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Aberrations of growth factor control in metastatic follicular thyroid cancerin vitro

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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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References

  1. 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.

    PubMed  Google Scholar 

  2. 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.

    PubMed  Google Scholar 

  3. 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.

    PubMed  Google Scholar 

  4. 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.

    PubMed  Google Scholar 

  5. 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.

    PubMed  Google Scholar 

  6. Clark OH and Duh QY, 1991, Thyroid cancer.Med Clin North Am,75, 211–33.

    PubMed  Google Scholar 

  7. Ozaki O, Ito K, Kobayashi K,et al. 1990, Thyroid carcinoma in Graves' disease.World J Surgery,14, 437–42.

    Google Scholar 

  8. 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.

    PubMed  Google Scholar 

  9. 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.

    Google Scholar 

  10. Lyons J, Landis CA, Harsh G,et al. 1990, Two G protein oncogenes in human endocrine tumors.Science,249, 655–8.

    PubMed  Google Scholar 

  11. 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.

    PubMed  Google Scholar 

  12. 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.

    PubMed  Google Scholar 

  13. 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.

    PubMed  Google Scholar 

  14. Egan SE, Wright JA, Jarolim L,et al. 1987, Transformation by oncogenes encoding protein kinases induces the metastatic phenotype.Science,238, 202–5.

    PubMed  Google Scholar 

  15. 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.

    Google Scholar 

  16. 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.

    PubMed  Google Scholar 

  17. 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.

    PubMed  Google Scholar 

  18. Niks M and Otto M, 1990, Towards an optimized MTT-assay.J Immunol Methods,130, 149–51.

    PubMed  Google Scholar 

  19. 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.

    PubMed  Google Scholar 

  20. Robbins J, 1991, Thyroid cancer: a lethal endocrine neoplasm.Ann Intern Med,115, 133–47.

    PubMed  Google Scholar 

  21. 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.

    PubMed  Google Scholar 

  22. Clark OH, 1982, Total thyroidectomy—the treatment of choice for patients with differentiated thyroid cancer.Ann Surgery,196, 361–70.

    Google Scholar 

  23. 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.

    PubMed  Google Scholar 

  24. 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.

    PubMed  Google Scholar 

  25. 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.

    PubMed  Google Scholar 

  26. 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.

  27. 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.

    PubMed  Google Scholar 

  28. 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.

    PubMed  Google Scholar 

  29. 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.

    PubMed  Google Scholar 

  30. 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.

    PubMed  Google Scholar 

  31. 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.

    PubMed  Google Scholar 

  32. 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.

    PubMed  Google Scholar 

  33. Klein G, The role of oncogenes, transcriptional enhancers and growth factors. 1990,BioEssays,12,347–51.

  34. Kerbel RS, 1992, Expression of multi-cytokine resistance and multi-growth factor independence in advanced stage metastatic cancer.Am J Pathol,141, 519–24.

    PubMed  Google Scholar 

  35. Silberstein G and Daniel C, 1987, Reversible inhibition of mammary gland growth by transforming growth factor beta.Science,237, 291–3.

    PubMed  Google Scholar 

  36. 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.

    PubMed  Google Scholar 

  37. 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.

    PubMed  Google Scholar 

  38. Nicolson GL, 1993, Comment on: Kohn EC, Liotta LA. Invasion and metastases: new approach to an old problem.Oncology,7, 47–62.

    Google Scholar 

  39. 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.

    PubMed  Google Scholar 

  40. 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.

    Google Scholar 

  41. 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.

    PubMed  Google Scholar 

  42. 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.

    PubMed  Google Scholar 

  43. 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.

    Google Scholar 

  44. 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.

    Google Scholar 

  45. 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.

    Google Scholar 

  46. Smith P, Wynford-Thomas D, Stringer BMJ and Williams ED, 1986, Growth factor control of rat thyroid follicular cell proliferation.Endocrinology,119, 1439–45.

    PubMed  Google Scholar 

  47. 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.

    PubMed  Google Scholar 

  48. 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.

    PubMed  Google Scholar 

  49. Huber GK and Davis TF, 1990, Human fetal thyroid cell growthin vitro: system characterization and cytokine inhibition.Endocrinology,126, 869–75.

    PubMed  Google Scholar 

  50. 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.

    PubMed  Google Scholar 

  51. 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.

    Google Scholar 

  52. 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.

    Google Scholar 

  53. 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.

    Google Scholar 

  54. 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.

    PubMed  Google Scholar 

  55. 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.

    PubMed  Google Scholar 

  56. 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.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Surgical Service, Veterans Affairs Medical Center and Department of Surgery, Mount Zion Medical Center of the University of California, San Francisco, CA, USA

    Thomas Hoelting, Andreas Zielke, Allan E. Siperstein, Orlo H. Clark & Quan -Yang Duh

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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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