A prerequisite for the success of radioiodide treatment is the retention of the radioisotope for a sufficiently long time so the necessary dose is delivered to destroy the malignant tissue. The retention time of radioiodide in thyrocytes is determined by uptake and I- efflux. At steady-state conditions, I- accumulation reflects the equilibrium between the rates of influx and efflux (Figure 4).
In the healthy thyroid gland, NIS mediates the active accumulation of whereas the mechanisms involved in efflux are poorly understood (see efflux: pendrin and AIT" below). I" organification - i.e., the TPO-mediated iodination of the tyrosine residues on the thyroglobulin molecule - occurs on the colloidal surface of the apical membrane. lodinated thyroglobulin molecules remain in the colloid, surrounded
Efflux; passive I transport down its concentration gradient, possibly mediated by AIT, pendrin, or CI" channels
by the thyroid epithelial cells, thus increasing the radioiodide retention time in the thyroid gland. In contrast, in thyroid cancer, the typical follicular architecture of normal thyroid tissue is not conserved, as the malignantly transformed epithelial cells lose their polarity (53). Hence, these cells display no well-defined colloidal space, and as a result, thyroglobulin leaks out into the extracellular space and the bloodstream. Most differentiated thyroid cancers exhibit TPO protein expression, but at levels lower than those considered normal (54-56); TPO gene mutations have also been reported in some differentiated thyroid carcinomas (57). Furthermore, earlier studies in humans showed impaired or absent organification in thyroid cancer (58), underscoring the loss or reduction of organification in thyroid cancer.
More recently, the organification effect in radioiodide retention time has been assessed in vivo in non-NIS-expressing tumors into which both rat and human NIS have been introduced under the control of tissue-specific promoters. Since these tumors do not express TPO, they do not organify I". Cho et al (59) reported radioiodide retention time greater than 24 h in hNIS-expressing xenografted human glioma cells in rats, and observed a longer survival in animals with NlS-expressing tumors versus control animals with non-NIS-expressing tumors. Spitzweg et al (60) introduced NIS in a recombinant adenovirus into a human prostate carcinoma cell line under the regulation of the prostate specific antigen (PSA) promoter. They reported a retention time of 5.6+/-1.4 h in NIS-expressing prostate carcinoma xenografts in nude mice and a remarkable decrease (over 80%) of the size of these xenografts after a single ip injection of 3 mCi 1311. Dingli and colleges (61), for their part, expressed NIS in a myeloma cell line using a transcriptionally targeted lentiviral vector, where the therapeutic or reporter gene is under the control of minimal immunoglobulin promoter and enhancer elements (immunoglobulin K-light chain enhancer elements). These authors also investigated the so-called bystander effect. [3-particles emitted during the decay of 1311 can travel a distance of 0.2-2.4 mm. Therefore, the isotope is capable of destroying "bystanding" non-NIS-expressing cells. Dingli et al. (61) also treated myeloma xenografts containing variable numbers of radioiodide-transporting, NIS- and non-NIS-transduced tumor cells. The result was striking: all tumors in which 50-100% of the cells expressed NIS had completely regressed two weeks after a single dose of 1 mCi
The above results provide strong evidence against the widely held notion that radioiodide therapy is likely to be ineffective in non-thyroidal cells that, while functionally expressing NIS (whether endogenously or by targeted transfection), lack the ability to organify The reasoning was that the absence of organification resulted in the isotope not being retained in the cells for a sufficiently long time. Yet, in the mentioned studies (59, 61, 62), radioiodide treatment was effective even in the absence of T organification.
If organification is not essential for radioiodide therapy to be effective, sufficient iodide uptake mediated by NIS and slow I- efflux are the requirements for successful radioiodide therapy.
l~ efflux: pendrin and AIT
Several groups have tried to identify the mediator of apical I" efflux in thyroid epithelial cells. Two recently cloned molecules are the main candidates: pendrin and the apical iodide transporter (AIT) (Figure 1).
In 1997, a gene defective in Pendred syndrome (PDS) was identified by positional cloning (63). Pendred syndrome is characterized by sensorineural (most often prelin-gual) deafness and goiter with defective organification. In PDS, goiter can develop at any age or may be absent, whereas deafness is generally present (63). Pendrin has been localized on the apical membrane of the thyroid epithelial cells by immunohistochemistry (64). In heterologous expression systems, pendrin has been shown to transport iodide, chloride, formate, and nitrate (65).
The organification defect characteristic of Pendred syndrome was attributed to defective pendrin-mediated apical transport into the colloid, where organification occurs (Figure 1). Surprisingly, although the recently generated Pds-knockout mice are completely deaf, they do not exhibit a pathologic thyroidal phenotype (66); therefore, pendrin's function as the apical I- transporter remains to be further investigated.
By means of a PCR cloning strategy based on NIS-sequence homologies, a 610-amino-acid protein-coding gene was recently cloned from a human kidney cDNA library. The newly identified protein shares both a strikingly high identity (46%) and similarity (70%) to hNIS (67). This protein, called the human apical iodide transporter (hAIT), has been localized to the apical membrane of thyroid epithelial cells; however, a thorough molecular and kinetic characterization is required to unequivocally establish whether hAIT mediates "downhill" movements of I- from the cytosol to the colloid.
AIT (SLC5A8) expression in thyroid carcinomas has not yet been investigated. Interestingly, Li et al (68) found, while screening hypermethylated sequences in colon carcinoma cell lines and human colon carcinoma tissues, that the hAIT gene is heavily methylated and hAIT mRNA expression is decreased or absent. Reintroducing AIT into colon cancer cell lines harboring methylated endogenous AIT suppressed their ability to form colonies in soft agar and xenograft tumors in athymic mice. Based on their observations, the authors suggested that AIT could play a role as a tumor suppressor in colon cancer (68).
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