Apoptosis in Thyroid Diseases: A Histochemical Study.

Tanimoto, Chikako; Hirakawa, Shuzo; Kawasaki, Hidetaka; Hayakawa, Nobuhiko; Ota, Zensuke

doi:10.1507/endocrj.42.193

Cited by 82 publications

(55 citation statements)

References 34 publications

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“…These results suggest that the percentage of apoptotic cells increases in the more advanced stage of thyroid tumours. Our results are in agreement with those reported by Staunton and Gaffney (1995) and Tanimoto et al (1995), who reported an apoptotic index ranging from 0 to 1.2 in papillary thyroid carcinoma and a value from 1.9 to 2.9 in anaplastic subtypes. Taken together, these results suggest that thyroid neoplastic progression is directly correlated to the increase of apoptotic index.…”

Section: Discussionsupporting

confidence: 94%

Apoptosis and proliferation in thyroid carcinoma: correlation with bcl-2 and p53 protein expression

Basolo

Pollina²,

Fontanini³

et al. 1997

Br J Cancer

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Summary The aim of this study was to determine the apoptotic cell death in 92 thyroid carcinomas of different histotypes (42 papillary, PTC; 12 poorly differentiated, PDC; 21 undifferentiated, UC; and 17 medullary, MC) by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-digoxigenin nick end labelling (TUNEL). Apoptotic index (Al, evaluated as a percentage of TUNEL-positive cells of neoplastic cells) was calculated in each tumour. The Al was very low in all subtypes of thyroid carcinoma, ranging from a median value of 0.2 in PTC to 1.4 in UC. The proliferative activity was determined by immunohistochemistry using monoclonal antibody, MIB-1. The percentage of proliferating cells was significantly different among the histotypes, increasing with tumour aggressiveness (from the mean value of 3.1 for PTC to 5.6 for PDC and 51.8 for UC). In addition, the ratio between proliferative activity and apoptosis was significantly higher in UC than in the other histotypes. The expression of bcl-2 and p53 protein (important in the modulation of cell death) was correlated (bcl-2, inverse correlation, r2 = 0.1, P= 0.04; p53, direct correlation, r2= 0.11, P= 0.02) with apoptotic index in PTC.Keywords: apoptosis p53; bcl-2; thyroid cancer Cell numbers are regulated by a balance between proliferation, growth arrest and programmed cell death (apoptosis, PCD). Until recently, the majority of the studies on oncogenesis have focused on the regulation of cell proliferation. The finding that alterations of negative growth control, including growth arrest and PCD, play a key role in the development of human cancer has been demonstrated by the explosion of reports in this field (Barr and Tomei, 1994; Canman and Kastan, 1995;Katsikis and Leben, 1995;Salomon and Diaz-Cano, 1995; Stauton and Gaffeney, 1995). PCD is an active cellular process involved in a variety of physiological events in which rapid elimination of unwanted cells must occur. Its importance in the turnover of self-renewing tissues, morphogenesis, embryonic development, maturation of cells of the immune system, as well as in the development of cancer and other pathologies, is increasingly being recognized (Chandler et al, 1994; Cotman and Anderson, 1995;Isner et al, 1995;Osborne, 1995). Apoptotic cells can be identified both by nuclear morphology and by techniques that detect fragmentated DNA. The latter methodology could be applied for the in situ visualization of apoptosis by specific labelling of DNA fragmentation. By using Gavrieli's method (Gavrieli et al, 1992), apoptosis can be detected at singlecell level in formalin-fixed, paraffin-embedded tissue sections, thereby allowing the study of retrospective cases.In the present study, we analysed apoptosis in thyroid carcinoma, focusing on its association with the proliferation rate of the tumours themselves. In addition, since apoptosis can be regulated by the p53 tumour-suppressor gene and by bcl-2, we analysed the p53 and bcl-2 expression on the tumour. WHO (Hedinger, 1988) and subsequent updating (Sakamoto et ...

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Section: Discussionsupporting

confidence: 94%

Apoptosis and proliferation in thyroid carcinoma: correlation with bcl-2 and p53 protein expression

Basolo

Pollina²,

Fontanini³

et al. 1997

Br J Cancer

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“…However, to our knowledge, no reports have been available about ceramide-induced apoptosis and effect of ceramide on PLD activity in thyroid cell. In thyroid cells, apoptosis is suspected of being involved in the regulation of normal glandular size and appears to be one of the major modes of thyrocyte death in autoimmune thyroid disease (Kotani et al, 1995;Tanimoto et al, 1995). With these premises, in the present study we have examined the effects of ceramide on apoptotic cell death and the possibility that PLD may be involved in apoptotic cell death in FRTL-5 thyroid cells.…”

Section: Introductionmentioning

confidence: 99%

Effect of ceramide on apoptosis and phospholipase D activity in FRTL-5 thyroid cells

Park¹,

Kim²,

Han³

et al. 1999

Exp Mol Med

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Ceramide, a product of sphingomyelin hydrolysis, is now recognized as an intracellular lipid messenger, which mediates the effects of extracellular agents on cellular growth, differentiation and apoptosis. Recently, ceramide has been implicated in the regulation of phospholipase D (PLD). In this study, we examined the effects of ceramide on the activity and mRNA level of PLD during apoptotic process in FRTL-5 thyroid cells. C 2 -ceramide (N-acetyl sphingosine) induced apoptosis in FRTL-5 thyroid cells. Fluorescent staining showed that ceramide induced the typical features of apoptosis including condensed or fragmented nuclei. DNA fragmentation was also observed by agarose gel electrophoresis. Flow cytometric cell cycle analysis showed more clearly that ceramide induced apoptotic cell death in FRTL-5 thyroid cells. The treatment of FRTL-5 thyroid cells with thyroid-stimulating hormone (TSH) resulted in an increased PLD activity in a dose-and time-dependent manner. However, the TSH-induced increase in PLD activity was down-regulated within 2 h after ceramide treatment. Furthermore, the levels of PLD mRNA were found to be decreased throughout apoptotic process as inferred by reverse transcription-polymerase chain reaction. However, the decreases in PLD mRNA levels were not correlated with those in PLD activities after ceramide treatment. Taken together, these data suggest that ceramide inhibits the PLD activity in an early apoptotic phase and down-regulation of the levels of PLD mRNA may be implicated in apoptotic process in FRTL-5 thyroid cells.

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“…The percentage of apoptotic thyrocytes in situ is increased in Hashimoto's thyroiditis, but decreased in Graves' disease (Giordano et al, 1997;Hammond et al, 1997;Tanimoto et al, 1995), suggesting the importance of apoptotic cell death of thyrocytes in the regulation of functions and numbers of these cells in autoimmune thyroid diseases.…”

mentioning

confidence: 99%

“…Immunohistological studies have revealed Fas expression on thyrocytes in patients with Graves' disease and Hashimoto's thyroiditis (Giordano et al, 1997;Hammond et al, 1997;Tanimoto et al, 1995). We recently reported that Fas is functionally expressed on human thyrocytes in vitro, and Fas-mediated apoptosis of these cells by anti-Fas IgM is significantly suppressed by the addition of TSH or TSAb containing IgG (Kawakami et al, 1997b).…”

mentioning

confidence: 99%

CD4+ T Cell-Mediated Cytotoxicity Toward Thyrocytes: The Importance of Fas/Fas Ligand Interaction Inducing Apoptosis of Thyrocytes and the Inhibitory Effect of Thyroid-Stimulating Hormone

Kawakami

Matsuoka

Tsuboi

et al. 2000

Laboratory Investigation

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SUMMARY:The accumulation of activated CD4 ϩ T cells and antigen (Ag)-dependent cellular interactions between thyrocytes and CD4 ϩ T cells have been determined in thyroid gland from patients with Graves' disease. The Fas/Fas ligand (FasL) interaction between antigen-presenting cells and T cells regulates the apoptosis of the former cells triggered by the latter cells. The inhibition of Fas-mediated apoptosis in thyrocytes could be a underlying mechanism of hyperplasia of thyrocytes in patients with Graves' disease. We investigated the potential role of Fas/FasL interaction between thyrocytes and CD4 ϩ T cells in the induction of Fas-mediated apoptosis of the former cells induced by the latter cells. The presence of only a few specific T cells responsive to a putative autoantigen has hampered the investigation of specific T cell activation toward antigen-presenting cells (APCs). Therefore, we used a superantigen, staphylococcal enterotoxin B (SEB), to examine specific T cell activation toward thyrocytes in vitro since it stimulates a large proportion of T cells with particular V␤ elements. Spontaneous apoptosis of thyrocytes in culture was not found even in the presence of various kinds of cytokines. In contrast, a clear induction of Fas-mediated apoptosis by anti-Fas IgM was determined in interferon-␥ (IFN-␥)-stimulated thyrocytes. In addition, a significant cytotoxicity of purified CD4 ϩ T cells toward IFN-␥-stimulated thyrocytes in the presence of SEB was induced, and the addition of anti-HLA-DR and -DQ monoclonal antibodies (mAbs) or blockade of the Fas/FasL interaction reduced this cytotoxicity. FasL expression of CD4 ϩ T cells cocultured with IFN-␥-stimulated thyrocytes in the presence of SEB was clearly induced. Furthermore, the addition of mAbs against CD54 and CD58 inhibited both cytotoxicity and FasL expression of CD4 ϩ T cells. The cytotoxicity of CD4 ϩ T cells toward IFN-␥-stimulated, SEB-pulsed thyrocytes was markedly inhibited when we used thyrocytes cultured with IFN-␥ in the presence of thyroid-stimulating hormone (TSH) as target cells. Our results suggest that 1) CD4 ϩ T cells were activated by thyrocytes expressing MHC class II molecules in an SEB-dependent manner and then expressed FasL. 2) These activated FasL ϩ CD4 ϩ T cells killed thyrocytes by interacting with Fas on thyrocytes and FasL on activated CD4 ϩ T cells. The presence of costimulating molecules such as CD54 and CD58 on thyrocytes was also necessary to generate activated FasL ϩ CD4 ϩ T cells. 3) Since the actions of thyroid stimulating antibody (TSAb) toward thyrocytes are similar to those of TSH, one goitrogenic activity of TSAb may, in part, be due to the inhibitory effect on Fas-mediated apoptosis of thyrocytes triggered by activated CD4 ϩ T cells. (Lab Invest 2000, 80:471-484).

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Apoptosis in Thyroid Diseases: A Histochemical Study.

Cited by 82 publications

References 34 publications

Apoptosis and proliferation in thyroid carcinoma: correlation with bcl-2 and p53 protein expression

Apoptosis and proliferation in thyroid carcinoma: correlation with bcl-2 and p53 protein expression

Effect of ceramide on apoptosis and phospholipase D activity in FRTL-5 thyroid cells

CD4+ T Cell-Mediated Cytotoxicity Toward Thyrocytes: The Importance of Fas/Fas Ligand Interaction Inducing Apoptosis of Thyrocytes and the Inhibitory Effect of Thyroid-Stimulating Hormone

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