Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer.

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.
Authors	Tanaya Shree, 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
Journal	Genes & development (Genes Dev) Vol. 25 Issue 23 Pg. 2465-79 (Dec 01 2011) ISSN: 1549-5477 [Electronic] United States
PMID	22156207 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents Etoposide Doxorubicin Cathepsins Paclitaxel
Topics	Animals Antineoplastic Agents (pharmacology, therapeutic use) Cathepsins (metabolism) Cell Line, Tumor Doxorubicin (pharmacology, therapeutic use) Drug Interactions Drug Resistance, Neoplasm Etoposide (pharmacology, therapeutic use) Female Lung Neoplasms (prevention & control, secondary) Macrophages (pathology) Mammary Neoplasms, Animal (drug therapy, enzymology, pathology) Mice Mice, Inbred C57BL Mice, Inbred Strains Neoplasm Invasiveness Paclitaxel (pharmacology, therapeutic use)

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