Abstract
Advanced human thyroid cancers are densely infiltrated with tumor-associated macrophages (TAMs) and this correlates with a poor prognosis. We used BRAF-induced papillary thyroid cancer (PTC) mouse models to examine the role of TAMs in PTC progression. Following conditional activation of BRAF(V600E) in murine thyroids there is an increased expression of the TAM chemoattractants Csf-1 and Ccl-2. This is followed by the development of PTCs that are densely infiltrated with TAMs that express Csf-1r and Ccr2. Targeting CCR2-expressing cells during BRAF-induction reduced TAM density and impaired PTC development. This strategy also induced smaller tumors, decreased proliferation and restored a thyroid follicular architecture in established PTCs. In PTCs from mice that lacked CSF-1 or that received a c-FMS/CSF-1R kinase inhibitor, TAM recruitment and PTC progression was impaired, recapitulating the effects of targeting CCR2-expressing cells. Our data demonstrate that TAMs are pro-tumorigenic in advanced PTCs and that they can be targeted pharmacologically, which may be potentially useful for patients with advanced thyroid cancers.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anisoles / pharmacology*
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Carcinoma / drug therapy
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Carcinoma / genetics*
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Carcinoma / metabolism
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Carcinoma / pathology
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Carcinoma, Papillary / drug therapy
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Carcinoma, Papillary / genetics*
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Carcinoma, Papillary / metabolism
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Carcinoma, Papillary / pathology
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Cell Movement / drug effects
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Chemokine CCL2 / genetics
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Chemokine CCL2 / metabolism
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Disease Progression
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Gene Expression Regulation, Neoplastic / drug effects*
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Humans
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Macrophage Colony-Stimulating Factor / genetics
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Macrophage Colony-Stimulating Factor / metabolism
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Macrophages / drug effects*
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Macrophages / metabolism
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Macrophages / pathology
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Mice
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Mice, Transgenic
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins B-raf / genetics*
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Proto-Oncogene Proteins B-raf / metabolism
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Pyrimidines / pharmacology*
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Receptor, Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
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Receptor, Macrophage Colony-Stimulating Factor / genetics
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Receptor, Macrophage Colony-Stimulating Factor / metabolism
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Receptors, CCR2 / genetics
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Receptors, CCR2 / metabolism
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Signal Transduction / drug effects
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Thyroid Cancer, Papillary
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Thyroid Neoplasms / drug therapy
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Thyroid Neoplasms / genetics*
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Thyroid Neoplasms / metabolism
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Thyroid Neoplasms / pathology
Substances
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5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine
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Anisoles
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Ccl2 protein, mouse
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Ccr2 protein, mouse
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Chemokine CCL2
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Protein Kinase Inhibitors
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Pyrimidines
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Receptors, CCR2
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Macrophage Colony-Stimulating Factor
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Receptor, Macrophage Colony-Stimulating Factor
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Braf protein, mouse
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Proto-Oncogene Proteins B-raf