Genetic and Pharmacological Targeting of CSF-1/CSF-1R Inhibits Tumor-Associated Macrophages and Impairs BRAF-Induced Thyroid Cancer Progression Journal Article
| Authors: | Ryder, M.; Gild, M.; Hohl, T. M.; Pamer, E.; Knauf, J.; Ghossein, R.; Joyce, J. A.; Fagin, J. A. |
| Article Title: | Genetic and Pharmacological Targeting of CSF-1/CSF-1R Inhibits Tumor-Associated Macrophages and Impairs BRAF-Induced Thyroid Cancer Progression |
| 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 BRAFV600E 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. © 2013 Ryder et al. |
| Keywords: | signal transduction; controlled study; protein expression; unclassified drug; cancer growth; nonhuman; drug targeting; cell proliferation; tumor associated leukocyte; animal cell; mouse; animals; mice; animal tissue; gene targeting; mus; carcinoma, papillary; animal experiment; animal model; antineoplastic activity; tumor regression; drug selectivity; pyrimidines; carcinogenesis; mice, transgenic; protein tyrosine kinase inhibitor; protein kinase inhibitors; cancer inhibition; gene expression regulation, neoplastic; disease progression; carcinoma; murinae; cell movement; thyroid neoplasms; cell density; macrophages; thyroid papillary carcinoma; b raf kinase; chemokine receptor ccr2; receptors, ccr2; monocyte chemotactic protein 1; chemokine ccl2; diphtheria toxin; proto-oncogene proteins b-raf; colony stimulating factor 1; cytokine receptor; anisoles; colony stimulating factor 1 receptor; receptor, macrophage colony-stimulating factor; macrophage colony-stimulating factor; gw 2580; plx 6134 |
| Journal Title: | PLoS ONE |
| Volume: | 8 |
| Issue: | 1 |
| ISSN: | 1932-6203 |
| Publisher: | Public Library of Science |
| Date Published: | 2013-01-01 |
| Start Page: | e54302 |
| Language: | English |
| DOI: | 10.1371/journal.pone.0054302 |
| PROVIDER: | scopus |
| PMCID: | PMC3553126 |
| PUBMED: | 23372702 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 March 2013" - "Source: Scopus" |
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