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  • Endothelin appears to have direct effects on neoplastic


    Endothelin 1 appears to have direct effects on neoplastic explanation by inducing cellular proliferation, angiogenesis, migration, invasion, and inhibition of apoptosis [10]. Endothelin 1 mediates mitogenic effects in some epithelial tumors such as colorectal, ovarian, and prostate cancers [11], [12], [13]. The ET-1/ETAR autocrine pathway is crucial in carcinogenesis and metastasis in certain cancers [14], [15]. Increased expression of ET-1 or ETAR has been associated with advanced pathological stages and poorer prognosis in different cancers [16], [17]. Vascular endothelial growth factor was shown to be related to ET-1 in angiogenesis. Endothelin 1, through ETAR, up-regulates VEGF, which, in turn, stabilizes the VEGF regulatory protein Hypoxia-inducible factor 1-alpha (HIF-1α) [18]. Previous studies have demonstrated that ET-1 expression is strongly correlated with neovascularization and VEGF expression via ETAR [19], [20]. In papillary thyroid cancer, the role of ETs has seldom been studied [21], [22], [23], [24]. In this study, we would like to improve the understanding of angiogenesis in thyroid cancer by investigating the roles of ET-1 and its receptor ETAR in a large cohort of patients with papillary thyroid carcinoma.
    Materials and methods
    Discussion In papillary thyroid carcinoma, ET-1 production and antagonism of ETAR have been demonstrated in human thyroid cancer cells lines [22]. Endothelin 1 or ETAR has been only investigated at the tissue level for thyroid cancer in 2 research groups. Lenziardi et al [21] studied the ET-1 in 27 patients with papillary thyroid carcinoma by immunohistochemistry and noted that 90% of them expressed the protein. Donckier et al [24] have shown higher expression of ET-1 and ETAR mRNA in 12 patients with papillary thyroid carcinomas than noncancer thyroid tissues with immunohistochemistry and RT-PCR. In another study, they noted that ET-1 mRNA expression in thyroid cancers correlated with nitric oxide pathway activation [24]. The current study was done on a large cohort of patients with papillary thyroid carcinoma (n = 123). The results showed variable expression of ET axis (ET-1 or ) in all papillary thyroid carcinoma, metastatic carcinoma in lymph nodes, and noncancer thyroid tissues, which correlates with the clinical and pathological parameters. Also, 40 matched primary and metastatic cancers from the same patient were studied to confirm the difference in expression profiles between them. In the current study, a significant difference was observed between ET-1 expression levels and sex, in the primary thyroid carcinomas. To determine if this result was due to violation of the χ2 assumptions because of the higher number of patients in the female group, we performed Monte Carlo–style analysis. The expression difference of ET-1 in the population of the study was again established with this test (P = .044). There is no immediately obvious reason for this expression difference but may be related to the fact that thyroid cancers are more common in women (74.9%) and the sex difference in clinical behavior in thyroid cancers, with men more often showing aggressive cancer. There was a significant difference between ETAR expression level and cancer size, as larger cancers expressed higher levels of ETAR. This would make sense in terms of increased sensitivity to angiogenic signals for larger cancers with higher oxygen demands, and although the difference was not significant, our data also show a trend of increased ET-1 expression in larger tumors. It has been shown that ETAR overexpression is associated with aggressive cancer behavior and a worse prognosis in ovarian cancer [27]. Indeed, in our study, we also found increased expression of ET-1 in metastatic thyroid cancer. Therefore, it can be hypothesized that ETAR or ET-1 overexpression enhances cancer progression or establishment of early growth of tumor masses. There was also a significant subpopulation of metastatic thyroid cancers that showed low ET-1 expression. Whether this group represents a biologically distinct group or whether the reduced expression is due to a relative difference in the vasculature present is not clear but may bear investigation in the future. It is also worth noting that higher ET-1 expression was noted in tumor with calcified stroma. The reason is not clear. It can be hypothesized that the larger cancers with high ET-1 expression were often take more time to grow and have more time to form calcification.