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A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth.

Qian B, Deng Y, Im JH, Muschel RJ, Zou Y, Li J, Lang RA, Pollard JW - PLoS ONE (2009)

Bottom Line: Using 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.Furthermore, imaging of intact lungs revealed that macrophages are required for efficient tumor cell extravasation.These 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental and Molecular Biology and the Department of Obstetrics/Gynecology and Woman's Health, Center for the Study of Reproductive Biology and Woman's Health, Albert Einstein College of Medicine, Bronx, NY, USA.

ABSTRACT

Background: The 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 findings: Using 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/significance: These 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.

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Related in: MedlinePlus

Model for macrophage promotion of metastasis at distant sites.Based on the data in current study, we suggest a model for the macrophage enhancement of metastasis at the distal target organ. Following arrest of the tumor cells in capillaries of metastasis target organ, monocytes are quickly recruited and differentiate in situ into metastasis associated macrophage phenotype whereafter they promote the different steps of metastatic seeding, initial and persistent growth as indicated in the figure and described in the discussion. Figure modified from Joyce and Pollard, 2009.
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pone-0006562-g008: Model for macrophage promotion of metastasis at distant sites.Based on the data in current study, we suggest a model for the macrophage enhancement of metastasis at the distal target organ. Following arrest of the tumor cells in capillaries of metastasis target organ, monocytes are quickly recruited and differentiate in situ into metastasis associated macrophage phenotype whereafter they promote the different steps of metastatic seeding, initial and persistent growth as indicated in the figure and described in the discussion. Figure modified from Joyce and Pollard, 2009.

Mentions: Metastasis remains an intractable problem clinically and is therefore the major cause of death in cancer patients. Based on the data in current study, we suggest a model for the macrophage enhancement of metastasis at the distal target organ (Figure 8). Following arrest of the tumor cells in capillaries of metastasis target organ, monocytes were quickly recruited and differentiated in situ into metastasis associated macrophage phenotype with a distinctly defined cell surface marker phenotype. This recruitment is at least in part under the influence of locally synthesized CSF-1, a well-documented growth and differentiation factor for macrophages. In addition as these macrophages express receptors for CCL-2 and VEGF (CCR2 and VEGFR1 respectively), both cytokines that are chemotactic for macrophages, it is likely that such signaling molecules will play a role in this recruitment process. These CD11b+macrophages recognizes extravasating tumor cells and our imaging shows that they interact with them directly and help them invade into the lung parenchyma. This is presumably through the secretion of proteases, growth, and motility and survival factors. In the absence of these newly differentiated macrophages, this process of tumor cell extravasation is very inefficient and the tumor cells rapidly die by apoptosis and thus the seeding efficiency is very low. Once extravascular the tumor cells continue to send signals to recruit and also possibly influence the differentiation of the macrophages into trophic ones [46] that further enhance tumor cell viability and growth. When the tumors attain a certain size these macrophages are also likely to provide angiogenic factors as they have been documented to do in the primary tumor [45] that then help in the vascularization needed for continuous metastatic growth. In this scenario several macrophage signaling pathways and functions are likely to be engaged at the different steps of tumor cell seeding, initial and persistent growth. These are continuous process and overlapping processes as ablation of macrophages after the metastatic lesions are established retards their growth significantly. These data suggests that macrophages themselves or their unique signaling pathways represent new therapeutic targets that may be efficacious in reducing cancer mortality.


A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth.

Qian B, Deng Y, Im JH, Muschel RJ, Zou Y, Li J, Lang RA, Pollard JW - PLoS ONE (2009)

Model for macrophage promotion of metastasis at distant sites.Based on the data in current study, we suggest a model for the macrophage enhancement of metastasis at the distal target organ. Following arrest of the tumor cells in capillaries of metastasis target organ, monocytes are quickly recruited and differentiate in situ into metastasis associated macrophage phenotype whereafter they promote the different steps of metastatic seeding, initial and persistent growth as indicated in the figure and described in the discussion. Figure modified from Joyce and Pollard, 2009.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2721818&req=5

pone-0006562-g008: Model for macrophage promotion of metastasis at distant sites.Based on the data in current study, we suggest a model for the macrophage enhancement of metastasis at the distal target organ. Following arrest of the tumor cells in capillaries of metastasis target organ, monocytes are quickly recruited and differentiate in situ into metastasis associated macrophage phenotype whereafter they promote the different steps of metastatic seeding, initial and persistent growth as indicated in the figure and described in the discussion. Figure modified from Joyce and Pollard, 2009.
Mentions: Metastasis remains an intractable problem clinically and is therefore the major cause of death in cancer patients. Based on the data in current study, we suggest a model for the macrophage enhancement of metastasis at the distal target organ (Figure 8). Following arrest of the tumor cells in capillaries of metastasis target organ, monocytes were quickly recruited and differentiated in situ into metastasis associated macrophage phenotype with a distinctly defined cell surface marker phenotype. This recruitment is at least in part under the influence of locally synthesized CSF-1, a well-documented growth and differentiation factor for macrophages. In addition as these macrophages express receptors for CCL-2 and VEGF (CCR2 and VEGFR1 respectively), both cytokines that are chemotactic for macrophages, it is likely that such signaling molecules will play a role in this recruitment process. These CD11b+macrophages recognizes extravasating tumor cells and our imaging shows that they interact with them directly and help them invade into the lung parenchyma. This is presumably through the secretion of proteases, growth, and motility and survival factors. In the absence of these newly differentiated macrophages, this process of tumor cell extravasation is very inefficient and the tumor cells rapidly die by apoptosis and thus the seeding efficiency is very low. Once extravascular the tumor cells continue to send signals to recruit and also possibly influence the differentiation of the macrophages into trophic ones [46] that further enhance tumor cell viability and growth. When the tumors attain a certain size these macrophages are also likely to provide angiogenic factors as they have been documented to do in the primary tumor [45] that then help in the vascularization needed for continuous metastatic growth. In this scenario several macrophage signaling pathways and functions are likely to be engaged at the different steps of tumor cell seeding, initial and persistent growth. These are continuous process and overlapping processes as ablation of macrophages after the metastatic lesions are established retards their growth significantly. These data suggests that macrophages themselves or their unique signaling pathways represent new therapeutic targets that may be efficacious in reducing cancer mortality.

Bottom Line: Using 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.Furthermore, imaging of intact lungs revealed that macrophages are required for efficient tumor cell extravasation.These 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental and Molecular Biology and the Department of Obstetrics/Gynecology and Woman's Health, Center for the Study of Reproductive Biology and Woman's Health, Albert Einstein College of Medicine, Bronx, NY, USA.

ABSTRACT

Background: The 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 findings: Using 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/significance: These 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.

Show MeSH
Related in: MedlinePlus