Preclinical Mouse Models of Thyroid Cancer

Division Of Basic Sciences - Nci

Investigators

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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; ThrbPV/PVPten+/- mice), we aimed to elucidate a cause-effect relationship at the molecular level. The ThrbPV/PVPten+/- mouse expresses a dominantly negative thyroid hormone receptor beta (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 ThrbPV/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 ThrbPV/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. Dysregulation of genes perpetuates cancer progression. During carcinogenesis, cancer cells acquire dependency of aberrant transcriptional programs (known as transcription addiction) to meet the high demands for uncontrolled proliferation. The needs for transcription programs for cancer growth could be cancer-type-selective. The dependencies of certain transcription regulators could be exploited for therapeutic benefits. Anaplastic thyroid cancer (ATC) is an extremely aggressive human cancer for which new treatment modalities are urgently needed. Its resistance to conventional treatments and the lack of therapeutic options for improving survival might have been attributed to extensive genetic heterogeneity due to subsequent evolving genetic alterations and clonal selections during carcinogenesis. Despite this genetic complexity, mounting evidence has revealed a characteristic transcriptional addiction of ATC cells resulting in evolving diverse oncogenic signaling for cancer cell survival. The transcriptional addiction has presented a huge challenge for effective targeting as shown by the failure of previous targeted therapies. However, an emerging notion is that many different oncogenic signaling pathways activated by multiple upstream driver mutations might ultimately converge on the transcriptional responses, which would provide an opportunity to target transcriptional regulators for treatment of ATC. Indeed, we found that inhibitors (JQ1 and PLX51107) of bromodomain and extra-terminal domain (BET) proteins and acetylated histones potently suppress the expression of cMYC to inhibit ATC tumor growth. Further, we showed that combined treatment of PLX51107 (PLX) with a MEK inhibitor, PD0325901(PD), inhibit the recruitment of BET proteins to the promoter of the c-MYC gene, to be more effectively suppress c-MYC transcription, and to markedly reduce tumor growth. These findings of preclinical studies clearly indicated that combined treatments of BET inhibitors and MEK inhibitors via epigenetic modifications could be effective for treating human ATC.