There are conflicting studies on

There are conflicting studies on ET axis and its relationship with clinicopathologic parameters in various cancers. Endothelin axis expression in the tissue and in blood has been associated with advanced cancer characteristics in colorectal, breast, and prostate cancer, while showing no linkage to clinicopathologic parameters in APY29 cancer [28], [29], [30], [31]. It is thus clear that activation of the ET-1 axis is likely highly cancer specific, perhaps representing differences in tissue organization and the ability of primary tissue to use ETs. In the present study, there was a significant positive correlation between ET-1 and expression levels in the primary thyroid carcinomas and also between the primary thyroid carcinomas and metastatic carcinoma in lymph nodes. These findings show that ET-1/ETAR autocrine pathway is implicated in papillary thyroid cancer progression, although its linkage to the most severe forms has not been established. Notwithstanding, this pathway acts through different cancer relevant processes such as proliferation, angiogenesis, inhibition of apoptosis, migration, invasion, and metastasis [10]. Endothelin 1 is also known to stimulate multiple cancer-related processes including EMT through ETAR [15]. During EMT, cancer cells lose epithelial cell junction proteins to acquire a mesenchymal cell phenotype that gives them the ability to invade extracellular matrix and become motile. Our results indicate that these factors are likely at work in large and metastatic thyroid lesions. In our study, elevated ET-1 and ETAR expression levels were mostly detected in thyroid carcinomas with lymph node metastases and metastatic cancer in lymph nodes. In patients with both primary cancer and metastatic cancer to compare, the expression of the latter was found to increase in many patients. Our finding concurs with Hagemann et al [32], who found that ET-1 was up-regulated in the serum of patients with breast cancer and lymph node metastases compared with patients without lymph node metastasis. The authors suggested that highly vascularized metastatic lymph nodes may produce ETs. Our findings support the hypothesis of an autocrine role of the ET-1/ETAR pathway in thyroid cancers. The ET-1/ETAR axis was noted to enhance metastasis. Therefore, these findings identify ETAR as a potential therapeutic target for thyroid cancers, but also show the necessity of identifying tissue-specific effects before general use of ET axis modifiers. In our investigation, ET-1 immunostaining showed high expression in 94% of cases and ETAR staining showed high expression in 95% of cases. The results confirmed the findings of high expression of proteins in 2 previous studies on papillary thyroid carcinomas that examined smaller numbers of thyroid cancers [21], [23]. The high expressions of these proteins in situ reflected the findings of their corresponding mRNAs. These findings confirm the importance of ET-1/ETAR expression in thyroid cancer. In addition, we demonstrated that the proteins, ET-1 and ETAR, were located in specific cellular locations in thyroid tissue, no matter whether they are in benign, malignant, or even metastatic tumors. The expression of ET-1/ETAR proteins appears to be different in various cancers. Wülfing et al [33] observed staining of ET-1 in 26.8% of bladder cancer tissue samples and in 58.8% in ETAR of the same cases. In another study, Eltze et al [34] identified ET-1 and ETAR staining in 62% and 93% of bladder cancer samples, respectively. Differences in ET-1 and ETAR immunostaining in these and our studies indicate that ET axis expression levels are different in various cancer types and may depend on the propensity of the originating cell type to use certain vascular triggers, rather than being an intrinsic response of the vasculature to cancer. In conclusion, elevated ET-1/ETAR expression levels seen in our research were produced by primary thyroid cancers or metastases compared with primary cancers and may also be produced by endothelial cells within highly vascularized primary tumors and metastases. These results suggest that ET axis expression could be used as a possible indicator to predict the aggression levels of papillary thyroid carcinomas, identifying which carcinomas have metastasised as well as helping to locate the presence of new and developing metastases in lymph nodes and other locations, owing to the role of the axis in establishing tumor vasculature. Although we have identified a link between ET axis expression and cancer aggression, more research is needed to determine whether ET axis levels in thyroid cancer tissues could serve as prognostic markers or an indicator of response to therapy.