Abstract
Thyrotropin (TSH) is a thyroid-specific growth factor inducing differentiated function and growth of thyrocytes in vitro. In thyroid cancer, loss of TSH-receptor (TSHR) expression is a sign of de-differentiation and is believed to contribute to the malignant phenotype. The present studies aimed to determine the in vitro and in vivo effects of functioning tSHR in the follicular thyroid cancer cell line HTC, a subclone of FTC133 cells, lacking endogenous expression of TSHR, and HTCtshr+cells transfected with human TSHR-cDNA. HTCtshr+cells grew faster in vitro (doubling time 1.15 vs 1.56 d, p<0.05) and TSH caused a dose-dependent growth response. Adhesion to and invasion through reconstituted basement membrane were reduced in HTCtshr+cells, but when stimulated with TSH increased to levels comparable to naïve HTC cells. In vivo, tumor latency was 11 d for naïve HTC as compared to 21 d for HTCtshr+xenografts. Smaller tumor volumes were registered for HTCtshr+cells (250±217 vs 869±427 mm3, p<0.05). Angiogenesis, as determined by vascular surface density density (VSD) of experimental tumors, was enhanced in naïve HTC tumors (VSD 0.87±0.1 μm−1 vs 0.55±0.2μm−1 in HTCtshr+, p<0.05). VEGF secretion was more pronounced in naïve HTC cells stimulated with EGF, than in HTCtshr+cells stimulated with either TSH or EGF. In conclusion, regained expression of functional TSHR in the follicular thyroid cancer cell line HTC alters in vitro features commonly associated with the malignant phenotype. Smaller tumors and reduced angiogenesis of xenotransplanted HTC cells with functioning TSHR suggest a less aggressive in vivo phenotype. The present data highlight the pivotal role of TSHR to affect transformed thyrocytes in vitro and in vivo. They also suggest a role for EGF as a modulator of angiogenesis in thyrocytes devoid of TSHR.
Similar content being viewed by others
References
Dunhill, T. (1937). Trans. Med. Soc. London 60, 234–248.
Balme, H. W. (1954). Lancet 266, 812–813.
Pujol, P., Daures, J. P., Nsakala, N., Baldet, L., Bringer, J., and Jaffiol, C. (1996). J. Clin. Endocrinol. Metab. 81, 4318–4323.
Derwahl, M., Bröcker, M., Meyer, K., Schatz, H., and Studer, H. (1992). Acta Endocrinol. 126, 50–55.
Clark, O. H., and Gerend, P. L. (1985). J. Clin. Endocrinol. Metab. 61, 773–778.
Duh, Q. Y., Gum, E. T., Gerend, P. L., Raper, S. E. and Clark, O. H. (1990) World J. Surgery 14, 410–418.
Wyllie, F. S., Dawson, T., Bond, J. A., et al. (1998). Mol. Cell. Endocrinol. 76, 13–18.
Holting, T., Tezelman, S., Siperstein, A. E., Duh, Q. Y., and Clark, O. H. (1993). Biochem. Biophys. Res. Commun. 195, 1230–1234.
Holting, T., Zielke, A., Siperstein, A. E., Clark, O. H., and Duh, Q. Y. (1994). J. Clin. Endocrinol. Metab. 79, 806–813.
Holting, T., Zielke, A., Siperstein, A. E., Clark, O. H., and Duh, Q. Y. (1994). Clin. Exp. Metastasis. 12, 315–323.
Duh, Q. Y. and Grossman, R. F. (1995). Surg. Clin. North. Am. 75, 421–437.
Zielke, A., Hoffman, S., Paul, U., Duh, Q. Y., Clark, O. H., and Rothmund, M. (1999). Exp. Clin. Endocrinol. Diabetes 107, 361–369.
Bergstrohm, J. D., Westermark, B., and Heldin, N. E. (2000). Exp. Cell Res. 259, 293–299.
Akslen, L. A., Myking, A. O., Salvesen, H., and Varhaug, J. E. (1993). Br. J. Cancer 68, 808–812.
Ness, G. O., Haugen, D. R., Varhaug, J. E., Akslen, L. A., and Lillehaug, J. R. (1996). Int. J. Cancer 65, 161–167.
Mastuda, H., Sugenoya, A., Kobajashi, S., Kasuga, Y., and Iida, F. (1988). World J. Surgery 12, 616–622.
Westermark, K., Westermark, B., Karlson, K. A., and Erickson, L. E. (1986). Endocrinology 118, 1040–1046.
Asmis, L. M., Gerber H., Kaempf, J., and Studer, H. (1995). J. Endocrinol. 145, 513–520.
Gabler, B., Aicher, T., Heiss, P., and Senekowitsch-Schmidtke, R. (1997). Anticancer Res. 17, 3157–3159.
Schlumberger, M. J. (1998). N. Engl. J. Med. 338, 297–306.
Tanaka, K., Sonoo, H., Yamamoto, Y., et al. (2000). J. Surg. Oncol. 75, 108–116.
Dralle, H. (1989). In: Growth regulation of the thyroid gland and thyroid tumors. Goretzki, P. E. and Röher, H. D. (eds.), Karger: München, pp. 109–122.
Smeds, S., Boeryd, B., Jöstro, E., and Lenquist, S. (1989). In: Growth regulation of the thyroid gland and thyroid tumors. Goretzki, P. E. and Röher, H. D. (eds.) Karger: München, pp. 98–108.
Wenisch, H. J. C., Schumm-Dräger, P. M., and Encke A. (1992). Exp. Clin. Endocrinol. Diabetes 100, 48–50.
Goretzki, P. E., Simon, D., Dotzenrath, C., Schulte, K. M., and Röher, H. D. (2000). World J. Surg. 24, 913–922.
Derwahl, M., Kuemmel, M., Goretzki, P. E., Schatz, H., and Broecker, M. (1993). Biochem. Biophys. Res. Commun. 191, 1131–1138.
Broecker, M., Mayr, G. W., and Derwahl, M. (1997). Endocrinology 138, 3787–3796.
Ambiosi-Impiombato, F. S., Parks, L. A. M., and Coon, H. G. (1980). Proc. Natl. Acad Sci. USA 77, 3455–3459.
Isaacs, T., and Coffey, D. S. (1981). Cancer Res. 41, 5070–5074.
Barth, P. J., Weingärtner, K., Köhler, H. H., and Bittinger A. (1996). Hum. Pathol. 27, 1306–1310.
Zielke, A., Middeke, M., Hoffmann, S., et al. (2002). Surgery 6, 1056–1063.
Hofbauer, L. C., Kluger, S., Küne, C. A., et al. (2002). J. Cell. Biochem. 86, 642–650.
Middeke, M., Hoffmann, S., Hassan, I., Wunderlich, A., Hofbauer, L. C., and Zielke, A. (2002). Exp. Clin. Endocrinol. Diabetes 110, 386–392.
Brocker, M., deBuhr, I., Papageorgiou, G., Schatz, H., and Derwahl, M. (1996). Exp. Clin. Endocrinol. Diabetes 104, 20–23.
Wright, P. A., Lemoine, N. R., Goretzki, P., et al. (1991). Oncogene 6, 1693–1697.
Gustavsson, B., Hermansson, A., Andersson, A. C., et al. (1996). Mol. Cell. Endocrinol. 121, 143–151.
Derwahl, M., Hamacher, C., Russo, D., et al. (1996). J. Clin. Endocrinol. Metab. 81, 1898–1904.
Demeure, M. J., Damsky, C. H., Elfman, F., Goretzki, P. E., Wong, M. G., and Clark, O. H. (1992). World J. Surg. 16, 770–776.
Wenisch, H. J. (1996). Exp. Clin. Endocrinol. Diabetes 3, 61–63.
Ossendorp, F. A., Bruining, P. F., Schuuring, E. M., et al. (1990). Endocrinology 127, 419–430.
Sagartz, J. E., Jhiang, S. M., Tong, Q., and Capen, C. C. (1997). Lab. Invest. 76, 307–318.
Al-Sobhi, S. S., Soh W. Y., Wong, M. G., Siperstein, A. E., Duh, Q. Y., and Clark, O. H. (1998). World J. Surg. 22, 552–554.
Tezelman, S. T., Holting, T., Jossart, G. H., et al. (1998). World J. Surg. 22, 544–548.
Braga, M., Ringel, M. D., and Cooper, D. S. (2001). J. Clin. Endocrinol. Metab. 86, 5148–5151.
Dulgeroff, A. J., and Hershman, J. M. (1994). Endocr. Rev. 15, 500–515.
Klein, M., Picard, E., Vignaud, J. M., et al. (1999). J. Endocrinol. 161, 41–49.
Katoh, R., Miyagi, E., Kawaoi, A., et al., (1999). Hum. Pathol. 30, 891–897.
Biglietto, G., Maglione, D., Rambaldi, M., et al. (1995). Ongene 11, 1569–1179.
Sato, K., Yamazaki, K., et al. (1995). J. Clin. Invest. 96, 1295–1302.
Soh, E. Y., Sobhi, S. A., Wong, M. G., et al. (1996). Surgery 120, 944–947.
Fenton, C., Patel, A., Dinauer, C., Robie, D. K., Tuttle, R. M., and Francis, G. L. (2000). Thyroid 10, 349–357.
Klein, M., Vignaud, J. M., Hennequin, V., et al. (2001). J. Clin. Endocrinol. Metab. 86, 656–658.
Lennard, C. M., Patel, A., Wilson, J., et al. (2001). Surgery 129, 552–558.
Kotlarz, G., Wegrowski, Y., Martiny, L., Declerck, P. J., and Bellon, G. (2002). Biochem. Biophys. Res. Commun. 295, 737–743.
Hoffmann, S., Hofbauer, L. C., Scharrenbach, S., et al. (2004). J. Clin. Endocrinol. Metab. 89, 6139–6145.
Gorgoulis, V., Aninos, D., Priftis, C., et al. (1992). In vivo 6, 291–296.
Lemoine, N. R., Hughes, C. M., Gullik, W. J., Brown, C. L., and Wynford-Thomans, D. (1991). Int. J. Cancer 49, 558–561.
Brocker, M., Hammer, J., and Derwahl M. (1996). Thyroid (Suppl 1) 5, S4.
Dewahl, M., Broecker, M., and Kraiem, Z. (1999). J. Clin. Endocrinol. Metab. 84, 829–834.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hoffmann, S., Maschuw, K., Hassan, I. et al. Functional thyrotropin receptor attenuates malignant phenotype of follicular thyroid cancer cells. Endocr 30, 129–138 (2006). https://doi.org/10.1385/ENDO:30:1:129
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1385/ENDO:30:1:129