Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer Academic Article uri icon

Overview

MeSH Major

  • Antineoplastic Agents
  • Cathepsins
  • Macrophages
  • Mammary Neoplasms, Animal
  • Paclitaxel

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.

publication date

  • December 2011

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3243057

Digital Object Identifier (DOI)

  • 10.1101/gad.180331.111

PubMed ID

  • 22156207

Additional Document Info

start page

  • 2465

end page

  • 79

volume

  • 25

number

  • 23