THYROID Volume 5, Number 1, 1995 Mary Ann Liebert, Inc., Publishers Biphasic Effects of Thyrotropin on Invasion and Growth of Papillary and Follicular Thyroid Cancer in Vitro THOMAS HOELTING, SERDAR TEZELMAN, ALLAN E. SIPERSTEIN, QUAN-YANG DUH, and ORLO H. CLARK ABSTRACT The rationale for TSH suppression in the treatment of follicular thyroid cancer (FTC) and papillary thyroid can- cer (PTC) is to inhibit tumor growth, prevent recurrent disease, and eventually prolong survival. We analyzed the effects of TSH on invasion and growth of 3 FTC cell lines from 1 patient (FTC133, primary; FTC236, lymph node; FTC238, lung metastasis) and 2 PTC cell lines (PTC-UC1, PTC-UC3). Cell growth and invasion through an 8-|dm pore polycarbonate membrane coated with Matrigel were measured using the MTT assay. The dose-response to TSH was biphasic, stimulating invasion and growth of FTC and PTC at low concentrations (0.1-10 mU/mL), and inhibiting them at high concentrations (100 mU/mL). Interestingly, the metastatic FTC cell lines had higher basal invasion, but were less responsive to TSH than the primary tumor. TSH (1 mU/mL) stimulated invasion of FTC 133 by 21%, FTC236 by 8%, and FTC238 by 8% (p < 0.01). At 100 mU/mL, TSH inhibited invasion of FTC133 by 21%, compared to 11% in FTC236 and 12% in FTC238. Also, TSH dose-dependently influenced proliferation of follicular thyroid cancer cells. At low concentrations it stimulated growth of FTC133 (20%) and inhibited it at high concentrations (23% ;p < 0.01). Again, the amplitude of TSH effects was significantly smaller in the cell lines from metastatic tumors. TSH affected invasion and growth of PTC-UC1 and PTC-UC3 also biphasically. These results show that TSH may act as a mitogenic and antimitogenic growth factor for invasion and proliferation of well-dif- ferentiated thyroid cancer cells in vitro. INTRODUCTION The rationale for the widely accepted use of TSH sup- pression in the postoperative management of well-differ- entiated thyroid cancer is that TSH stimulates growth of nor- mal and malignant human thyroid tissue (1-3). Thus, TSH suppression by exogenous thyroid hormone was shown to in- hibit tumor growth, prevent recurrent disease, and eventually prolong survival. One important explanation is that other than undifferentiated thyroid cancer, most papillary (PTC) and fol- licular (FTC) thyroid carcinomas retain many functional prop- erties of normal thyroid tissue, i.e., they are responsive to TSH (4). However, even though most historical, clinical, and labo- ratory data support the value of TSH suppressive therapy in the postoperative management of differentiated thyroid carcinoma, some studies found some thyroid cancers continue to grow or recur despite TSH suppression (5,6). The exact role of TSH for thyroid cell growth is not clear, and controversial results are described. The in vitro effects of TSH on growth of follicular thyroid cells in different species vary between stimulation (7), dose-dependent biphasic re- sponses (8), and inhibition (9). The purpose of our investiga- tion was to determine whether TSH affects invasion and growth of follicular and papillary thyroid carcinomas. MATERIALS AND METHODS Tumor cells All three follicular thyroid cancer (FTC) cell lines were ob- tained from a single patient's primary tumor (FTC 133) and from metachronous métastases (FTC236, lymph node; FTC238, lung metastasis). All FTC cell lines were kindly provided by Surgical Service, Veterans Affairs Medical Center, and Department of Surgery, Mount Zion Medical Center of the University of California, San Francisco, California 94121. 35