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Abstract
BackgroundThe stromal microenvironment and particularly the macrophage component of primary tumors influence their malignant potential. However, at the metastatic site the role of these cells and their mechanism of actions for establishment and growth of metastases remain largely unknown.Methodology/Principal FindingsUsing animal models of breast cancer metastasis, we show that a population of host macrophages displaying a distinct phenotype is recruited to extravasating pulmonary metastatic cells regardless of species of origin. Ablation of this macrophage population through three independent means (genetic and chemical) showed that these macrophages are required for efficient metastatic seeding and growth. Importantly, even after metastatic growth is established, ablation of this macrophage population inhibited subsequent growth. Furthermore, imaging of intact lungs revealed that macrophages are required for efficient tumor cell extravasation.Conclusion/SignificanceThese data indicate a direct enhancement of metastatic growth by macrophages through their effects on tumor cell extravasation, survival and subsequent growth and identifies these cells as a new therapeutic target for treatment of metastatic disease.
Highlights
Metastatic disease is the major cause of cancer mortality
We have shown in the past that CSF-1R is expressed in all macrophages and PyMT tumor cells do not express the colony stimulating factor-1 (CSF-1) receptor (CSF-1R) [8,14]
There is a growing body of evidence that indicates that macrophages in the primary tumor promote tumor progression to the metastatic phenotype [43]
Summary
Metastatic disease is the major cause of cancer mortality. This fact indicates that metastases are refractory to current treatments such as the traditional modalities of irradiation and chemotherapy as well as the more recent targeted biological therapies. The failure of available treatments suggests that the biological mechanisms that underlie metastatic disease are poorly understood It is known that metastasis is a multi-step process with tumor cells needing to escape from the primary site as well as arriving and prospering at distant sites [1]. Genetic experiments whereby particular classes of cells are ablated in the tumor have revealed major roles for mast cells and macrophages in tumor progression and for macrophages in promoting metastasis [14,15,16] In the latter case macrophages stimulates tumor cell migration, invasion and intravasation in mouse models of breast cancer [8,9]. We show that macrophage depletion even inhibits the growth of established metastatic nodules
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