Endogenous expression of the sodium iodide symporter mediates uptake of iodide in murine models of colorectal carcinoma

Abstract

The sodium iodide symporter (NIS) mediates iodide uptake into the thyroid. Because of this mechanism, differentiated thyroid cancer is susceptible for radioiodine therapy. Functional NIS expression in extrathyroidal tumors has been reported mainly in breast cancer. We screened colorectal tumors for NIS expression and investigated the mechanisms regulating NIS activity. Cell lines were screened for iodide uptake in vitro and NIS expression was evaluated by real-time RT-PCR, immunocytochemistry and immunoblotting. Iodide and pertechnetate uptake were evaluated in allograft tumors by biodistribution studies and scintigraphy. Tumors of transgenic mouse models for colorectal cancer harboring mutations in the oncogenes KRAS, b-catenin or the tumor-suppressor gene adenomatous-polyposis coli (APC) were screened for NIS expression by RT-PCR. In vitro, functional NIS activity was detected in murine CMT93 rectal carcinoma cells and NIS expression was verified on mRNA and protein level. Inhibition of tyrosine kinases increased iodide uptake. Inhibition of tyrosine phosphatases decreased iodide uptake. In vivo, functional NIS expression was preserved in CMT93 tumors and tumor uptake could be enhanced by treatment of mice with tyrosine kinase inhibitors. In transgenic murine models of colorectal cancer, 14% of endogenous tumors expressed elevated levels of NIS mRNA. We conclude that NIS is functionally expressed in a subset of murine colorectal tumors and its activity is regulated by tyrosine phosphorylation. Therefore, with specific tyrosine kinase inhibition, these tumors might be susceptible for radioiodine treatment. Further studies are justified to identify the specific pathways regulating NIS activity and to transfer these findings to human cell lines and tissues. ' UICCKey words: sodium iodide symporter; endogenous expression; radioiodine uptake; colorectal cancer; extrathyroidal tumorsThe sodium iodide symporter (NIS) is a glycoprotein located in the basolateral membrane of thyrocytes. It mediates the active transport of iodide from the extracellular space into the thyrocytes as the first step of thyroid hormone synthesis.1 This mechanism is used for diagnostic and therapeutic purposes in nuclear medicine. Analogous to iodide, NIS also effectively transports pertechnetate (TcO 42 ) into the intracellular space. 2 This is important for nuclear medicine applications as the widely available radionuclide 99m

The uptake of soluble and nanoparticulate imaging isotope in model liver tumours after intra-venous and intra-arterial administration

“…Active uptake of pertechnetate has been noted before in other tumours [27,28], where it has been shown to be due to endogenous iodide symporter (NIS) expression, but in the case of VX2 liver tumours we found that while a competitive inhibitor of the NIS (perchlorate)…”

Synchronous primary cancers of the thyroid and breast: A case report and review of the literature

“…Furthermore, studies regarding the hormones in close proximity to the thyroid, which may be involved in the sychronous primary tumor mechanism, such as thyroid hormone ( 9 ), thyroid peroxidase antibody ( 10 ) and thyroid Ras-regulating enzymes ( 11 ), have been undertaken. The sodium iodide symporter (NIS) was proposed as a potential co-passageway for thyroid and BC ( 12 , 13 ), indicating a potential therapeutic target during radioiodine therapy. Therefore, the specific signaling pathways regulating NIS activity require investigation and a method to upregulate NIS must be determined.…”

Quantitation of cytokine mRNA by real-time RT-PCR during a vaccination trial in a rabbit model of fascioliasis

“…Because of its specificity and sensitivity, qRT-PCR is the method of choice for quantifying mRNA expression levels of cytokines, which normally are expressed at very low levels (Giulietti et al, 2001). Most qRT-PCR protocols have been developed to quantify cytokines in mice and humans, owing to the availability of a complete collection of leukocyte expressed sequences tags (ESTs) and complete genomic sequences for those species (Bilate et al, 2008; Castilho et al, 2008; Dantas et al, 2009; Fang et al, 2009; Gaertner et al, 2009; Suksumek et al, 2008; Walsh et al, 2009). In contrast, very few assays have been developed for quantification of cytokines in domestic animals (Ledger et al, 2004; Leutenegger et al, 1999a,b).…”