Analysis of tumour-and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S

被引:298
作者
Sevenich, Lisa [1 ]
Bowman, Robert L. [1 ]
Mason, Steven D. [1 ]
Quail, Daniela E. [1 ]
Rapaport, Franck [2 ]
Elie, Benelita T. [1 ]
Brogi, Edi [3 ]
Brastianos, Priscilla K. [4 ,5 ]
Hahn, William C. [4 ]
Holsinger, Leslie J. [6 ]
Massague, Joan [1 ,7 ,8 ]
Leslie, Christina S. [2 ]
Joyce, Johanna A. [1 ,7 ,8 ]
机构
[1] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA
[2] Mem Sloan Kettering Canc Ctr, Computat Biol Program, New York, NY 10065 USA
[3] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA
[4] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA
[5] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02214 USA
[6] Virobay Inc, Menlo Pk, CA 94025 USA
[7] Mem Sloan Kettering Canc Ctr, Brain Tumor Ctr, New York, NY 10065 USA
[8] Mem Sloan Kettering Canc Ctr, Metastasis Res Ctr, New York, NY 10065 USA
基金
加拿大健康研究院;
关键词
BREAST-CANCER METASTASIS; GENE-EXPRESSION; MATRIX METALLOPROTEINASES; PROTEOMIC IDENTIFICATION; TIGHT JUNCTION; MICROENVIRONMENT; PROTEASES; TARGETS; BARRIER; DISSEMINATION;
D O I
10.1038/ncb3011
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Metastasis remains the most common cause of death in most cancers, with limited therapies for combating disseminated disease. While the primary tumour microenvironment is an important regulator of cancer progression, it is less well understood how different tissue environments influence metastasis. We analysed tumour stroma interactions that modulate organ tropism of brain, bone and lung metastasis in xenograft models. We identified a number of potential modulators of site-specific metastasis, including cathepsin S as a regulator of breast-to-brain metastasis. High cathepsin S expression at the primary site correlated with decreased brain metastasis-free survival in breast cancer patients. Both macrophages and tumour cells produce cathepsin S, and only the combined depletion significantly reduced brain metastasis in vivo. Cathepsin S specifically mediates blood brain barrier transmigration through proteolytic processing of the junctional adhesion molecule, JAM-B. Pharmacological inhibition of cathepsin S significantly reduced experimental brain metastasis, supporting its consideration as a therapeutic target for this disease.
引用
收藏
页码:876 / 888
页数:13
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