Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer
- Tanaya Shree1,4,
- Oakley C. Olson1,4,
- Benelita T. Elie1,
- Jemila C. Kester1,
- Alfred L. Garfall1,
- Kenishana Simpson1,
- Katherine M. Bell-McGuinn1,
- Emily C. Zabor2,
- Edi Brogi3 and
- Johanna A. Joyce1,5
- 1Cancer Biology and Genetics Program,
- 2Department of Epidemiology and Biostatistics,
- 3Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA
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↵4 These authors contributed equally to this work.
Abstract
The microenvironment is known to critically modulate tumor progression, yet its role in regulating treatment response is poorly understood. Here we found increased macrophage infiltration and cathepsin protease levels in mammary tumors following paclitaxel (Taxol) chemotherapy. Cathepsin-expressing macrophages protected against Taxol-induced tumor cell death in coculture, an effect fully reversed by cathepsin inhibition and mediated partially by cathepsins B and S. Macrophages were also found to protect against tumor cell death induced by additional chemotherapeutics, specifically etoposide and doxorubicin. Combining Taxol with cathepsin inhibition in vivo significantly enhanced efficacy against primary and metastatic tumors, supporting the therapeutic relevance of this effect. Additionally incorporating continuous low-dose cyclophosphamide dramatically impaired tumor growth and metastasis and improved survival. This study highlights the importance of integrated targeting of the tumor and its microenvironment and implicates macrophages and cathepsins in blunting chemotherapeutic response.
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Footnotes
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↵5 Corresponding author.
E-mail joycej{at}mskcc.org.
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.180331.111.
- Received January 5, 2011.
- Accepted October 12, 2011.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press