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

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.

2020 ◽  
Vol 26 (13) ◽  
pp. 1417-1427 ◽  
Author(s):  
Carolin J. Curtaz ◽  
Constanze Schmitt ◽  
Kinga G. Blecharz-Lang ◽  
Norbert Roewer ◽  
Achim Wöckel ◽  
...  

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.


2021 ◽  
Vol 3 (Supplement_3) ◽  
pp. iii18-iii18
Author(s):  
Lauritz Miarka ◽  
Catia Moteiro ◽  
Celine Dalmasso ◽  
Coral Fustero-Torre ◽  
Natalia Yebra ◽  
...  

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.


2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii17-ii17
Author(s):  
L Miarka ◽  
C Monteiro ◽  
C Dalmasso ◽  
N Yebra ◽  
C Fustero-Torre ◽  
...  

Abstract BACKGROUND 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. MATERIAL AND METHODS We have applied WBRT to experimental brain metastasis from lung and breast adenocarcinoma and validated their resistance in vivo. RESULTS An unbiased search to identify potential mediators of resistance identified the S100A9-RAGE-NFκB-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. 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.


Author(s):  
Simon Bernatz ◽  
Elena I. Ilina ◽  
Kavi Devraj ◽  
Patrick N. Harter ◽  
Klaus Mueller ◽  
...  

Abstract Background Breast cancer (BC) is the most frequent malignant tumor in females and the 2nd most common cause of brain metastasis (BM), that are associated with a fatal prognosis. The increasing incidence from 10% up to 40% is due to more effective treatments of extracerebral sites with improved prognosis and increasing use of MRI in diagnostics. A frequently administered, potent chemotherapeutic group of drugs for BC treatment are taxanes usually used in the adjuvant and metastatic setting, which, however, have been suspected to be associated with a higher incidence of BM. The aim of our study was to experimentally analyze the impact of the taxane docetaxel (DTX) on brain metastasis formation, and to elucidate the underlying molecular mechanism. Methods A monocentric patient cohort was analyzed to determine the association of taxane treatment and BM formation. To identify the specific impact of DTX, a murine brain metastatic model upon intracardial injection of breast cancer cells was conducted. To approach the functional mechanism, dynamic contrast-enhanced MRI and electron microscopy of mice as well as in-vitro transendothelial electrical resistance (TEER) and tracer permeability assays using brain endothelial cells (EC) were carried out. PCR-based, immunohistochemical and immunoblotting analyses with additional RNA sequencing of murine and human ECs were performed to explore the molecular mechanisms by DTX treatment. Results Taxane treatment was associated with an increased rate of BM formation in the patient cohort and the murine metastatic model. Functional studies did not show unequivocal alterations of blood-brain barrier properties upon DTX treatment in-vivo, but in-vitro assays revealed a temporary DTX-related barrier disruption. We found disturbance of tubulin structure and upregulation of tight junction marker claudin-5 in ECs. Furthermore, upregulation of several members of the tubulin family and downregulation of tetraspanin-2 in both, murine and human ECs, was induced. Conclusion In summary, a higher incidence of BM was associated with prior taxane treatment in both a patient cohort and a murine mouse model. We could identify tubulin family members and tetraspanin-2 as potential contributors for the destabilization of the blood-brain barrier. Further analyses are needed to decipher the exact role of those alterations on tumor metastatic processes in the brain.


Therapy ◽  
2006 ◽  
Vol 3 (1) ◽  
pp. 97-112 ◽  
Author(s):  
Rose Marie Tyson ◽  
Dale F Kraemer ◽  
Matthew A Hunt ◽  
Leslie L Muldoon ◽  
Peter Orbay ◽  
...  

2022 ◽  
Author(s):  
Sumanta Samanta ◽  
Vadim Le Joncour ◽  
Olivia Wegrzyniak ◽  
Vigneshkumar Rangasami ◽  
Harri Ali-Loytty ◽  
...  

The poor permeability of theranostic agents across the blood-brain-barrier (BBB) significantly hampers the development of new treatment modalities for neurological diseases. We have discovered a new biomimetic nanocarrier using heparin (HP) that effectively passes the BBB and targets glioblastoma. Specifically, we designed HP coated gold nanoparticles (HP-AuNPs) that were labeled with three different imaging modalities namely, fluorescein (FITC-HP-AuNP), radioisotope 68Gallium (68Ga-HP-AuNPs), and MRI active gadolinium (Gd-HP-AuNPs). The systemic infusion of FITC-HP-AuNPs in three different mouse strains (C57BL/6JRj, FVB, and NMRI-nude) displayed excellent penetration and revealed uniform distribution of fluorescent particles in the brain parenchyma (69-86%) with some accumulation in neurons (8-18%) and microglia (4-10%). Tail-vein administration of radiolabeled 68Ga-HP-AuNPs in healthy rats also showed 68Ga-HP-AuNP inside the brain parenchyma and in areas containing cerebrospinal fluid, such as the lateral ventricles, the cerebellum, and brain stem. Finally, tail-vein administration of Gd-HP-AuNPs (that display ~3 fold higher relaxivity than that of commercial Gd-DTPA) in an orthotopic glioblastoma (U87MG xenograft) model in nude mice demonstrated enrichment of T1-contrast at the intracranial tumor with a gradual increase in the contrast in the tumor region between 1h-3h. We believe, our finding offers the untapped potential of HP-derived-NPs to deliver cargo molecules for treating neurological disorders.


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