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Original Studies |
Departments of Pathology (B.C., M.T.), Nuclear Medicine (E.B., M.S.), and Clinical Biology (F.T., J.-M.B.), Institut Gustave-Roussy, 94805 Villejuif, France; and Dipartimento di Medicina Sperimentale e Clinica, Policlinico Mater Domini (S.F.), 88100 Catanzaro, Italy
Address all correspondence and requests for reprints to: Dr. B. Caillou, Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TSH regulates every step of thyroid iodine metabolism through the cAMP cascade. Iodine uptake has been demonstrated to be under the control of TSH, as stimulation by TSH increases radioiodine uptake in vivo and in vitro as well as hNIS expression in cultured thyroid cells (7, 8). Variations in hNIS expression or in its functional activity may contribute, together with other factors (such as the iodine supply), to the differences in radioiodine uptake observed among thyroid diseases. Inactivating mutations in the hNIS gene have been described in patients with congenital hypothyroidism and low iodine uptake (9, 10, 11). Radioiodine uptake is increased in patients with Graves’ disease and decreased in benign and malignant thyroid tumors. Increased hNIS expression has been found in Graves’ thyroid tissue (7), whereas hNIS expression was lower in thyroid carcinoma than in normal thyroid tissue (6). However, an increased expression of hNIS was recently reported in the majority of papillary thyroid carcinomas studied (12). On the other hand, transfection of the hNIS gene into malignant rat thyroid cells that did not concentrate iodide resulted in a 60-fold increase in cells accumulating 125I in vitro (13). These observations suggest that both the expression and functional integrity of hNIS are critical for iodide transport and accumulation. This is of paramount importance in patients with differentiated thyroid carcinoma in whom radioiodine is used to both detect and eradicate neoplastic tissue (14, 15).
In the present report we have examined hNIS expression in thyroid tissues using purified polyclonal antibodies raised against a synthetic peptide mimicking the carboxyl-terminal region of this protein. Site-directed antibodies have proven useful for the detection and analysis of the topology of various transmembrane proteins, and this approach has recently been used to characterize rat NIS (16, 17). Immunohistochemical studies were designed for the detection and localization of hNIS at the cellular level in tissue sections obtained from normal thyroid tissues and from patients with benign and malignant conditions. hNIS expression was also compared to that of the TSH receptor (TSHR).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A peptide spanning the hNIS-(615–643) region was synthesized by a conventional solid phase method using an PE Applied Biosystems model 431A peptide synthesizer (Foster City, CA). After completion of synthesis, the identity and purity of the peptide were verified by 1) amino acid analysis on an Alpha LKB analyzer (Rockville, MD), 2) high performance liquid chromatography, and 3) microsequence analysis of each high performance liquid chromatography peak on an automated PE Applied Biosystems 477A protein sequencer. The hNIS-(615–643) peptide was conjugated to keyhole limpet hemocyanin using benzidine as the coupling agent.
Production and characterization of antipeptide antisera to hNIS
Two rabbits were immunized by intradermal injection of the hNIS-(615–643) synthetic peptide-carrier conjugate. After three subsequent boosts at 3-week intervals, animals were bled, and their sera were tested in an enzyme-linked immunosorbent assay. Antisera, at various dilutions, were checked for their capacity to react with the hNIS-(615–643) synthetic peptide coated on microtiter plates. Antibody binding was then revealed by peroxidase-labeled goat antirabbit antibody (Nordic, Tilburg, The Netherlands). The anti-NIS antiserum with the highest titer was purified by affinity chromatography on a protein A-Sepharose CL4b column run on a fast protein liquid chromatography device (Pharmacia LKB, Uppsala, Sweden). Competitive experiments were generated, as previously described (18). The monoclonal antibody directed against the human TSHR (R171) was provided by Prof. E. Milgrom (INSERM U-135, Bicetre, France) (19).
Immunohistochemistry
Normal thyroid samples were taken at a distance from solitary thyroid adenomas (n = 5). Pathological thyroid tissue specimens were obtained from patients suffering from Graves’ disease (n = 2), autoimmune thyroiditis (n = 2), diffuse nodular hyperplasia (n = 2), benign adenoma (n = 6), and follicular carcinoma (n = 5; comprising one well differentiated, minimally invasive; one well differentiated, widely invasive; and three poorly differentiated, widely invasive lesions), and papillary carcinoma (n = 9; of which four were follicular variants). These pathological specimens were classified according to WHO recommendations (20).
Specimens were frozen at -70 C in isopentane and stored in liquid nitrogen. Serial frozen cryostat tissue sections (5 mm) were cut and fixed in acetone for 10 min. These sections were then incubated with either the anti-NIS antiserum or the anti-TSHR monoclonal antibody, diluted at 1:500, for 30 min. Whole and purified anti-NIS antisera were diluted at 1:750 and 30 µg/mL, respectively. Sections were washed three times in Tris-HCl buffer for 5 min each time and then incubated in a biotinylated antibody (K674, Dako Corp., Carpinteria, CA). They were again washed three times and incubated with alkaline phosphatase-labeled streptavidin (K674, Dako Corp.) for 10 min. After three further washes, staining was completed after incubation with substrate chromogen solution (K699 fast red, Dako Corp.). Sections incubated with irrelevant antibodies (preimmune serum) or with the anti-hNIS antiserum preabsorbed with the corresponding excess peptide were used as negative controls.
Thyroid and 131I total body scans
Thyroid scintigraphy was performed in all patients with palpable thyroid nodules or goiter. In patients who had undergone thyroidectomy for thyroid carcinoma, a 131I total body scan was performed after the withdrawal of the thyroid hormone, with either 3.7 gigabecquerels (100 mCi) of radioiodine for ablation of thyroid remnants or 74–180 megabecquerels for follow-up total body scan. However, 131I uptake in neoplastic tissue could be assessed only in patients with residual disease outside the thyroid bed.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Rabbit antiserum titers obtained after immunization with the hNIS-(615–643) synthetic peptide-carrier conjugate were determined by enzyme-linked immunosorbent assay. Both animals produced antisera exhibiting high affinity binding to the synthetic carboxyl-terminal portion of the hNIS protein. Competitive inhibition experiments (data not shown) indicated that the affinity of these antisera for the synthetic peptide was approximately 2 x 10-6 mol/L. The antiserum displaying the highest titer (10-5) was purified by affinity chromatography; whole and purified antiserum provided similar immunohistochemical results.
Staining with hNIS in control tissues (muscle, thymus) was negative.
Furthermore, applying the hNIS antiserum preincubated with the
corresponding excess peptide led to negative immunohistochemical
results (Fig. 1B
).
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The results of the immunohistochemical studies are summarized in
Table 1. The percentages of hNIS and TSHR immunostained
follicular cells are indicated according to histopathological
classification.
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The follicular epithelial cells of all normal thyroid specimens
exhibited a heterogeneous pattern when stained with hNIS
antibodies. Inside a given follicle, isolated follicular cells were
strongly immunostained by the anti-hNIS antiserum and were totally
distinct from weakly positive or negative cells (Fig. 1A
). A similar staining pattern was
present in all follicles, but some follicles had a higher number of
strongly hNIS-positive cells that were either grouped together or
isolated. A different pattern was observed for the TSHR, which was
consistently present in all normal follicular cells. In positive cells,
hNIS staining was confined to the basolateral membrane (Fig. 1C). Basal
staining was stronger than lateral staining. Stromal cells,
lymphocytes, intrafollicular macrophages, and vascular endothelial
cells did not react with the hNIS antibody.
Graves’ disease
The majority of the follicular cells were strongly immunostained
by the antiserum (Fig. 1D).
Autoimmune thyroiditis
The follicular cells in contact with lymphocytes exhibited strong
hNIS immunostaining, whereas those distant from lymphocytic infiltrates
were generally negative or weakly immunostained (Fig. 1E).
Diffuse nodular hyperplasia
In macrofollicular hyperplasia, hNIS immunostaining displayed a
characteristic pattern. In the large follicles, there was a distinct
zone of strongly positive proliferating follicular cells, whereas
nonproliferating cells were negative (Fig. 1F). Some macrofollicles
displayed several areas of proliferating hNIS-positive cells. In normo-
or microfollicular hyperplasia, hNIS immunostaining was similar to that
in normal thyroid tissue, but the number of positive cells was
generally greater. All follicular cells were immunostained for the
TSHR.
Adenoma
In six adenomas that appeared to be hypofunctioning at thyroid scintigraphy, no hNIS immunostaining was detectable in the majority of follicles. Only a few follicles were stained, and in these positive follicles, the number of positive cells was smaller than that in normal thyroid tissue. In contrast, all follicular cells were immunostained for the TSHR (data not shown).
Follicular carcinoma
In the minimally invasive follicular carcinoma and in widely invasive or poorly differentiated follicular carcinomas, either a small minority of tumor cells were immunostained by the anti-hNIS antiserum or immunostaining was absent. The number of positive cells was apparently higher in well differentiated than in poorly differentiated cancers. In contrast, most tumor cells were positive for the TSHR (data not shown), but staining was heterogeneous and weaker than that in normal thyroid tissue.
Papillary carcinoma
In papillary carcinoma, hNIS immunostaining was negative or
positive in only a few tumor cells (Fig. 1G). In the mixed papillary
and follicular type, positivity was generally located in follicular
structures (Fig. 1H). In these cases, the number of positive cells for
TSHR was lower than that in normal tissue but much greater than that
for hNIS (data not shown). In the follicular variant of papillary
carcinoma, hNIS immunostaining was nonuniform. However, some tumor
follicles showed positive cells, as in normal tissue. Immunostaining
for TSHR was positive in most tumor cells (data not shown), but
staining was heterogeneous and weaker than that in normal thyroid
tissue.
Total body 131I scan
Assessment of 131I uptake in neoplastic tissue
in vivo was possible in four patients with lymph node
metastases from a thyroid carcinoma. In one patient, there was no
detectable uptake and no hNIS immunostaining. The other three patients
had uptake in lymph node metastases, and hNIS expression, albeit low,
was found in the primary thyroid tumor (Table 2).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In normal thyroid tissue, hNIS expression was limited to a minority of follicular cells. In line with its physiological role, hNIS was expressed in cells located close to capillary vessels. In contrast, all follicular cells were positive for the TSHR. This marked discrepancy between TSHR and hNIS immunostaining suggests that other factors, functioning in concert with TSH, modulate hNIS expression in normal thyroid cells. This is consistent with the heterogeneity of iodine distribution in thyroid cells, as shown by autoradiography and more recently by ion microscopy (21). In contrast, in overstimulated thyroid tissue, such as in Graves’ disease, the great majority of follicular cells display strong hNIS immunostaining. This observation is in agreement with previous in vitro studies on rat and human thyroid cells that clearly indicate that hNIS expression is TSH induced (8, 17), being increased in Graves’ thyroid tissue (7).
In diffuse nodular hyperplasia, hNIS expression was heterogeneous and often confined to proliferating cells located at one pole of the follicle. In contrast, all follicular cells were TSHR positive. This is in agreement with data on the pathogenesis of nodular goiter, in which functional activity varies widely between follicles and even between individual cells within the same follicle (22).
In autoimmune thyroiditis, strong hNIS staining was observed in cells in close contact with lymphocytes. hNIS has recently been considered as a major autoantigen in autoimmune thyroiditis along with thyroglobulin, thyroperoxidase, and TSHR (23, 24) and may attract cytotoxic lymphocytes. The heterogeneous hNIS distribution in these lesions can be related to tissue modifications due to lymphocytic infiltrate.
Adenomas that were hypofunctioning at thyroid scintigraphy showed weak heterogeneous hNIS staining compared to that of normal tissue or showed no staining. In minimally or widely invasive follicular carcinomas, results were similar to those observed in nonfunctioning adenomas. In papillary carcinomas, hNIS staining was heterogeneous but much weaker than that in normal tissue and was mostly found in follicular structures. TSHR staining was also heterogeneous and weaker in these tumors than in normal tissue. This could account in part for the low number of hNIS-positive cells. This weak hNIS protein expression in these cancers is consistent with their low iodide-trapping ability and the low messenger ribonucleic acid level, as shown by Northern blot analysis (6).
Recently, Saito et al. (12) found in the majority of
papillary carcinomas an increase in hNIS expression at the messenger
ribonucleic acid and protein levels. Moreover, cytoplasmic localization
of hNIS immunostaining was demonstrated, whereas, as shown in Fig. 1C, we have found that hNIS positivity was restricted to the basolateral
membrane of positive thyroid cells. This localization, similar to that
observed for TSHR, corresponds exactly to the expected localization of
a membrane transporter. These discordant results may be due to
methodological differences, particularly to distinct peptide immunogens
and/or to the procedure used for fixation of thyroid specimens.
Although the number of cases studied with radioiodine scans is low, it is noteworthy that three cases with iodine uptake in lymph nodes metastases had positive hNIS cells in the primary tumors, whereas no positive hNIS cells were found in the carcinoma with no iodine uptake in residual neoplastic tissue. These limited, but quite striking, findings suggest that hNIS-positive cells detected in primary thyroid tumors could be predictive of radioiodine uptake by neoplastic thyroid and metastatic tissues.
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Acknowledgments |
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Footnotes |
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Received February 12, 1998.
Revised June 12, 1998.
Accepted July 17, 1998.
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V. Lazar, J.-M. Bidart, B. Caillou, C. Mahé, L. Lacroix, S. Filetti, and M. Schlumberger Expression of the Na+/I- Symporter Gene in Human Thyroid Tumors: A Comparison Study with Other Thyroid-Specific Genes J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3228 - 3234. [Abstract] [Full Text]
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G. M. Venkataraman, M. Yatin, R. Marcinek, and K. B. Ain Restoration of Iodide Uptake in Dedifferentiated Thyroid Carcinoma: Relationship to Human Na+/I- Symporter Gene Methylation Status J. Clin. Endocrinol. Metab., July 1, 1999; 84(7): 2449 - 2457. [Abstract] [Full Text]
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 T. Kogai, J. J. Schultz, L. S. Johnson, M. Huang, and G. A. Brent Retinoic acid induces sodium/iodide symporter gene expression and radioiodide uptake in the MCF-7 breast cancer cell line PNAS, July 18, 2000; 97(15): 8519 - 8524. [Abstract] [Full Text] [PDF]
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