in Breast Cancer Metastasis

2020 ◽  
Vol 26 (13) ◽  
pp. 1417-1427 ◽  
Author(s):  
Carolin J. Curtaz ◽  
Constanze Schmitt ◽  
Kinga G. Blecharz-Lang ◽  
Norbert Roewer ◽  
Achim Wöckel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Brain Barrier ◽  
Target Cells ◽  
Breast Cancer Patients ◽  
Blood Brain ◽  
The Brain

Brain metastases are a major cause of death in breast cancer patients. A key event in the metastatic progression of breast cancer in the brain is the migration of cancer cells across the blood-brain barrier (BBB). The BBB is a natural barrier with specialized functions that protect the brain from harmful substances, including antitumor drugs. Extracellular vesicles (EVs) sequestered by cells are mediators of cell-cell communication. EVs carry cellular components, including microRNAs that affect the cellular processes of target cells. Here, we summarize the knowledge about microRNAs known to play a significant role in breast cancer and/or in the BBB function. In addition, we describe previously established in vitro BBB models, which are a useful tool for studying molecular mechanisms involved in the formation of brain metastases.

scholarly journals Blood-Brain Barrier Integrity and Breast Cancer Metastasis to the Brain

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Farheen Arshad ◽  
Lili Wang ◽  
Christopher Sy ◽  
Shalom Avraham ◽  
Hava Karsenty Avraham
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Brain Barrier ◽  
Treatment Modalities ◽  
Blood Brain ◽  
The Brain

Brain metastasis, an important cause of cancer morbidity and mortality, occurs in at least 30% of patients with breast cancer. A key event of brain metastasis is the migration of cancer cells through the blood-brain barrier (BBB). Although preventing brain metastasis is immensely important for survival, very little is known about the early stage of transmigration and the molecular mechanisms of breast tumor cells penetrating the BBB. The brain endothelium plays an important role in brain metastasis, although the mechanisms are not clear. Brain Microvascular Endothelial Cells (BMECs) are the major cellular constituent of the BBB. BMECs are joined together by intercellular tight junctions (TJs) that are responsible for acquisition of highly selective permeability. Failure of the BBB is a critical event in the development and progression of several diseases that affect the CNS, including brain tumor metastasis development. Here, we have delineated the mechanisms of BBB impairment and breast cancer metastasis to the brain. Understanding the molecular mediators that cause changes in the BBB should lead to better strategies for effective treatment modalities targeted to inhibition of brain tumors.

scholarly journals A PET study in healthy subjects of brain exposure of 11C-labelled osimertinib – A drug intended for treatment of brain metastases in non-small cell lung cancer

2019 ◽  
Vol 40 (4) ◽  
pp. 799-807 ◽  
Author(s):  
Andrea Varrone ◽  
Katarina Varnäs ◽  
Aurelija Jucaite ◽  
Zsolt Cselényi ◽  
Peter Johnström ◽  
...  
Keyword(s):  
White Matter ◽  
Brain Metastases ◽  
Blood Brain Barrier ◽  
Healthy Subjects ◽  
Standardized Uptake Value ◽  
Brain Barrier ◽  
Pharmacokinetic Parameters ◽  
Blood Brain ◽  
Brain Exposure ◽  
The Brain

Osimertinib is a tyrosine kinase inhibitor (TKI) of the mutated epidermal growth factor receptor (EGFRm) with observed efficacy in patients with brain metastases. Brain exposure and drug distribution in tumor regions are important criteria for evaluation and confirmation of CNS efficacy. The aim of this PET study was therefore to determine brain distribution and exposure of 11C-labelled osimertinib administered intravenously in subjects with an intact blood–brain barrier. Eight male healthy subjects (age 52 ± 8 years) underwent one PET measurement with 11C-osimertinib. The pharmacokinetic parameters Cmax (brain) (standardized uptake value), Tmax (brain) and AUC0–90 min brain/blood ratio were calculated. The outcome measure for 11C-osimertinib brain exposure was the total distribution volume ( VT). 11C-osimertinib distributed rapidly to the brain, with higher uptake in grey than in white matter. Mean Cmax, Tmax and AUC0–90 min brain/blood ratio were 1.5 (range 1–1.8), 13 min (range 5–30 min), and 3.8 (range 3.3–4.1). Whole brain and white matter VT were 14 mL×cm−3 (range 11–18) and 7 mL×cm−3 (range 5–12). This study in healthy volunteers shows that 11C-osimertinib penetrates the intact blood–brain barrier. The approach used further illustrates the role of molecular imaging in facilitating the development of novel drugs for the treatment of malignancies affecting the brain.

scholarly journals Disruption of the blood brain barrier by brain metastases of triple-negative and basal-type breast cancer but notHER2/neu-positive breast cancer

Cancer ◽  
2010 ◽  
Vol 116 (2) ◽  
pp. 302-308 ◽  
Author(s):  
Kan Yonemori ◽  
Koji Tsuta ◽  
Makiko Ono ◽  
Chikako Shimizu ◽  
Akihiro Hirakawa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Blood Brain Barrier ◽  
Triple Negative ◽  
Brain Barrier ◽  
Blood Brain ◽  
Basal Type ◽  
Positive Breast Cancer

scholarly journals Uptake of ANG1005, A Novel Paclitaxel Derivative, Through the Blood-Brain Barrier into Brain and Experimental Brain Metastases of Breast Cancer

2009 ◽  
Vol 26 (11) ◽  
pp. 2486-2494 ◽  
Author(s):  
Fancy C. Thomas ◽  
Kunal Taskar ◽  
Vinay Rudraraju ◽  
Satyanarayana Goda ◽  
Helen R. Thorsheim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals RADI-03. A strategy to personalize the use of radiation in patients with brain metastasis based on S100A9-mediated resistance

2021 ◽  
Vol 3 (Supplement_3) ◽  
pp. iii18-iii18
Author(s):  
Lauritz Miarka ◽  
Catia Moteiro ◽  
Celine Dalmasso ◽  
Coral Fustero-Torre ◽  
Natalia Yebra ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Unmet Need ◽  
Brain Barrier ◽  
Breast Adenocarcinoma ◽  
Therapeutic Benefits ◽  
Blood Brain ◽  
The Brain

Abstract Finding effective treatment options for patients with brain metastasis remains an unmet need. Given the limitations imposed by the blood-brain-barrier for systemic approaches, radiotherapy offers a superior ability to access the brain. While clinical practice recently adapted the use of stereotactic radiosurgery (SRS), Whole-Brain-Radiotherapy (WBRT) continuous to be an important treatment option, since many patients present with multifocal lesions or bad performance scores, rendering them ineligible for SRS. Unfortunately, overall survival of patients remains unaffected by radiotherapy. Despite this clinical data, the molecular mechanisms that allow metastatic cells to resist radiotherapy in the brain is unknown. We have applied WBRT to experimental brain metastasis from lung and breast adenocarcinoma and validated their resistance in vivo. An unbiased search to identify potential mediators of resistance identified the S100A9-RAGE-NFkB-JunB pathway. Targeting this pathway genetically reverts the resistance to radiotherapy and increases therapeutic benefits in vivo. In two independent cohorts of brain metastasis from lung and breast adenocarcinoma patients, levels of S100A9 correlate with the response to radiotherapy, offering a novel approach to stratify patients according to their expected benefit. In order to make this biomarker also available for brain metastasis patients receiving palliative WBRT without preceding surgery, we complemented our tumor-specimen based approach with the less invasive detection of S100A9 from liquid biopsies. Here, serum S100A9 also correlated with a worse response to WBRT in brain metastasis patients. Furthermore, we have validated the use of a blood-brain-barrier permeable RAGE inhibitor to restore radio-sensitivity in experimental brain metastasis models in vivo and in patient-derived organotypic cultures of radio-resistant brain metastasis ex vivo. In conclusion, we identified S100A9 as a major mediator of radio-resistance in brain metastasis and offer the molecular framework to personalize radiotherapy by exploiting it as a biomarker and as a therapeutic target, thus maximizing the benefits for the patient.

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