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
Notes: --- - "Export Date: 3 January 2012" - "CODEN: GEDEE" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Emily Craig Zabor
    131 Zabor
  2. Edi Brogi
    306 Brogi
  3. Johanna A Joyce
    67 Joyce
  4. Benelita Tina S Elie
    5 Elie
  5. Tanaya Shree
    4 Shree
  6. Oakley Christopher Olson
    12 Olson
  7. Jemila Caplan Kester
    4 Kester