Key Role of Hyaluronan Metabolism for the Development of Brain Metastases in Triple-Negative Breast Cancer

被引:6
|
作者
Hamester, Fabienne [1 ]
Stuerken, Christine [2 ,3 ]
Legler, Karen [1 ]
Eylmann, Kathrin [1 ]
Moller, Katrin [1 ]
Rossberg, Maila [1 ]
Gorzelanny, Christian [4 ]
Bauer, Alexander T. [4 ]
Windhorst, Sabine [5 ]
Schmalfeldt, Barbara [1 ]
Laakmann, Elena [1 ]
Muller, Volkmar [1 ]
Witzel, Isabell [1 ]
Oliveira-Ferrer, Leticia [1 ]
机构
[1] Univ Med Ctr Hamburg Eppendorf, Dept Gynecol, Martinistr 52, D-20246 Hamburg, Germany
[2] Univ Med Ctr Hamburg Eppendorf, Dept Anat & Expt Morphol, Martinistr 52, D-20246 Hamburg, Germany
[3] Med Univ, Fac Med, MSH Med Sch Hamburg, D-20251 Hamburg, Germany
[4] Univ Med Ctr Hamburg Eppendorf, Dept Dermatol & Venerol, Martinistr 52, D-20246 Hamburg, Germany
[5] Univ Med Ctr Hamburg Eppendorf, Dept Biochem & Signal Transduct, Martinistr 52, D-20246 Hamburg, Germany
关键词
breast cancer brain metastases; blood-brain barrier; pericellular Hyaluronan-coat; adhesion; invasion; CELL-LINES; SURVIVAL; BARRIER; MANAGEMENT; EXPRESSION; SINGLE;
D O I
10.3390/cells11203275
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Breast cancer (BC) is the second-most common cause of brain metastases (BM) and BCBM patients have a reduced quality of life and a poor prognosis. Hyaluronan (HA), and in particular the hyaluronidase Hyal-1, has been already linked to the development of BCBM, and therefore presents an interesting opportunity to develop new effective therapeutic options. HA metabolism was further discovered by the CRISPR/Cas9-mediated knockout of HYAL1 and the shRNA-mediated down-regulation of HA-receptor CD44 in the brain-seeking triple-negative breast cancer (TNBC) cell line MDA-MB-231-BR. Therefore, the impact of Hyal-1 on adhesion, disruption, and invasion through the brain endothelium, both in vitro and in vivo, was studied. Our analysis points out a key role of Hyal-1 and low-molecular-weight HA (LMW-HA) in the formation of a pericellular HA-coat in BC cells, which in turn promotes tumor cell adhesion, disruption, and migration through the brain endothelium in vitro as well as the extent of BM in vivo. CD44 knockdown in MDA-MB-231-BR significantly reduced the pericellular HA-coat on these cells, and, consequently, tumor cell adhesion and invasion through the brain endothelium. Thus, the interaction between Hyal-1-generated LMW-HA fragments and the HA-receptor CD44 might represent a potential target for future therapeutic options in BC patients with a high risk of cerebral metastases formation.
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页数:23
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