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Nat Cell Biol. 2014 Sep;16(9):876-88. doi: 10.1038/ncb3011. Epub 2014 Aug 3.

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

Author information

1
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
2
1] Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2].
3
Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
4
Pathology Department, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
5
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts 02214, USA.
6
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
7
Virobay Inc., 1360 Willow Road, Menlo Park, California 94025, USA.
8
1] Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [3] Metastasis Research Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.

Abstract

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.

PMID:
25086747
PMCID:
PMC4249762
DOI:
10.1038/ncb3011
[Indexed for MEDLINE]
Free PMC Article

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