Inflammation suppression prevents tumor cell proliferation in a mouse model of thyroid cancer

Sunmi Park; Minjun Kim; Jack Zhu; Woo Kyung Lee; Grégoire Altan-Bonnet; Paul Meltzer; Sheue-Yann Cheng

Inflammation suppression prevents tumor cell proliferation in a mouse model of thyroid cancer

Am J Cancer Res. 2020 Jun 1;10(6):1857-1870. eCollection 2020.

Authors

Sunmi Park¹, Minjun Kim¹, Jack Zhu², Woo Kyung Lee¹, Grégoire Altan-Bonnet³, Paul Meltzer², Sheue-Yann Cheng¹

Affiliations

¹ Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda, MD 20892, Maryland, USA.
² Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda, MD 20892, Maryland, USA.
³ Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda, MD 20892, Maryland, USA.

PMID: 32642296
PMCID: PMC7339265

Abstract

The incidence of thyroid cancer, the most frequent endocrine neoplasia, is rapidly increasing. Significant progress has recently been made in the identification of genetic lesions in thyroid cancer; however, whether inflammation contributes to thyroid cancer progression remains unknown. Using a mouse model of aggressive follicular thyroid cancer (FTC; Thrb^PV/PVPten^+/- mice), we aimed to elucidate a cause-effect relationship at the molecular level. The Thrb^PV/PVPten^+/- mouse expresses a dominantly negative thyroid hormone receptor β (denoted as PV) and a deletion of a single allele of the Pten gene. These two oncogenic signaling pathways synergistically activate PI3K-AKT signaling to drive cancer progression as in human FTC. At the age of 5-7 weeks, thyroids of Thrb^PV/PVPten^+/- mice exhibited extensive hyperplasia accompanied by 77.5-fold infiltration of inflammatory monocytes as compared with normal thyroids. Global gene expression profiling identified altered expression of 2387 genes, among which 1353 were upregulated and 1034 were down-regulated. Further analysis identified markedly elevated expression of inflammation mediators and cytokines such as, Csf1r, Csf1, SPP1, Aif1, IL6, Ccl9, Ccl3, Ccl12, and Ccr2 genes and decreased expression of Kit, Ephx2, Cd163, IL15, Ccl11, and Cxcl13 genes. These changes elicited the inflammatory responses in the hyperplastic thyroid of Thrb^PV/PVPten^+/- mice, reflecting early events in thyroid carcinogenesis. We next tested whether attenuating the inflammatory responses could mitigate thyroid cancer progression. We treated the mice with an inhibitor of colony-stimulating factor 1 receptor (CSF1R), pexidartinib (PLX-3397; PLX). CSF1R mediates the activity of the cytokine, colony stimulating factor 1 (CSF1), in the production, differentiation, and functions of monocytes and macrophages. Treatment with PLX decreased 94% and 62% of inflammatory monocytes in the thyroid and bone marrow, respectively, versus controls. Further, PLX suppressed the expression of critical cytokine and inflammation-regulating genes such as Csf1r, SPP1 (OPN), Aif1, IL6, Ccl9, Ccl3, Ccl12, and Ccr2 (25%-80%), resulting in inhibition of 89% tumor cell proliferation, evidenced by Ki-67 immunostaining. These preclinical findings suggest that inflammation occurs in the early stage of thyroid carcinogenesis and plays a critical in cancer progression. Importantly, attenuation of inflammation by inhibitors such as PLX would be beneficial in preventing thyroid cancer.

Keywords: CSF1R inhibitors thyroid cancer; Inflammation; colony-stimulating factor 1 receptor; monocytes; mouse model; pexidartinib (PLX-3397).