Assessment of Biomarkers for Clinical Diagnosis of Papillary Thyroid Carcinoma with Distant Metastasis

Abstract

Early diagnosis and treatment of thyroid cancers are critical for better prognosis and better survival rates. The purpose of this study was to identify potential diagnostic markers for papillary thyroid carcinomas with distant metastasis. Fifty-eight papillary thyroid tumor specimens (27 papillary thyroid carcinomas with distant metastasis and 31 without metastasis) were examined, and protein expression of pituitary tumor-transforming gene (PTTG), E-cadherin, p27kip1, vascular endothelial growth factor (VEGF)-C, metalloproteinase (MMP) 2, MMP9, chemokine receptor CXCR4, and basic fibroblast growth factor (bFGF) in these tumors was assessed by immunohistochemistry. The clinicopathological variables with diagnostic significance were determined by multivariate analysis, and their diagnostic values were evaluated by ROC curve analysis. PTTG, VEGF-C, MMP2, MMP9, CXCR4, and bFGF were overexpressed in metastatic papillary thyroid carcinomas, whereas p27kip1 expression was elevated only in carcinomas lacking metastasis. Multiple-factor binary ordinal logistic regression analysis revealed that PTTG, VEGF-C, MMP2, and bFGF were independently related to biological metastatic behavior in thyroid tumors, suggesting their potential use as biomarkers. ROC curve analysis showed that among these four proteins, VEGF-C and bFGF were the best diagnostic biomarkers. A VEGF-C and bFGF cluster was the most useful factor for the differential diagnosis between metastatic and non-metastatic papillary thyroid cancers. Thus, the combined use of VEGF-C and bFGF as biomarkers may improve the diagnostic accuracy of papillary thyroid carcinoma and may be useful in multimodal screening programs for the clinical diagnosis of papillary thyroid carcinoma and early detection of papillary thyroid carcinoma with distant metastasis.

The Wnt/β-catenin pathway drives increased cyclin D1 levels in lymph node metastasis in papillary thyroid cancer

“…In the small body of work examining metastatic PTC disease, 2 small cohorts demonstrated that vascular endothelial growth factor-C (VEGF-C), metallomatrix proteinase 2, and basic fibroblast growth factor (bFGF) were expressed more frequently in PTC primary tumors with nodal metastases, but the nodal deposits were not surveyed [27,28]. Previous studies examining cell cycle markers in benign, malignant, and metastatic thyroid neoplasms demonstrated that cyclin D1, cyclin E1, p16, p21, and p27 were expressed at higher levels in PTC primary tumors [11,27]. Melck et al [11] also reported that p16 expression correlated significantly with extrathyroidal tumor extension and the presence of cancer in lymph nodes.…”

The relevance and role of vascular endothelial growth factor C, matrix metalloproteinase-2 and E-cadherin in epithelial ovarian cancer

“…Tang [8] found that both VEGF-C and its receptor highly expressed in 51 cases of pancreas cancer, which might result in lymph node metastasis by promoting formation of lymphatic vessels. Moreover, VEGF-C was a diagnostic biomarker, which was used to detect the metastasis of papillary thyroid cancer [9]. However, the mechanisms of VEGF-C participating in the invasion and metastasis of ovarian cancer are unclear.…”

Securin promotes migration and invasion via matrix metalloproteinases in glioma cells

“…In a study by Xia et al (26), the downregulation of PTTG by siRNA markedly decreased the expression of MMP2 and MMP9 in the cutaneous squamous cell carcinoma SCL-1 cell line, and also inhibited cell proliferation. A different study demonstrated that the overexpression of PTTG in metastatic papillary thyroid carcinomas was accompanied by an increased expression level of MMP2 and MMP9 (24). Furthermore, the transient or stable transfection of HEK293 cells with PTTG cDNA has been demonstrated to confer a significant increase in the secretion and expression of MMP2.…”

“…Certain studies identified that PTTG, MMP2 and MMP9 were simultaneously overexpressed in metastatic papillary thyroid carcinomas (23,24). In HEK293 cells, transfection with PTTG cDNA significantly increased the secretion and expression of MMP2 (25).…”