Expression of Transforming Growth Factor β₁, β₂, and β₃ in Multinodular Goiters and Differentiated Thyroid Carcinomas: A Comparative Study

Abstract

The various isoforms of transforming growth factor-beta (TGFbeta) are growth-inhibiting cytokines for cells of epithelial origin. In malignant thyroid tumors, several studies documented a high expression of TGFbeta in the majority of thyroid follicular cells suggesting a possible role as an inhibitor of cell proliferation. In contrast to this uniform pattern of TGFbeta expression in thyroid cancer, scarce and controversial data have been reported on the expression of TGFbeta in benign multinodular goiter. In the present study, we therefore analyzed the expression of TGFbeta1, TGFbeta2, and TGFbeta3 in normal thyroid tissue, multinodular goiters and papillary thyroid carcinomas by immunohistochemistry. In normal thyroid tissue, expression of the 3 TGFbeta isoforms was barely detectable. However, in the carcinomas, almost all epithelial cells displayed immunoreactivity for the three TGFbeta isoforms. In the nodules from multinodular goiters, all 3 isoforms were found to be expressed although the immunolocalization of the 3 proteins was highly variable. TGFbeta-immunostaining was found in scattered clusters of variable size and, its expression pattern was heterogenous among individual cells within single follicles. TGFbeta-positivity was present in spite of immunostaining for proliferating cell nuclear antigen (PCNA), a marker for actively proliferating cells. In conclusion, this study shows that thyroid carcinomas and benign tumors express the TGFbeta1, TGFbeta2, and TGFbeta3 isoforms. In contrast to the abundant and homogeneous expression in differentiated thyroid carcinomas, TGFbeta expression displays a highly variable interfollicular and intrafollicular pattern in multinodular goiters, suggesting an important role of TGFbeta isoforms in tumorigenesis of thyroid cells.

Expression of SMAD proteins, TGF-beta/activin signaling mediators, in human thyroid tissues

“…However, TGF-β and activin are overexpressed in several carcinomas (17,19,25). Similarly, we have previously shown high TGF-β and activin protein expression in thyroid cancer, while the expression in normal tissue is predominantly negative (20,21). Despite the increased expression of these proteins in neoplastic cells, loss of TGF-β/activin responsiveness is frequently observed in cancer (2).…”

“…Although both TGF-β and activin exert inhibitory effects on the proliferation of normal thyroid follicular cells, we have previously reported that thyroid tumors express the TGF-β isoforms, TGFβ-1, TGFβ-2 and TGFβ-3 as well as activin isoforms, activin A and activin B (20,21). An impairment of signal transduction has been identified in the development and progression of several epithelial cancers (17,22).…”

Transforming growth factor-β1 and activin A generate antiproliferative signaling in thyroid cancer cells

“…Thyroid cancer is the most prevalent endocrine malignancy, papillary carcinoma being the most common thyroid carcinoma (DeLellis & Williams 2004). In previous studies, we observed TGF-b1, ActA, and also SMADs expression in thyroid neoplasms (Kimura et al 1999, Cerutti et al 2003. The co-expression of TGF-b1 and ActA does not permit us to distinguish the individual role of each of these growth factors in the thyroid.…”

MicroRNA miR-146b-5p regulates signal transduction of TGF-β by repressing SMAD4 in thyroid cancer

“…Despite its anti-proliferative activity, expression of TGF-b1 is elevated in thyroid carcinomas, suggesting that tumor cells become unresponsive to the TGF-b inhibitory signal (Kimura et al, 1999). Although chromosomal deletions involving the SMAD4 locus are frequently found in pancreatic adenocarcinomas, metastatic colorectal cancers, and small intestinal carcinomas , these deletions are rarely observed in thyroid tumors.…”