Immunohistochemical analysis of thymic carcinoma focusing on the possibility of molecular targeted and hormonal therapies

Omatsu, Mutsuko; Kunimura, Toshiaki; Mikogami, Tetsuya; Hamatani, Shigeharu; Shiokawa, Akira; Masunaga, Atsuko; Kitami, Akihiko; Suzuki, Takashi; Kadokura, Mitsutaka; Morohoshi, Toshio

doi:10.1007/s11748-012-0160-x

Cited by 14 publications

(16 citation statements)

References 25 publications

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“…TLR4 mRNA levels were found to be higher in thymic tissue of non-thymomatous MG patients and thymic tissue adjacent to thymomas compared to thymuses from cardiac surgery patients without MG [69]. The findings on RAGE, HMGB1 and their respective other ligands and receptors may warrant further study in autoimmune disease and cancer to elucidate therapeutic targets [70], [71].…”

Section: Discussionmentioning

confidence: 99%

Expression of RAGE and HMGB1 in Thymic Epithelial Tumors, Thymic Hyperplasia and Regular Thymic Morphology

et al. 2014

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Recently, a role of the receptor for advanced glycation endproducts (RAGE) in myasthenia gravis was described. RAGE and its ligand high mobility group box 1 (HMGB1) play key roles in autoimmunity and cancer. To test whether these molecules are involved in patients with thymic abnormalities we applied immunohistochemical analysis in 33 cases of thymic epithelial tumors, comprising 27 thymomas and 6 thymic carcinomas, and 21 nonneoplastic thymuses. Both molecules were detected in neoplastic epithelial cells: RAGE staining was most intense in WHO type B2 thymomas and thymic carcinomas (p<0.001). HMGB1 nuclear staining was strongest in A and AB, and gradually less in B1 = B2>B3>thymic carcinoma (p<0.001). Conversely, HMGB1 cytoplasmic staining intensities were as follows: A and AB (none), B1 (strong), B2 (moderate), B3 and thymic carcinoma (weak); (p<0.001). Fetal thymic tissue showed a distinct expression of RAGE and HMGB1 in subcapsular cortical epithelial cells which was found in 50% of myasthenic patients. Furthermore RAGE and HMGB1 were expressed in thymocytes, macrophages, Hassall's corpuscles, thymic medulla, and germinal center cells in myasthenic patients. Immunohistochemistry results were complemented by systemic measurements (immunosorbent assay): serum levels of soluble RAGE were significantly reduced in patients with epithelial tumors (p = 0.008); and in invasive tumors (p = 0.008). Whereas RAGE was equally reduced in thymic hyperplasia and epithelial tumors (p = 0.003), HMGB1 was only elevated in malignancies (p = 0.036). Results were most pronounced in thymic carcinomas. Thus, RAGE and HMGB1 are involved in the (patho-)physiology of thymus, as evidenced by differentiated thymic and systemic expression patterns that may act as diagnostic or therapeutic targets in autoimmune disease and cancer.

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Section: Discussionmentioning

confidence: 99%

Expression of RAGE and HMGB1 in Thymic Epithelial Tumors, Thymic Hyperplasia and Regular Thymic Morphology

et al. 2014

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“…LAT1 expression has been intensively investigated in other types of malignancies located such as in the lungs, pancreas, and liver, with results demonstrating that patients with LAT1-immunopositive malignancies have poor prognosis (Kaira et al 2009a(Kaira et al , 2012Li et al 2013;Toyoda et al 2014;Honjo et al 2016). Moreover, to the best of our knowledge, two studies have been presented in English regarding LAT1 and thymic carcinoma, with seemingly controversial results (Kaira et al 2009b;Omatsu et al 2012). These authors considered that LAT1 immunoreactivity was positive only when distinct membrane signal was present.…”

Section: Discussionmentioning

confidence: 99%

“…Many studies have revealed cancer-specific LAT1 expression in various organs and also demonstrated poor prognosis of patients with high LAT1 expression levels (Kaira et al 2009a(Kaira et al , 2012Li et al 2013;Toyoda et al 2014;Honjo et al 2016). In regard to thymic carcinoma, two studies have presented seemingly inconsistent results (Kaira et al 2009b;Omatsu et al 2012); namely, Kaira et al (2009b) used an anti-LAT1 polyclonal antibody and demonstrated that LAT1 immunoreactivity was frequently detected in thymic carcinoma but was undetectable in thymoma. On the other hand, Omatsu et al (2012) used an anti-LAT1 monoclonal antibody and reported that LAT1 immunoreactivity was not frequently detected in both thymic carcinoma and thymoma tissues.…”

Section: Introductionmentioning

confidence: 99%

“…In regard to thymic carcinoma, two studies have presented seemingly inconsistent results (Kaira et al 2009b;Omatsu et al 2012); namely, Kaira et al (2009b) used an anti-LAT1 polyclonal antibody and demonstrated that LAT1 immunoreactivity was frequently detected in thymic carcinoma but was undetectable in thymoma. On the other hand, Omatsu et al (2012) used an anti-LAT1 monoclonal antibody and reported that LAT1 immunoreactivity was not frequently detected in both thymic carcinoma and thymoma tissues. In the present study, to elucidate the association between LAT1 expression in thymic carcinoma and patient prognosis, we conducted a retrospective clinicopathological study.…”

Section: Introductionmentioning

confidence: 99%

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L-Type Amino Acid Transporter 1 Immunoreactivity as a Possible Diagnostic and Prognostic Marker of Thymic Carcinoma

Maeda

Nakazato

Hayashi

et al. 2018

Tohoku J. Exp. Med.

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L-type amino acid transporter 1 (LAT1) functions to transport large neutral amino acids, such as leucine, isoleucine, valine, phenylalanine, tyrosine, tryptophan, methionine, and histidine. These amino acids are essential for cell growth and proliferation. Many studies have demonstrated LAT1 expression in various types of cancer, and its high expression level was associated with poor prognosis. However, the significance of LAT1 expression in thymic epithelial tumors is controversial. We conducted this retrospective study to investigate the LAT1 immunoreactivity in thymic epithelial tumors and its impact on prognosis. We analyzed 32 patients with thymoma and 14 patients with thymic carcinoma who underwent surgery at our institute. Immunohistochemical analysis was performed using formalin-fixed paraffinembedded surgical tissues and an anti-LAT1 polyclonal antibody. We thus found that LAT1 immunoreactivity was undetectable in all of the thymoma specimens, regardless of the subtypes of thymoma. By contrast, LAT1 immunoreactivity was consistently detected in the cytosol of thymic carcinoma cells; namely, all 14 thymic carcinoma specimens demonstrated LAT1 immunoreactivity in the cytosol. Among these 14 thymic carcinoma specimens, four carcinoma specimens also showed LAT1 immunoreactivity in the cell membrane. Survival analysis indicated that the thymic carcinoma with the LAT1 membrane signal was associated with poor prognosis, compared with the specimens with the LAT1 cytosol signal. We therefore propose that LAT1 is expressed in the cytosol of thymic carcinoma cells, which could be a diagnostic marker of thymic carcinoma. Moreover, LAT1 expression in the cell membrane is a prognostic marker of thymic carcinoma.

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“…http TCs exhibit specific genetic alterations and appeared to be more aggressive and more likely to relapse and metastasis than thymomas [11,16,17]. Many potential targets have been investigated such as growth factors, cell cycle proteins and molecules belonging to the PI3K/AKT pathway [18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Antitumor activity in advanced cancer patients with thymic malignancies enrolled in early clinical drug development programs (Phase I trials) at Gustave Roussy

Duchemann

Boutros²,

Caramella³

et al. 2015

Lung Cancer

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Immunohistochemical analysis of thymic carcinoma focusing on the possibility of molecular targeted and hormonal therapies

Abstract: Therefore, by examining the expressions of PPARγ and IGF1R, it would be possible to identify therapy-responsive patients and to improve results of thymic carcinoma treatment.

Cited by 14 publications

References 25 publications

Expression of RAGE and HMGB1 in Thymic Epithelial Tumors, Thymic Hyperplasia and Regular Thymic Morphology

Expression of RAGE and HMGB1 in Thymic Epithelial Tumors, Thymic Hyperplasia and Regular Thymic Morphology

L-Type Amino Acid Transporter 1 Immunoreactivity as a Possible Diagnostic and Prognostic Marker of Thymic Carcinoma

Antitumor activity in advanced cancer patients with thymic malignancies enrolled in early clinical drug development programs (Phase I trials) at Gustave Roussy

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