Cyclooxygenase‐2 Expression in Human Thyroid Carcinoma and Hashimoto's Thyroiditis

Cornetta, Anthony J.; Russell, John P.; Cunnane, Mary F.; Keane, William M.; Rothstein, Jay L.

doi:10.1097/00005537-200202000-00008

Cited by 66 publications

(65 citation statements)

References 26 publications

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“…The cells residing within thyroid follicles of large thyroid tumors expressed the myeloid markers CD11b and F4/80, a phenotype consistent with macrophages (34), a cell type known to secrete a variety of mediators contributing to the cytokine expression profile observed in RP3-transgenic thyroids (35). Indeed, intrafollicular macrophages, fibroblasts, and vascular endothelium produced Il6, whereas only Cox2 protein was found within thyroid epithelial cells, data consistent with the expression of RET/PTC proteins in PTC (29). Thus, the transformed thyroid microenvironment may be modeled as a complex mixture of resident thyroid epithelial cells producing chemokines that induce the infiltration of inflammatory cells, including activated macrophages, that respond to these mediators and secrete additional factors.…”

Section: Discussionsupporting

confidence: 63%

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Proinflammatory Mediators and Genetic Background in Oncogene Mediated Tumor Progression

Russell

Engiles

Rothstein

2004

The Journal of Immunology

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RET/PTC3 (RP3) is an oncogenic fusion protein which is frequently expressed in papillary thyroid carcinomas and has been detected in thyroid tissue from patients diagnosed with Hashimoto’s thyroiditis. The constitutive activation of the tyrosine kinase domain in the carboxyl-terminal end of RP3 induces signaling pathways within thyrocytes and causes cellular transformation. One of the signaling pathways activated in RP3-expressing cells involves the activity of the transcription factor NF-κB and the production of downstream targets including GM-CSF and macrophage chemotactic protein 1. These factors are known to be immunostimulatory, making RP3 a molecular adjuvant and potentially promoting tissue-specific immunity. However compelling, these in vitro data do not reliably predict gene function in vivo or the cumulative effects of time-dependent processes such as angiogenesis, inflammation, or the influence of genetic background. To address these issues, we analyzed the production of proinflammatory mediators in mouse thyroid organs and demonstrate consistency with in vitro studies performed previously that Il1α, Il1β, Il6, and Tnfα and the enzyme Cox2 are produced by RP3-transgenic thyroid tissue, but absent from nontransgenic thyroids. Furthermore, we find that that the genetic background of the host is important in the observed RP3-induced inflammation and tumor progression. These findings provide support for the notion that oncogene-induced cytokine secretion is important for the development and progression of thyroid carcinomas in genetically permissive hosts.

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Section: Discussionsupporting

confidence: 63%

“…Thus, to evaluate the coincident expression of RP3 with a marker of inflammation, the protein Cox2 was used since it is an intracellular enzyme induced during thyroid inflammatory responses and can be localized to individual cells using immunohistochemical staining (29). Data in Fig.…”

Section: Coordinate Expression Of Inflammatory Mediators and Rp3 In Dmentioning

confidence: 99%

Proinflammatory Mediators and Genetic Background in Oncogene Mediated Tumor Progression

Russell

Engiles

Rothstein

2004

The Journal of Immunology

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“…[26][27][28][29] Thyroid tumors generally express higher levels of COX-2 than normal tissues and thyroid tissues from patients with thyroiditis. [26][27][28][29] Thromboxane A2 (TXA 2 ) synthase and prostaglandin (PG) I 2 synthase are enzymes located downstream from COX-1 and COX-2, and catalyze synthesis of PG H, TXA 2 and PGI 2 ( Figure 1). TXA 2 stimulates platelet aggregation, while PGI 2 inhibits aggregation of platelets.…”

mentioning

confidence: 99%

Role of COX-2, thromboxane A2 synthase, and prostaglandin I2 synthase in papillary thyroid carcinoma growth

et al. 2005

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The development of papillary thyroid carcinoma is influenced by many factors including genetic alterations, growth factors, and physical agents such as radiation. Arachidonic acid and its derivatives including prostaglandins (PG) and thromboxane along with the enzymes involved in their synthesis have been shown to influence the growth of various tumors. We analyzed the immunoreactivity for cyclooxygenase-2 (COX-2) and mRNA expression levels of the enzymes COX-2, thromboxane A 2 (TXA 2 ) synthase, and PGI 2 synthase by RT-PCR in papillary carcinomas and matching normal tissues to determine the role of these enzymes in the development of papillary thyroid carcinomas. A papillary thyroid carcinoma cell line TPC-1 was also studied in vitro to determine the role of the specific COX-2 inhibitor NS-398 on COX-2 and vascular endothelial growth factor-A, since COX-2 also has a role in regulating tumor angiogenesis. RT-PCR analysis showed significant increases in TXA 2 synthase mRNA levels in papillary thyroid carcinomas compared to normal thyroid tissues. Although COX-2 mRNA levels were generally increased in papillary carcinomas, the differences were not statistically significant. There were no significant differences in PGI 2 synthase mRNA levels. COX-2 protein expression was greater in papillary carcinoma compared to normal thyroid tissues; however, the levels were quite variable. In vitro studies with a COX-2 inhibitor, NS-398, showed inhibition of tumor growth along with increased levels of COX-2 and vascular endothelial growth factor-A mRNA expression. These results indicate that specific enzyme levels in the PG synthesis pathway such as TXA 2 synthase are increased in papillary thyroid carcinomas. COX-2 also has a role in papillary thyroid growth, since a specific inhibitor of COX-2 regulates papillary thyroid carcinoma cell proliferation. These results implicate several enzymes in the synthesis of prostanoids as regulators of thyroid papillary carcinoma proliferation and suggest that increased levels of expression of these enzymes may play a role in the pathogenesis of these tumors.

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“…But Hashimoto's thyroiditis might represent the host immune response to preexisting PTC; PTC might be induced or triggered by preexisting Hashimoto's thyroiditis, and a common mechanism, such as imbalance between apoptotic/antiapoptotic pathways, may be involved in the two diseases [26]. Previous studies have reported that chronic inflammation responses such as those associated with autoimmune thyroiditis might act as carcinogens [27] or rearranged in transformation/PTC oncogene that is known to be highly specific to PTC might be expressed in Hashimoto's thyroiditis [28]. Chronic inflammatory change may occur in the whole thyroid gland with multifocal foci, so increase the incidence of multifocality and contralateral cancer.…”

Section: Discussionmentioning

confidence: 99%

Predictive Factors for Incidental Contralateral Carcinoma in Patients with Unilateral Micropapillary Thyroid Carcinoma

et al. 2012

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Background: Whether thyroid lobectomy alone is a sufficient treatment for papillary thyroid microcarcinoma (PTMC) remains controversial. The aim of this study is to evaluate the predictive factors for incidental contralateral carcinoma in patients confirmed of unilateral PTMC preoperatively. Methods: Between January 2007 and December 2009, 393 patients underwent thyroid surgery for unifocal and unilateral PTMC preoperatively at Pusan National University Hospital. A total thyroidectomy with central neck dissection was routinely performed for these patients during this study period. Results: Among the 393 cases in the cohort, 77 patients (19.6%) had incidental PTMC in the contralateral lobe. In patients with incidental contralateral carcinoma, there was higher prevalence in extrathyroid extension, occult ipsilateral carcinoma, pathologic Hashimoto's thyroiditis, and central lymph node metastasis compared to those without contralateral carcinoma. The mean tumor size also increased in patients with contralateral carcinoma. Multivariate logistic regression showed that extrathyroid extension (P = 0.049), occult ipsilateral carcinoma (P < 0.001), pathologic Hashimoto's thyroiditis (P = 0.038), and central lymph node metastasis (P = 0.002) were predictive factors for incidental contralateral carcinoma. Conclusion:In conclusion, multifocality in the ipsilateral lobe, central lymph node metastasis, extrathyroid extension, and Hashimoto's thyroiditis is associated with the presence of contralateral carcinoma. Thus, if these factors are found by preoperative and/or postoperative evaluation, total thyroidectomy or completion thyroidectomy is necessary for the treatment of PTMC. (Endocrinol Metab 27:194-199, 2012)

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Cyclooxygenase‐2 Expression in Human Thyroid Carcinoma and Hashimoto's Thyroiditis

Cited by 66 publications

References 26 publications

Proinflammatory Mediators and Genetic Background in Oncogene Mediated Tumor Progression

Proinflammatory Mediators and Genetic Background in Oncogene Mediated Tumor Progression

Role of COX-2, thromboxane A2 synthase, and prostaglandin I2 synthase in papillary thyroid carcinoma growth

Predictive Factors for Incidental Contralateral Carcinoma in Patients with Unilateral Micropapillary Thyroid Carcinoma

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