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Stromal iodothyronine deiodinase 2 (DIO2) promotes the growth of intestinal tumors in Apc?716 mutant mice.

ABSTRACT: Iodothyronine deiodinase 2 (DIO2) converts the prohormone thyroxine (T4) to bioactive T3 in peripheral tissues and thereby regulates local thyroid hormone (TH) levels. Although epidemiologic studies suggest the contribution of TH to the progression of colorectal cancer (CRC), the role of DIO2 in CRC remains elusive. Here we show that Dio2 is highly expressed in intestinal polyps of Apc?716 mice, a mouse model of familial adenomatous polyposis and early stage sporadic CRC. Laser capture microdissection and in situ hybridization analysis show almost exclusive expression of Dio2 in the stroma of Apc?716 polyps in the proximity of the COX-2-positive areas. Treatment with iopanoic acid, a deiodinase inhibitor, or chemical thyroidectomy suppresses tumor formation in Apc?716 mice, accompanied by reduced tumor cell proliferation and angiogenesis. Dio2 expression in Apc?716 polyps is strongly suppressed by treatment with the COX-2 inhibitor meloxicam. Analysis of The Cancer Genome Atlas data shows upregulation of DIO2 in CRC clinical samples and a close association of its expression pattern with the stromal component, consistently with almost exclusive expression of DIO2 in the stroma of human CRC as revealed by in situ hybridization. These results indicate essential roles of stromal DIO2 and thyroid hormone signaling in promoting the growth of intestinal tumors.

SUBMITTER: Kojima Y

PROVIDER: S-EPMC6676103 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Stromal iodothyronine deiodinase 2 (DIO2) promotes the growth of intestinal tumors in Apc<sup>Δ716</sup> mutant mice.

Kojima Yasushi Y Kondo Yuriko Y Fujishita Teruaki T Mishiro-Sato Emi E Kajino-Sakamoto Rie R Taketo Makoto Mark MM Aoki Masahiro M

Cancer science 20190707 8

Iodothyronine deiodinase 2 (DIO2) converts the prohormone thyroxine (T4) to bioactive T3 in peripheral tissues and thereby regulates local thyroid hormone (TH) levels. Although epidemiologic studies suggest the contribution of TH to the progression of colorectal cancer (CRC), the role of DIO2 in CRC remains elusive. Here we show that Dio2 is highly expressed in intestinal polyps of Apc<sup>Δ716</sup> mice, a mouse model of familial adenomatous polyposis and early stage sporadic CRC. Laser captur ...[more]

PMID: 31215118

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Project description:PurposeThe development of the selective RET inhibitors selpercatinib and pralsetinib has revolutionized the treatment of metastatic progressive RET-mutant medullary thyroid carcinoma (MTC) and other RET-driven cancers, given their more favorable side-effect profile. The aim of this study is to investigate the mechanisms of selpercatinib-induced thyroid dysfunction in athyreotic patients with RET-mutant MTC and in patients with RET-mutant non-small-cell lung cancer (NSCLC) who had a functional thyroid.Materials and methodsThyroid hormone levels were evaluated in an observational cohort of five athyreotic patients with MTC and 30 patients with NSCLC before and after initiation of selpercatinib. In vitro experiments to identify the mechanism of selpercatinib-induced thyroid dysfunction were conducted in cells expressing endogenous D1, D2, and D3 iodothyronine deiodinases.ResultsUpon initiating treatment with selpercatinib, athyreotic patients developed clinical hypothyroidism with approximately 60% lower T3 levels despite adequate levothyroxine supplementation, whereas in patients with NSCLC, who retain a normal thyroid, selpercatinib resulted in a more attenuated reduction in serum T3, which was dose-dependent. We conducted studies in cells endogenously expressing either D1, D2, or D3, the three iodothyronine deiodinases. Selpercatinib inhibited D2-mediated T3 production in MSTO-211 cells by 50%. A modest repression of D2 mRNA was present in human thyroid cancer TT cells that express RET, but not in the MSTO-211 cells that do not. No effect of the drug was observed on D1 (activating deiodinase) or D3 (inactivating deiodinase). Thus, a nontranscriptional effect of selpercatinib on D2 activity is the most plausible explanation for the low T3 levels.ConclusionAn off-target effect of selpercatinib on D2-mediated T3 production leads to clinical hypothyroidism, primarily in levothyroxine-treated athyreotic patients. Liothyronine supplementation was needed to achieve normal T3 levels and restore clinical euthyroidism.

Dataset Information

Stromal iodothyronine deiodinase 2 (DIO2) promotes the growth of intestinal tumors in Apc?716 mutant mice.

Publications

Stromal iodothyronine deiodinase 2 (DIO2) promotes the growth of intestinal tumors in Apc<sup>Δ716</sup> mutant mice.

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