Abstract
The aggressiveness of follicular thyroid cancer (FTC) varies widely, and metastasis is the primary cause of death. Uncontrolled proliferation of cancer cells may be associated with loss of growth factor control. We investigated the effects of stimulating (epidermal growth factor [EGF]; thyreotropin [TSH] in low concentrations) and inhibiting growth factors (transforming growth factor beta 1 [TGF beta 1]; TSH in high concentrations) on invasion and growth of FTC cell lines from the thyroid tumor (FTC133) and from the lymph node (FTC236) and lung (FTC238) metastases of the same patient. Invasion—penetration through an 8μm pore membrane, covered by Matrigel (basement membrane)—and growth were measured using the MTT-method. EGF (10 ng/ml) and TSH in low concentrations (1 mU/ml) stimulated invasion and growth of all FTC cell lines, but the amplitude of stimulation differed significantly. The parental cell line FTC133 was considerably more responsive to growth factor stimulation than the metastatic clones. Invasion of FTC133 was enhanced by 42% (EGF;p<0.02) and 21% (TSH;p<0.01), invasion of FTC236 by 8% (EGF;p<0.02) and 8% (TSH;p<0.01), and invasion of FTC238 by 9% (EGF;p<0.02) and 8% (TSH;p<0.01). Conversely, invasion and growth of FTC133 were significantly more inhibited by TGF beta 1 (10 ng/ml) and supraphysiologic concentrations of TSH (100 mU/ml) than the cell lines from the lymph node and lung metastases. At day 7, invasion of FTC133 was inhibited by 32% (TGF beta 1;p<0.02) and 21% (TSH;p<0.01), invasion of FTC236 by 18% (TGF beta 1;p<0.02) and 11% (TSH;p<0.01), and invasion of FTC238 by 16% (TGF beta 1;p<0.02) and 12% (TSH;p<0.01). Moreover, we analyzed growth factor independence in minimally supplemented or unsupplemented medium. Growth, but no invasion was evident when cells were cultured completely unsupplemented over 7 days. These results suggest that metastatic FTCs may have developed by escaping from the normal control of TSH and other growth factors.
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Schroy P, Rifkin J, Coffey RJ, Winawer S and Friedman E, 1990, Role of transforming growth factor beta 1 in induction of colon carcinoma differentiation by hexamethylene bisacetamide.Cancer Res,50, 261–5.
Schwarz LC, Gingras MC, Goldberg G, Greenberg AH and Wright JA, 1988, Loss of growth factor dependence and conversation of transforming growth factor beta 1 inhibition to stimulation in metastatic H-ras-transformed murine fibroblasts.Cancer Res,48, 6999–7003.
Lu C, Vickers MF and Kerbel RS, 1992, Interleukin 6: a fibroblast-derived growth inhibitor of human melanoma cells from early but not advanced stages of tumor progression.Proc Natl Acad Sci USA,89, 9215–9.
Cornil I, Theodoresu D, Man S,et al. 1991, Fibroblast cell interactions with human melanoma cells affect tumor cell growth as a function of tumor progression.Proc Natl Acad Sci USA,88, 6028–32.
Mooradian DL, Purchio AF and Furcht LT, 1990, Differential effects of transforming growth factor beta 1 on the growth of poorly and highly differentiated murine melanoma cells.Cancer Res,50, 273–7.
Clark OH and Duh QY, 1991, Thyroid cancer.Med Clin North Am,75, 211–33.
Ozaki O, Ito K, Kobayashi K,et al. 1990, Thyroid carcinoma in Graves' disease.World J Surgery,14, 437–42.
Belfiore A, Garofalo MR, Giuffrida D,et al. 1990, Increased aggressiveness of thyroid cancer in patients with Graves' disease.J Clin Endocrinol Metab,70, 830–35.
Goretzki PE, Lyons J, Stacy-Phipps S,et al. 1992, Mutational activation of ras and gsp oncogenes in differentiated thyroid cancer and their biological implications.World J Surgery,16, 576–82.
Lyons J, Landis CA, Harsh G,et al. 1990, Two G protein oncogenes in human endocrine tumors.Science,249, 655–8.
Lemoine NR, Mayall ES, Willie FS,et al. 1989, High frequency of ras oncogene activation in all stages of human thyroid tumorigenesis.Oncogene,4, 159–65.
Santoro M, Melillo RM, Grieco M,et al. 1993, The trk and ret tyrosine kinase oncogenes cooperate with ras in the neoplastic transformation of a rat thyroid epithelial cell line.Cell Growth Diff,4, 77–84.
Fusco A, Grieco M, Berlingieri MT,et al. 1987, A new oncogene in human papillary thyroid carcinomas and their lymph-nodal metastases.Nature,328, 170–72.
Egan SE, Wright JA, Jarolim L,et al. 1987, Transformation by oncogenes encoding protein kinases induces the metastatic phenotype.Science,238, 202–5.
Goretzki PE, Frilling A, Simon D and Roeher HD, 1990, Growth regulation of normal thyroids and thyroid tumors in man.Rec Results Cancer Res,118, 48–54.
Ambiosi-Impiombato FS, Parks LAM and Coon HG, 1980, Culture of hormone-dependent functional epithelial cells from rat thyroids.Proc Natl Acad Sci USA,77, 3455–9.
Roehm NW, Rodgers GH, Hatfield SM and Glasebrook AL, 1991, An improved calorimetric assay for cell proliferation and viability utilizing the tetrazolium salt XTT.J Immunol Methods,142, 257–65.
Niks M and Otto M, 1990, Towards an optimized MTT-assay.J Immunol Methods,130, 149–51.
Hansen MB, Nielsen SE and Berg K, 1989, Reexamination and further development of a precise and rapid dye method for measuring cell growth/cell kill.J Immunol Methods,119, 203–10.
Robbins J, 1991, Thyroid cancer: a lethal endocrine neoplasm.Ann Intern Med,115, 133–47.
Mizukami Y, Takatoshi M, Nonomura A,et al. 1990, Distant metastases in differentiated thyroid carcinoma: A clinical and pathologic study.Hum Pathol,21, 283–90.
Clark OH, 1982, Total thyroidectomy—the treatment of choice for patients with differentiated thyroid cancer.Ann Surgery,196, 361–70.
Brennan MD, Bergstralh EJ, van Heerden JA and McConahey WM, 1991, Follicular thyroid cancer treated at the Mayo Clinic, 1946 through 1970: initial manifestations, pathologic findings, therapy, and outcome.Mayo Clin Proc,66, 11–22.
Harness JK, Thompson NW, McLeod MK, Eckhauser FE and Lloyd RV, 1984, Follicular carcinoma of the thyroid gland: trends and treatment.Surgery,96, 972–8.
Kath R, Jambrosic J, Holland L, Rodeck U and Herlyn M, 1991, Development of invasive and growth-factor independent cell variants from primary human melanomas.Cancer Res,51, 2205–11.
Demeure MJ, Damsky CH, Elfman F,et al. Invasion by cultured human follicular thyroid cancer correlates with increased beta 1 integrins and production of proteases.World J Surgery,16, 770–76.
Verschueren H, Dekegel D and DeBaetselier P, 1987, Development of a monolayer invasion assay for the discrimination and isolation of metastatic lymphoma cells.Invasion Metastasis,7, 1–15.
Updyke TV and Nicolson GL, 1986, Malignant melanoma cell lines selectedin vitro for homotypic adhesion properties have increased experimental metastatic potential.Clin Exp Metastasis,4, 273–9.
Bresalier RS, Hujanen ES, Raper SE,et al. 1987, An animal model for colon cancer metastasis: establishment and characterization of murine cell lines with enhanced liver-metastasizing-ability.Cancer Res,47, 1398–402.
Puricelli L, Colombo LL, de Kier Joffe B and de Lustig ES, 1984, Invasivenessin vitro of two mammary adenocarcinoma tumors with different metastasizing ability.Invasion Metastasis,4, 238–47.
Mooradian DL, Purchio AF and Furcht LT, 1990, Differential effects of transforming growth factor beta 1 on the growth of poorly and highly metastatic murine melanoma cells.Cancer Res,50, 273–7.
Theodorescu D, Caltabiano M, Greig R, Rieman D and Kerbel RS, 1991, Reduction of TGF beta activity abrogates growth promoting tumor cell-cell interactionsin vivo.J Cell Physiol,148, 380–90.
Klein G, The role of oncogenes, transcriptional enhancers and growth factors. 1990,BioEssays,12,347–51.
Kerbel RS, 1992, Expression of multi-cytokine resistance and multi-growth factor independence in advanced stage metastatic cancer.Am J Pathol,141, 519–24.
Silberstein G and Daniel C, 1987, Reversible inhibition of mammary gland growth by transforming growth factor beta.Science,237, 291–3.
Kimchi A, Wang XF, Weinberg RA, Cheifetz S and Massague J, 1988, Absence of TGF beta receptors and growth inhibitory responses in retinoblastoma cells.Science,240, 196–9.
Leof EB, Proper JA and Moses HL, 1987, Modulation of transforming growth factor type beta action by activated ras and c-myc.Mol Cell Biol,7, 2649–52.
Nicolson GL, 1993, Comment on: Kohn EC, Liotta LA. Invasion and metastases: new approach to an old problem.Oncology,7, 47–62.
Steeg PS, Bevilacqua G, Koppler L,et al. 1988, Evidence for a novel gene associated with low tumor metastatic potential.J Natl Cancer Inst,80, 200–4.
Rodeck U, Herlyn M, Menssen HD, Furlanetto RW and Koprowski H, 1987, Metastatic but not primary melanoma cell lines growin vitro independently of exogenous growth factors.Intl J Cancer,40, 687–90.
Mancianti ML, Herlyn M, Weil D,et al. 1988, Growth and phenotype characteristics in human nevus cells in culture.J Invest Dermatol,90, 134–41.
Chadwick DE and Lagarde AE, 1988, Coincidental acquisition of growth autonomy and metastatic potential during the malignant transformation of factor-dependent CCL39 lung fibroblasts.J Natl Cancer Inst,80, 318–25.
Sadowski I, Pawson T and Lagarde AE, 1988, v-fps protein-tyrosine kinase coordinately enhanced the malignancy and growth factor responsiveness of pre-neoplastic lung fibroblasts.Oncogene,2, 2417–23.
Goretzki PE and Clark OH, 1988, Thyroid-stimulating hormone receptor studies. In: Roeher HD, Clark OH, eds.Thyroid tumors. Progress in Surgery 19. Basel: Karger, pp. 181–204.
Clark OH, Gerend PL and Nissenson RA, 1982, TSH-binding and adenylate cyclase activation in normal and neoplastic human thyroid tissue: lack of effect of thyroglobulin.J Endocrinol Metab,54, 1157–62.
Smith P, Wynford-Thomas D, Stringer BMJ and Williams ED, 1986, Growth factor control of rat thyroid follicular cell proliferation.Endocrinology,119, 1439–45.
Williams DW, Wynford-Thomas D and Williams ED, 1987, Control of human thyroid follicular cell proliferation in suspension and monolayer culture.Mol Cell Endocrinol,51, 33–40.
Westermark B, Karlsson FA and Walinder D, 1979, Thyrotropin is not a growth factor for human thyroid cells in culture.Proc Natl Acad Sci USA,76, 2022–6.
Huber GK and Davis TF, 1990, Human fetal thyroid cell growthin vitro: system characterization and cytokine inhibition.Endocrinology,126, 869–75.
Bidey SP, Lambert A and Robertson WR, 1988, Thyroid cell growth, differentiation and function in the FRTL-5 cell line: a survey.J Endocrinol,119, 365–76.
Goretzki PE, Frilling A, Simon D, Rastegar M and Ohmann C, 1989, Growth regulation of human thyrocytes by thyrotropin, cyclic adenosin monophosphate, epidermal growth factor and insulin-like growth factor. In: Goretzki PE, Roeher HD, eds.Growth Regulation of Thyroid Gland and Thyroid Tumors. Basel: Karger.
Derwahl M, Broecker M, Meyer K, Schatz H and Studer H, 1992, Molecular mechanism involved in thyroid tumorigenesis: Possible role of the human TSH receptor.Acta Endocrinol,126 (Suppl. 4), 50.
Duh QY, Siperstein AE, Miller RA,et al. 1990, Epidermal growth factor receptors and adenylate cyclase activity in human thyroid tissues.World J Surgery,14, 410–18.
Duh QY, Gum ET, Gerend PL, Raper SE and Clark OH, 1985, Epidermal growth factor receptors in normal and neoplastic thyroid tissue.Surgery,98, 1000–1007.
Lund-Johansen M, Bjerkvig R, Humphrey PA,et al. 1990, Effect of epidermal growth factor on glioma cell growth, migration, and invasionin vitro.Cancer Res,50, 6039–44.
Westermark B, Magnusson A and Heldin CH, 1982, Effect of epidermal growth factor in membrane motility and cell locomotion in cultures of human lioma cells.J Neurosci Res,8, 491–507.
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Hoelting, T., Zielke, A., Siperstein, A.E. et al. Aberrations of growth factor control in metastatic follicular thyroid cancerin vitro . Clin Exp Metast 12, 315–323 (1994). https://doi.org/10.1007/BF01753838
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DOI: https://doi.org/10.1007/BF01753838