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Response of the neurovascular unit to brain metastatic breast cancer cells.
Acta Neuropathol Commun 2019; 7(1):133AN

Abstract

Therapeutic resistance of cerebral secondary tumours largely depends on unique aspects linked to the neurovascular unit, especially cerebral endothelial cells and astrocytes. By using advanced microscopy techniques, here we explored novel mechanisms related to the neurovascular unit during extravasation and proliferation of triple negative breast cancer cells in the brain. Metastatic mammary carcinoma cells arrested and elongated within one hour in cerebral microvessels, but their number decreased by almost 80% in the first two days. Interestingly, malignant cells induced vasoconstriction and development of intraluminal endothelial plugs, which isolated invading cells from the circulation. During diapedesis - which usually took place on day four and five after inoculation of the tumour cells - continuity of cerebral endothelial tight junctions remained intact, indicating migration of cancer cells through the transcellular pathway. In addition, metastatic cells induced formation of multiluminal vessels and claudin-5-positive endothelial blebs. However, even severe endothelial blebbing could be reversed and the vessel morphology was restored shortly after the tumour cells completed transendothelial migration. Similar to neuro-inflammatory leukocytes, tumour cells migrated not only through the endothelial layer, but through the glia limitans perivascularis as well. Nevertheless, along with the growth of metastatic lesions by co-option of pre-existing capillaries, astrocytes and astrocyte end-feet were gradually expelled from the vessels to the border of the tumour. Taken together, we identified previously unknown mechanisms involved in the reaction of brain resident cells to invading breast cancer cells. Our results contribute to a better understanding of the complex cross-talk between tumour cells and host cells in the brain, which is essential for the identification of new therapeutic targets in this devastating disease.

Authors+Show Affiliations

Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Temesvári krt. 62, Szeged, 6726, Hungary.Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Temesvári krt. 62, Szeged, 6726, Hungary.Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Temesvári krt. 62, Szeged, 6726, Hungary. Theoretical Medicine Doctoral School, University of Szeged, Szeged, Hungary.Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Temesvári krt. 62, Szeged, 6726, Hungary. Doctoral School of Biology, University of Szeged, Szeged, Hungary.Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Temesvári krt. 62, Szeged, 6726, Hungary.Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Temesvári krt. 62, Szeged, 6726, Hungary.Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Temesvári krt. 62, Szeged, 6726, Hungary. Theoretical Medicine Doctoral School, University of Szeged, Szeged, Hungary.Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Temesvári krt. 62, Szeged, 6726, Hungary. Theoretical Medicine Doctoral School, University of Szeged, Szeged, Hungary.Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Temesvári krt. 62, Szeged, 6726, Hungary. Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary.Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Temesvári krt. 62, Szeged, 6726, Hungary. krizbai.istvan@brc.mta.hu. Institute of Life Sciences, Vasile Goldiş Western University of Arad, Arad, Romania. krizbai.istvan@brc.mta.hu.Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Temesvári krt. 62, Szeged, 6726, Hungary. wilhelm.imola@brc.mta.hu. Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary. wilhelm.imola@brc.mta.hu. Institute of Life Sciences, Vasile Goldiş Western University of Arad, Arad, Romania. wilhelm.imola@brc.mta.hu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31426859

Citation

Haskó, János, et al. "Response of the Neurovascular Unit to Brain Metastatic Breast Cancer Cells." Acta Neuropathologica Communications, vol. 7, no. 1, 2019, p. 133.
Haskó J, Fazakas C, Molnár K, et al. Response of the neurovascular unit to brain metastatic breast cancer cells. Acta Neuropathol Commun. 2019;7(1):133.
Haskó, J., Fazakas, C., Molnár, K., Mészáros, Á., Patai, R., Szabó, G., ... Wilhelm, I. (2019). Response of the neurovascular unit to brain metastatic breast cancer cells. Acta Neuropathologica Communications, 7(1), p. 133. doi:10.1186/s40478-019-0788-1.
Haskó J, et al. Response of the Neurovascular Unit to Brain Metastatic Breast Cancer Cells. Acta Neuropathol Commun. 2019 Aug 19;7(1):133. PubMed PMID: 31426859.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Response of the neurovascular unit to brain metastatic breast cancer cells. AU - Haskó,János, AU - Fazakas,Csilla, AU - Molnár,Kinga, AU - Mészáros,Ádám, AU - Patai,Roland, AU - Szabó,Gábor, AU - Erdélyi,Ferenc, AU - Nyúl-Tóth,Ádám, AU - Győri,Fanni, AU - Kozma,Mihály, AU - Farkas,Attila E, AU - Krizbai,István A, AU - Wilhelm,Imola, Y1 - 2019/08/19/ PY - 2019/06/13/received PY - 2019/08/12/accepted PY - 2019/8/21/entrez PY - 2019/8/21/pubmed PY - 2019/8/21/medline KW - Apoptotic and non-apoptotic blebbing KW - Astrocyte end-foot KW - Brain metastasis KW - Cerebral endothelial cell KW - Endothelial plug KW - Neurovascular unit KW - Transcellular pathway KW - Transendothelial migration KW - Triple negative breast cancer SP - 133 EP - 133 JF - Acta neuropathologica communications JO - Acta Neuropathol Commun VL - 7 IS - 1 N2 - Therapeutic resistance of cerebral secondary tumours largely depends on unique aspects linked to the neurovascular unit, especially cerebral endothelial cells and astrocytes. By using advanced microscopy techniques, here we explored novel mechanisms related to the neurovascular unit during extravasation and proliferation of triple negative breast cancer cells in the brain. Metastatic mammary carcinoma cells arrested and elongated within one hour in cerebral microvessels, but their number decreased by almost 80% in the first two days. Interestingly, malignant cells induced vasoconstriction and development of intraluminal endothelial plugs, which isolated invading cells from the circulation. During diapedesis - which usually took place on day four and five after inoculation of the tumour cells - continuity of cerebral endothelial tight junctions remained intact, indicating migration of cancer cells through the transcellular pathway. In addition, metastatic cells induced formation of multiluminal vessels and claudin-5-positive endothelial blebs. However, even severe endothelial blebbing could be reversed and the vessel morphology was restored shortly after the tumour cells completed transendothelial migration. Similar to neuro-inflammatory leukocytes, tumour cells migrated not only through the endothelial layer, but through the glia limitans perivascularis as well. Nevertheless, along with the growth of metastatic lesions by co-option of pre-existing capillaries, astrocytes and astrocyte end-feet were gradually expelled from the vessels to the border of the tumour. Taken together, we identified previously unknown mechanisms involved in the reaction of brain resident cells to invading breast cancer cells. Our results contribute to a better understanding of the complex cross-talk between tumour cells and host cells in the brain, which is essential for the identification of new therapeutic targets in this devastating disease. SN - 2051-5960 UR - https://www.unboundmedicine.com/medline/citation/31426859/Response_of_the_neurovascular_unit_to_brain_metastatic_breast_cancer_cells L2 - https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0788-1 DB - PRIME DP - Unbound Medicine ER -