Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer

• Published in: Genes & development Vol. 25; no. 23; pp. 2465 - 2479
• Main Authors: Shree, Tanaya, Olson, Oakley C, Elie, Benelita T, Kester, Jemila C, Garfall, Alfred L, Simpson, Kenishana, Bell-McGuinn, Katherine M, Zabor, Emily C, Brogi, Edi, Joyce, Johanna A
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01-12-2011
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cathepsins - metabolism; Cell Line, Tumor; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; Drug Interactions; Drug Resistance, Neoplasm; Etoposide - pharmacology; Etoposide - therapeutic use; Female; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Macrophages - pathology; Mammary Neoplasms, Animal - drug therapy; Mammary Neoplasms, Animal - enzymology; Mammary Neoplasms, Animal - pathology; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Neoplasm Invasiveness; Paclitaxel - pharmacology; Paclitaxel - therapeutic use; Research Paper
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.180331.111

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.