Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer Journal Article
| Authors: | Shree, T.; Olson, O. C.; Elie, B. T.; Kester, J. C.; Garfall, A. L.; Simpson, K.; Bell-Mcguinn, K. M.; Zabor, E. C.; Brogi, E.; Joyce, J. A. |
| Article Title: | 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. © 2011 by Cold Spring Harbor Laboratory Press. |
| Keywords: | cancer survival; controlled study; doxorubicin; cancer growth; nonhuman; antineoplastic agents; gemcitabine; paclitaxel; chemotherapy; animal cell; mouse; animals; mice; animal tissue; cell death; carboplatin; low drug dose; metastasis; enzyme inhibition; breast cancer; cell infiltration; etoposide; lung neoplasms; animal experiment; animal model; cyclophosphamide; in vivo study; drug resistance, neoplasm; cell line, tumor; mice, inbred c57bl; mice, inbred strains; neoplasm invasiveness; cathepsin; cathepsins; macrophage; macrophages; drug interactions; tumor microenvironment; mammary neoplasms, animal; proteolysis |
| Journal Title: | Genes and Development |
| Volume: | 25 |
| Issue: | 23 |
| ISSN: | 0890-9369 |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Date Published: | 2011-12-01 |
| Start Page: | 2465 |
| End Page: | 2479 |
| Language: | English |
| DOI: | 10.1101/gad.180331.111 |
| PROVIDER: | scopus |
| PUBMED: | 22156207 |
| PMCID: | PMC3243057 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 3 January 2012" - "CODEN: GEDEE" - "Source: Scopus" |
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