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Departments of Endocrinology and Metabolism (J.W.A.S., J.P.S.-v.d.E., M.K., I.Q., J.A.R.), Pediatrics (M.K.), and Nuclear Medicine (M.S.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; and Human and Animal Physiology Group (D.v.d.H.), Wageningen University, 6700 HB Wageningen, The Netherlands
Address all correspondence and requests for reprints to: Jan W. A. Smit, Department of Endocrinology, C4-R, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: . j.w.a.smit.endo{at}lumc.nl
Abstract
Uptake of iodide is a prerequisite for radioiodide therapy in thyroid cancer. However, loss of iodide uptake is frequently observed in metastasized thyroid cancer, which may be explained by diminished expression of the human sodium-iodide symporter (hNIS). We studied whether transfection of hNIS into the hNIS-deficient follicular thyroid carcinoma cell line FTC133 restores the in vivo iodide accumulation in xenografted tumors and their susceptibility to radioiodide therapy. In addition, the effects of low-iodide diets and thyroid ablation on iodide kinetics were investigated. Tumors were established in nude mice injected with the hNIS-transfected cell line FTC133-NIS30 and the empty vector transfected cell line FTC133-V4 as a control. Tumors derived from FTC133-NIS30 in mice on a normal diet revealed a high peak iodide accumulation (17.4% of administered activity, measured with an external probe) as compared with FTC133-V4 (4.6%). Half-life in FTC133-NIS30 tumors was 3.8 h. In mice kept on a low-iodide diet, peak activity in FTC133-NIS30 tumors was diminished (8.1%), whereas thyroid iodide accumulation was increased. In thyroid-ablated mice kept on a low-iodide diet, half-life of radioiodide was increased considerably (26.3 h), leading to a much higher area under the time-radioactivity curve than in FTC133-NIS30 tumors in mice on a normal diet without thyroid ablation. Experimental radioiodide therapy with 2 mCi (74 MBq) in thyroid-ablated nude mice, kept on a low-iodide diet, postponed tumor development (4 wk after therapy, one of seven animals revealed tumor vs. five of six animals without therapy). However, 9 wk after therapy, tumors had developed in four of the seven animals. The calculated tumor dose was 32.2 Gy.
We conclude that hNIS transfection into a hNIS-defective thyroid carcinoma cell line restores the in vivo iodide accumulation. The unfavorable iodide kinetic characteristics (short half-life) can be partially improved by conventional conditioning with thyroid ablation and low-iodide diet, leading to postponed tumor development after radioiodide therapy. However, to achieve sufficient radioiodide tumor doses for therapy, further strategies are necessary, aiming at the mechanisms of iodide efflux in particular.
THE PROGNOSIS OF differentiated thyroid carcinoma is generally considered favorable (1), but the overall survival declines to 40% when distant metastases are present (2). With the exception of small papillary tumors (T-1), nearly all patients with thyroid cancer will undergo total thyroidectomy (2, 3). The cornerstone of postsurgical therapy in differentiated thyroid carcinoma is the ability of thyroid tissue to accumulate iodide. Although some controversy exists on the routine application of 131I ablative therapy in low-risk patients, its role in high-risk patients and in metastatic disease is generally accepted. A major problem in this category of patients is the diminished or lost ability of thyroid cancer cells to accumulate radioiodide, as indicated by negative posttherapeutic whole-body scintigraphy. In these cases, the prognosis is poor, because alternative treatment options (external radiotherapy or chemotherapy) have limited success (2, 4). The discovery and molecular cloning of the rat and later the human sodium iodide symporter (hNIS) has contributed greatly to the understanding of the physiology and pathophysiology of iodide uptake by the thyroid gland (5, 6). The gene for hNIS is located on chromosome 19 and spans over 20 Kb of genomic sequences. The gene contains 15 exons and codes for a protein of 643 amino acids (7). The proposed symporter molecule has 13 transmembrane domains. hNIS transcription is dependent on TSH (8), Tg, and extracellular iodide concentrations (9). The hNIS promotor has been characterized (10). Transcription factors involved are TTF-1, TTF-2, PAX-8, and as yet uncharacterized factors (reviewed in Ref. 11). Apart from NIS, other proteins play an important role in the thyroidal metabolism of iodide; iodide is transported across the apical membrane of the thyroid epithelial cell through the action of pendrin (12). Next steps in the processing of iodide are oxidation and organification that are catalyzed by thyroid peroxidase (TPO) and thyroid oxidase (13).
The presence of hNIS in thyroid cancer has been well documented. Loss of hNIS mRNA expression was observed in cell lines (6, 14) and tissue samples from papillary and follicular thyroid cancers (15). Iodide uptake is an indicator of differentiated behavior, as is the expression of TPO, Tg, and the TSH receptor (TSHR). Loss of hNIS and TPO expression may be an early event in tumor progression, with relative preservation of Tg and TSHR (16, 17).
Enhancement of iodide uptake in thyroid carcinoma has traditionally been realized by increasing endogenous TSH levels by thyroid hormone withdrawal and low-iodide diets (18, 19) or recently by the administration of recombinant human TSH (20). Lithium has been applied to retain radioiodide within thyroid cancer (21, 22). Few attempts have been published to interfere in defective iodide uptake in thyroid carcinoma. Retinoids have been reported to enhance iodide uptake in vitro (23) and in patients (24), probably by increased hNIS transcription (25). In another study, in vitro hNIS transcription and iodide uptake were increased by chemical demethylation therapy (14).
Strategies to restore iodide uptake in thyroid cancer include the exploration of hNIS gene transfer into hNIS defective thyroid cancer. Shimura et al. (26) successfully transfected hNIS cDNA into a rat thyroid cell line (FRTL-5). hNIS has also been transfected into nonthyroid human cancer cell lines, including ovarian, melanoma (27), and prostate (28, 29). Spitzweg et al. (30) demonstrated successful experimental radioiodide treatment of hNIS-transfected prostate tumors in nude mice. We have recently reported the restoration of the in vitro iodide uptake in a hNIS-defective follicular thyroid carcinoma cell line stably transfected with hNIS (31). We found a rapid in vitro accumulation of iodide, reaching a plateau at 60 min, in which the uptake was approximately 24% of the radioactivity administered. However, a rapid release of radioactivity from the hNIS-transfected cell lines was observed, leading to an in vitro biological half-life of approximately 11 min.
In the present study, we investigated the in vivo iodide kinetics in tumors established by injection of a hNIS- and empty vector-transfected follicular thyroid carcinoma cell line in nude mice. Because we expected a rapid release of radioactivity in vivo as well, we studied whether low-iodide diets and thyroid ablative treatment would have a beneficial influence on the in vivo iodide kinetic properties, because it has been demonstrated that low-iodide diets enhance biological half-life in human thyroid carcinoma (18, 19). In addition, we attempted to perform experimental radioiodide therapy in hNIS-transfected human thyroid tumors in nude mice.
Materials and Methods
Cell lines, transfection, and culturing conditions
The follicular thyroid carcinoma cell line FTC133 (kindly donated by Dr. Goretzki and Dr. Simon, University of Düsseldorf, Germany) was derived from a 42-yr-old male with metastatic follicular thyroid carcinoma (32). FTC133 expresses Tg, TSHR, pendrin, PAX-8, and TTF-1 mRNA and protein, but not TPO or hNIS, and consequently does not accumulate iodide (25).
The stable transfection of hNIS cDNA into FTC133 has been described (31). In short, full-length hNIS cDNA (donated by Dr. Jhiang, Ohio State University), cloned into the EcoRI site of pcDNA3 (Invitrogene, Groningen, The Netherlands) was transfected into FTC133 using Fugene 6 (Roche Molecular Biochemicals). Two transfected colony cell lines were selected, FTC133-NIS30 (which accumulates 
24% of total radioactivity, which can be blocked completely by sodium perchlorate) and the empty vector-transfected cell line FTC133-V4, which reveals no uptake of radioiodide.
Cells were cultured in DMEM and modified HAM-F12 medium 1:1 supplemented with 10% FBS, penicillin/streptomycin, and geneticin to maintain an advantageous environment for transfected cells, in a humidified incubator at 37 C and 5% CO2. Cells were cultured in a serum-free medium, containing a mixture of six hormones (33) before injection in animals.
Nude mice, conditioning, and tumor establishment
To study the effects of hNIS re-expression on in vivo iodide kinetics, human thyroid tumors were established in BALB-c nu/nu mice. Four different protocols were followed (Table 1
). In the first protocol, 1 million tumor cells from FTC133-V4 were injected sc into BALB-c nu/nu mice (protocol I). Six animals were studied for iodide kinetics, and six for postmortem iodide accumulation assessment (see below). The mice were kept on a normal diet throughout the study. In the second protocol, 1 million FTC133-NIS30 cells per animal were injected. These mice were kept on a normal diet as well (protocol II). Nine animals in this protocol were studied for iodide kinetics, and six for postmortem assessment. To assess the effects of a low-iodide diet on iodide kinetics, in the third protocol, nude mice were injected with FTC133-NIS30 and kept on a low-iodide diet according to the American Institute of Nutrition (34), containing 55 ng iodide/g, throughout the study (protocol III). The diet was initiated 3 wk before tumor cell injection. The animals received T3 supplement (33 ng/d; Sigma, St. Louis, MO) throughout the study, but T3 was stopped 7 d before all interventions. Six mice were studied for iodide kinetics, and six for postmortem iodide accumulation assessment. To study the effects of thyroid ablation combined with a low-iodide diet, mice received thyroid ablation 3 wk before injection with FTC133-NIS30 (protocol IV). In this protocol, the mice were kept on a low-iodide diet during the whole experiment. Sodium perchlorate 1% was added to the drinking water during the first 2 d after initiating the low-iodide diet. Two weeks after initiating the low-iodide diet, thyroid glands were ablated with 500 µCi (18.5 MBq) Na131I (Mallinckrodt, Inc. Petten, The Netherlands). This activity had been demonstrated sufficiently for thyroid ablation in rats (35). Three weeks after thyroid ablative treatment, 1 million FTC133-NIS30 cells were injected sc. The animals received T3 supplement throughout the study, but T3 was stopped 7 d before all interventions. Seven mice received protocol IV for iodide kinetic studies (see above). From this group, one mouse died after tumor cell injection. In one mouse, no tumor developed, so iodide kinetics were studied in the five remaining mice. The six surviving mice also served as controls in the experimental radioiodide treatment protocol (see below). Five mice that followed protocol IV were studied for postmortem iodide accumulation.
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In vivo iodide kinetics were studied in tumors and thyroid glands in animals that had received protocols I-IV. Animals were studied 6 wk after injection of tumor cells, when visible tumors had developed. Ten µCi (0.37 MBq) Na125I (Mallinckrodt, Inc.) were injected sc in all mice. Accumulation of radioactivity was measured using a probe with an external collimator that had been developed for use in small laboratory animals (35). The angle of acquisition of the pinhole collimator is 11.3 degrees. The probe was placed directly on the surface of the tumor, parallel to the back of the mice, so that no interference with radioactivity from thyroid glands or bladder was present. To assess thyroid activity, the probe was placed perpendicular to the thyroid surface. Due to the positions of the tumors and the angle of acquisition of the probe, no interference with tumor associated radioactivity was present. Thyroid activity was corrected for nonthyroid-associated radioactivity. The administered activity was assessed by measuring a sample from the Na125I administered with the same probe. Radioactivity was measured in triplicate at regular time intervals until the activity was below 2.5%.
Postmortem radioiodide accumulation
Postmortem iodide accumulation was measured in tumors and thyroids isolated from mice that had followed protocols I-IV. They were killed 4 h after the administration of 10 µCi Na125I, 6 wk after injection of tumor cells. Tumors were weighted, and the radioactivity was counted in a 
-counter. The accumulated radioactivity in tumors and thyroids was expressed as percentage of the dose administered, and, for the tumors, was corrected for tumor mass. The administered activity was estimated by counting a sample from the Na125I administered in the -counter. From one tumor in each treatment group, a segment was removed for RNA isolation.
Experimental 131I therapy
Eight mice were conditioned according to protocol IV. Three weeks after injection of FTC133-NIS30 tumor cells, 2 mCi (74 MBq) Na131I was administered sc. At this stage, tumors were not visible. This activity was chosen because in a preliminary experiment, we did not find any beneficial effect of 200 µCi (36). In addition, Spitzweg et al. (30) had found a therapeutic effect with 3 mCi in hNIS-transfected prostate cancer tumors. One mouse died immediately after radioiodide therapy, so that seven mice could be followed. The six mice that had received protocol IV for iodide kinetic studies served as controls. Tumor development was assessed weekly. Tumor dose of radioactivity was estimated by the following formula: D = A·t·y·E·M-1, in which D = dose (Gy), A = activity (Bq), t = time (sec), y = abundance (%), E = mean energy of ß- particles (0.202 MeV in 131I), and M = estimated tumor mass (kg).
All animal experiments were approved by the institutional committee for animal experiments.
RT-PCR
Total RNA from the FTC133-V4 and FTC133-NIS30 cell lines and tumors from mice treated according to protocols I-IV and from one tumor that had developed after experimental radioiodide therapy was isolated and reverse transcribed. The cDNA was used as a template for PCR amplification. The internal standard QB2 was used to standardize cDNA for ß2 microglobulin expression by competitive PCR as described previously (37, 38). The sequences of the hNIS PCR primers were as reported by Smanik et al. (hNISF2 and hNISR2) (6). Primer sequences for TTF-1, PAX-8, Tg, TSHR, pendrin, and TPO were designed using primer III design software (http://www.genome.wi.mit.edu) and checked against GenBank to avoid cross reactivity with other known sequences. Amplicon lengths for hNIS, TTF-1, PAX-8, Tg, TSHR, and TPO were 415, 393, 399, 401, 400, and 298 bp, respectively. Sequences are available upon request from the author. Primers were manufactured by Eurogentec (Seraing, Belgium). cDNA was denatured at 95 C for 5 min, followed by 29–38 cycles of 95 C for 20 sec, 56 C for 60 sec, 72 C for 30 sec, and extension at 72 C for 3 min.
Statistical analyses
Continuous data are expressed as mean ± SD when distributed normally, as tested by the Kolmogorov-Smirnov test, otherwise as medians and ranges. Continuous data between groups were compared with one-way ANOVA, followed by the Newman-Keuls test for comparison of two groups. Proportional data were compared with the 
2 test. Terminal half-life of accumulated radioactivity was calculated by linear regression analysis of the terminal log-linear phase of the radioactivity-time curve. The area under the radioactivity-time curve was calculated using the trapezoidal method. A P value of <0.05 was considered significant.
Results
In vivo iodide kinetic studies
Data from the in vivo iodide kinetics studied in mice that had received protocols I-IV are given in Table 1
and Fig. 1. A much higher tumor peak radioactivity was observed in FTC133-NIS30 (protocols II and IV) than in FTC133-V4 (protocol I). Peak tumor activity in FTC133-NIS30 tumors in mice with intact thyroid glands on a low-iodide diet (protocol III) was significantly lower than in FTC133-NIS30 tumors in mice on normal diets (protocol II) or mice that had received combined thyroid ablative therapy and low-iodide diet (protocol IV), whereas thyroid radioiodide accumulation in protocol III was increased as compared with protocols II and IV. Terminal half-life of radioactivity in FTC133-NIS30 tumors was low in mice on a normal diet (3.8 h) but increased substantially in mice that had received thyroid ablation and a low-iodide diet (26.3 h). The area under the curve (AUC) values differed considerably, with highest values as expected in group IV.
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Postmortem radioiodide accumulation measured in tumors isolated from mice that had been killed 4 h after the administration of 10 µCi Na125I is given in Table 1.
Accumulation of radioactivity was considerably higher in FTC133-NIS30 (protocols II and IV) than in FTC133-V4 (protocol I). Accumulation of radioactivity in FTC133-NIS30 tumors in mice on a low-iodide diet (protocol III) was significantly lower than in FTC133-NIS30 tumors in mice on normal diets (protocol II) or mice that had received combined thyroid ablative therapy and low-iodide diet (protocol IV). The same differences were observed when accumulated radioactivity was corrected for tumor mass.
Radioactivity in thyroid glands obtained from mice on a low-iodide diet alone (protocol III) was significantly higher than in the other groups. In mice that had received thyroid ablation, radioactivity in the removed tracheal segments was significantly lower than in the other groups.
Experimental 131I therapy
Two milliCuries prevented tumor development in six of seven mice 4 wk after therapy and five of seven mice 5 wk after therapy, whereas five of six control mice had developed tumors at that time (P = 0.01; Table 2). However, 9 wk after therapy, the cumulative number of mice that had developed tumors after 2 mCi 131I had become four. In the four mice without visible tumors at that time (one in the group without 131I therapy and three in 131I therapy group), postmortem examination did not reveal tumors either. Using the formula for tumor dose mentioned in Materials and Methods, it could be calculated from the AUC of the radioactivity-time curve from the mice that had followed protocol IV for iodide kinetics, corrected for administered radioactivity and estimated tumor mass, that the average tumor dose after 2 mCi had been 32.2 Gy.
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Semiquantitative RT-PCR was performed with mRNA obtained from FTC133-NIS30 and V4 cell lines, tumors established according to protocols I-IV, and one tumor that had developed in a mouse treated with 2 mCi 131I. RT-PCR revealed comparable expression of TTF-1, PAX-8, Tg, TSHR, and absent TPO expression in all cell lines and all tumors, irrespective of the conditioning protocol or 131I treatment. FTC133-NIS30 cell lines and tumors revealed high hNIS mRNA expression, whereas no hNIS mRNA was observed in FTC133-V4. mRNA data for the cell lines are given in Fig. 2.
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In this study, we report the in vivo iodide kinetic characteristics of human thyroid tumors derived from the hNIS-transfected follicular thyroid carcinoma cell line FTC133-NIS30 using the empty vector transfected cell line FTC133-V4 as a control. In addition, the influence of a low-iodide diet and thyroid ablative treatment on iodide kinetics were investigated, and experimental therapy with radioiodide was performed.
Thyroid tumors derived from FTC133-NIS30 clearly accumulated radioiodide in contrast to FTC133-V4. Because not all animals reached their peak tumor values at the same point in time, the mean peak values in Table 1 are generally higher than is represented by the peak of the tumor-radioactivity curves in Fig. 1. A rapid efflux of iodide (half-life, 3.8 h) was observed from FTC133-NIS30 tumors in mice that were kept on a normal diet and had not undergone thyroid ablative therapy. This is longer than previously found in vitro using the same cell line (39). Explanations for this difference may be the experimental design of the in vitro efflux experiment, in which washing fluids are changed continuously, whereas in the animals, reuptake of radioiodide may take place. Alternatively, the histological architecture of the tumor may give rise to a slower efflux than observed in an in vitro monolayer culture.
The mechanism of iodide efflux from FTC133-NIS30 is not clear. Iodide efflux appears to be an active process, because high extracellular iodide concentrations did not influence iodide transport out of the cells (31). Because the FTC133 cell line expresses pendrin, this may be one of the factors involved in this transport. The involvement of the apical iodide channel as described by Yoshida et al. (38) is less likely because this channel appears to be dependent on extracellular iodide concentrations and would not mediate iodide efflux when extracellular iodide concentrations are high, as in the in vitro studies. It may be suggested that the lack of TPO expression contributes to the rapid efflux of iodide in our and other cell lines. However, TPO activity is located mainly at the exterior of thyroid epithelial cells so that even if the administered radioiodide would have been incorporated in Tg, this could probably not have prevented the rapid efflux of radioiodide from the tumor cells. Rapid efflux of iodide has also been observed in vitro in nonthyroid cell lines transfected with hNIS (27, 29). It is intriguing that in the studies of Spitzweg et al. (28, 30), a relatively long half-life is found in hNIS-transfected prostate carcinoma. The investigation of the mechanism of iodide retention in these cell lines is of utmost importance for understanding iodide kinetics in NIS-transfected cell lines.
In mice with intact thyroid glands that were kept on a low-iodide diet alone, peak radioiodide accumulation in FTC133-NIS30 tumors was diminished, as compared with mice with FTC133-NIS30 tumors with intact thyroids that were kept on a regular diet. This is explained by the fact that low-iodide diets lead to increased TSH levels. When thyroid glands are present, the increased TSH levels enhance iodide uptake by inducing hNIS expression. The transcription of hNIS in the hNIS-transfected FTC cell line, however, is not dependent on TSH because it lacks the TSH-driven hNIS promoter but instead is driven by the TSH-independent cytomegalovirus promoter. As a consequence, the competition between tumor and thyroid for iodide uptake would shift in favor of the thyroid in mice with FTC133-NIS30 tumors with intact thyroid glands during low-iodide diets. This is supported by the much higher accumulation of radioactivity by the thyroids of mice with FTC133-NIS30 tumors with intact thyroid glands during low-iodide diets than in FTC133-NIS30 tumors without low-iodide diets and FTC133-NIS30 tumors with low-iodide diet and thyroid ablation, as illustrated in Fig. 1. This observation underscores the need of total ablation of thyroid remnants to prevent competition for radioiodide uptake when 131I therapy is performed for residual, relapsing, or metastatic thyroid carcinoma.
Interestingly, half-life was prolonged considerably (26 h) in mice that had undergone thyroid ablation and received a low-iodide diet, leading to a much higher AUC than in the other tumors. This is in line with observations in humans, where low-iodine diets prolong half-life (18, 19). Interestingly, in human studies this effect is attributed at least in part to increased TSH levels and subsequent increased iodide uptake in thyroid tumors or remnants. As explained before, hNIS is constitutively expressed in FTC133-NIS30 and therefore probably not influenced by TSH. It could be hypothesized that high TSH levels could have influenced other thyroid proteins involved in iodide metabolism. However, the observation that the mRNA expression of thyroid proteins involved in iodide metabolism was not influenced by the different protocols does not support this explanation. Another explanation may be the diminished renal clearance of radioiodine as expected during a low-iodide diet. Although we did not measure this, this could result in a prolonged radioiodide retention and a subsequent higher amount of radioiodide available for reuptake by the tumor. The theory of reuptake of radioiodide was supported by the existence of a strong correlation (r2 = 0.77) between radioiodide accumulation and half-life within groups of mice.
The data on experimental 131I therapy in the FTC133-NIS30 tumors revealed a potential beneficial effect of this therapy, because tumor development appeared to be postponed. However, this effect was only temporary, because tumors did develop later in the experiment. It was estimated that the average tumor dose had been 32.2 Gy. Maxon et al. calculated a tumor dose of 80 Gy to achieve elimination of nodal metastases in 74% of the patients (40). Therefore, the tumor dose achieved in our experiment is insufficient for tumor elimination. Although theoretically activities as high as in humans (150 mCi) should be administered to fully explore the feasibility of 131I therapy in FTC133-NIS30 tumors, this is not achievable in the present animal model.
We conclude that re-expression of hNIS in differentiated thyroid cancer leads to restored in vivo iodide accumulation. However, favorable iodide kinetic properties are a precondition to realize sufficient dosages of radioiodide for therapy. We demonstrated that the conventional strategy of thyroid ablation and a low-iodide diet improved in vivo iodide retention considerably, even leading to postponed tumor development after 131I therapy. However, further research is needed into the mechanisms of iodide efflux as observed in the present model to further enhance the susceptibility for radioiode therapy.
Acknowledgments
Footnotes
This work was supported by a research grant from the Dutch Cancer Foundation (KWF) and the Dutch Organization for Scientific Research (NWO).
Abbreviations: AUC, Area under the curve; hNIS, human sodium iodide symporter; TPO, thyroid peroxidase; TSHR, TSH receptor.
Received June 20, 2001.
Accepted December 3, 2001.
References
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