Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer

Genes and Development - Tập 25 Số 23 - Trang 2465-2479 - 2011
Tanaya Shree1, Oakley C. Olson, Benelita T. Elie, Jemila C. Kester, Alfred L. Garfall, Kenishana Simpson, Katherine M. Bell‐McGuinn, Emily C. Zabor, Edi Brogi, Johanna A. Joyce
1Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

Tóm tắt

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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Genes and Development

Tập 25 Số 23

2465-2479

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