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. 1989 Oct;60(4):542–548. doi: 10.1038/bjc.1989.310

Production of TGF-alpha and TGF-beta by cultured keratinocytes, skin and oral squamous cell carcinomas--potential autocrine regulation of normal and malignant epithelial cell proliferation.

M Partridge 1, M R Green 1, J D Langdon 1, M Feldmann 1
PMCID: PMC2247118  PMID: 2478181

Abstract

Transforming growth factors have a wide range of biological activities related to cell proliferation and differentiation. In general TGF-alpha promotes cell proliferation while TGF-beta may stimulate or inhibit proliferation depending on the cell type and growth factor environment. Cultured human keratinocytes, skin and oral squamous cell carcinomas were analysed for the presence of transcripts and protein for the transforming growth factors alpha & beta. Both growth factors were detected in cultured keratinocytes (which have receptors for and respond to both ligands), and in medium conditioned by these cells. Additionally transcripts for TGF-alpha were found preferentially in the basal, proliferative compartment of cultured keratinocytes. Similarly both growth factors were detected in oral squamous cell carcinomas and a highly significant inverse correlation was found between the levels of TGF-alpha and the epidermal growth factor receptor in these tumours. The data for TGF-alpha are consistent with the existence of an autocrine growth control loop influencing cell proliferation in both a normal cell type and malignant epithelial tissues, a process that in keratinocytes and responsive squamous cell carcinomas could be modulated by TGF-beta.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allen-Hoffmann B. L., Rheinwald J. G. Polycyclic aromatic hydrocarbon mutagenesis of human epidermal keratinocytes in culture. Proc Natl Acad Sci U S A. 1984 Dec;81(24):7802–7806. doi: 10.1073/pnas.81.24.7802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Anzano M. A., Roberts A. B., Smith J. M., Sporn M. B., De Larco J. E. Sarcoma growth factor from conditioned medium of virally transformed cells is composed of both type alpha and type beta transforming growth factors. Proc Natl Acad Sci U S A. 1983 Oct;80(20):6264–6268. doi: 10.1073/pnas.80.20.6264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Auffray C., Rougeon F. Purification of mouse immunoglobulin heavy-chain messenger RNAs from total myeloma tumor RNA. Eur J Biochem. 1980 Jun;107(2):303–314. doi: 10.1111/j.1432-1033.1980.tb06030.x. [DOI] [PubMed] [Google Scholar]
  4. Aviv H., Leder P. Purification of biologically active globin messenger RNA by chromatography on oligothymidylic acid-cellulose. Proc Natl Acad Sci U S A. 1972 Jun;69(6):1408–1412. doi: 10.1073/pnas.69.6.1408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Barrandon Y., Green H. Cell migration is essential for sustained growth of keratinocyte colonies: the roles of transforming growth factor-alpha and epidermal growth factor. Cell. 1987 Sep 25;50(7):1131–1137. doi: 10.1016/0092-8674(87)90179-6. [DOI] [PubMed] [Google Scholar]
  6. Bell G. I., Fong N. M., Stempien M. M., Wormsted M. A., Caput D., Ku L. L., Urdea M. S., Rall L. B., Sanchez-Pescador R. Human epidermal growth factor precursor: cDNA sequence, expression in vitro and gene organization. Nucleic Acids Res. 1986 Nov 11;14(21):8427–8446. doi: 10.1093/nar/14.21.8427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cheifetz S., Weatherbee J. A., Tsang M. L., Anderson J. K., Mole J. E., Lucas R., Massagué J. The transforming growth factor-beta system, a complex pattern of cross-reactive ligands and receptors. Cell. 1987 Feb 13;48(3):409–415. doi: 10.1016/0092-8674(87)90192-9. [DOI] [PubMed] [Google Scholar]
  8. Coffey R. J., Jr, Derynck R., Wilcox J. N., Bringman T. S., Goustin A. S., Moses H. L., Pittelkow M. R. Production and auto-induction of transforming growth factor-alpha in human keratinocytes. 1987 Aug 27-Sep 2Nature. 328(6133):817–820. doi: 10.1038/328817a0. [DOI] [PubMed] [Google Scholar]
  9. Derynck R., Jarrett J. A., Chen E. Y., Eaton D. H., Bell J. R., Assoian R. K., Roberts A. B., Sporn M. B., Goeddel D. V. Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells. Nature. 1985 Aug 22;316(6030):701–705. doi: 10.1038/316701a0. [DOI] [PubMed] [Google Scholar]
  10. Derynck R., Roberts A. B., Winkler M. E., Chen E. Y., Goeddel D. V. Human transforming growth factor-alpha: precursor structure and expression in E. coli. Cell. 1984 Aug;38(1):287–297. doi: 10.1016/0092-8674(84)90550-6. [DOI] [PubMed] [Google Scholar]
  11. Elder J. T., Fisher G. J., Lindquist P. B., Bennett G. L., Pittelkow M. R., Coffey R. J., Jr, Ellingsworth L., Derynck R., Voorhees J. J. Overexpression of transforming growth factor alpha in psoriatic epidermis. Science. 1989 Feb 10;243(4892):811–814. doi: 10.1126/science.2916128. [DOI] [PubMed] [Google Scholar]
  12. Fischer S. M., Nelson K. D., Reiners J. J., Jr, Viaje A., Pelling J. C., Slaga T. J. Separation of epidermal cells by density centrifugation: a new technique for studies on normal and pathological differentiation. J Cutan Pathol. 1982 Feb;9(1):43–49. doi: 10.1111/j.1600-0560.1982.tb01040.x. [DOI] [PubMed] [Google Scholar]
  13. Frolik C. A., Wakefield L. M., Smith D. M., Sporn M. B. Characterization of a membrane receptor for transforming growth factor-beta in normal rat kidney fibroblasts. J Biol Chem. 1984 Sep 10;259(17):10995–11000. [PubMed] [Google Scholar]
  14. Gottlieb A. B., Chang C. K., Posnett D. N., Fanelli B., Tam J. P. Detection of transforming growth factor alpha in normal, malignant, and hyperproliferative human keratinocytes. J Exp Med. 1988 Feb 1;167(2):670–675. doi: 10.1084/jem.167.2.670. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Green M. R., Couchman J. R. Differences in human skin between the epidermal growth factor receptor distribution detected by EGF binding and monoclonal antibody recognition. J Invest Dermatol. 1985 Sep;85(3):239–245. doi: 10.1111/1523-1747.ep12276708. [DOI] [PubMed] [Google Scholar]
  16. Gunning P., Ponte P., Okayama H., Engel J., Blau H., Kedes L. Isolation and characterization of full-length cDNA clones for human alpha-, beta-, and gamma-actin mRNAs: skeletal but not cytoplasmic actins have an amino-terminal cysteine that is subsequently removed. Mol Cell Biol. 1983 May;3(5):787–795. doi: 10.1128/mcb.3.5.787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Han V. K., Hunter E. S., 3rd, Pratt R. M., Zendegui J. G., Lee D. C. Expression of rat transforming growth factor alpha mRNA during development occurs predominantly in the maternal decidua. Mol Cell Biol. 1987 Jul;7(7):2335–2343. doi: 10.1128/mcb.7.7.2335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hayashi I., Carr B. I. DNA synthesis in rat hepatocytes: inhibition by a platelet factor and stimulation by an endogenous factor. J Cell Physiol. 1985 Oct;125(1):82–90. doi: 10.1002/jcp.1041250111. [DOI] [PubMed] [Google Scholar]
  19. Hoath S. B., Lakshmanan J., Fisher D. A. Epidermal growth factor binding to neonatal mouse skin explants and membrane preparations--effect of triiodothyronine. Pediatr Res. 1985 Mar;19(3):277–281. doi: 10.1203/00006450-198503000-00004. [DOI] [PubMed] [Google Scholar]
  20. Hoath S. B., Lakshmanan J., Fisher D. A. Thyroid hormone effects on skin and hepatic epidermal growth factor concentrations in neonatal and adult mice. Biol Neonate. 1984;45(1):49–52. doi: 10.1159/000241762. [DOI] [PubMed] [Google Scholar]
  21. Holley R. W., Armour R., Baldwin J. H., Greenfield S. Activity of a kidney epithelial cell growth inhibitor on lung and mammary cells. Cell Biol Int Rep. 1983 Feb;7(2):141–147. doi: 10.1016/0309-1651(83)90027-9. [DOI] [PubMed] [Google Scholar]
  22. Jetten A. M., Shirley J. E., Stoner G. Regulation of proliferation and differentiation of respiratory tract epithelial cells by TGF beta. Exp Cell Res. 1986 Dec;167(2):539–549. doi: 10.1016/0014-4827(86)90193-x. [DOI] [PubMed] [Google Scholar]
  23. Knabbe C., Lippman M. E., Wakefield L. M., Flanders K. C., Kasid A., Derynck R., Dickson R. B. Evidence that transforming growth factor-beta is a hormonally regulated negative growth factor in human breast cancer cells. Cell. 1987 Feb 13;48(3):417–428. doi: 10.1016/0092-8674(87)90193-0. [DOI] [PubMed] [Google Scholar]
  24. Lawrence D. A., Pircher R., Jullien P. Conversion of a high molecular weight latent beta-TGF from chicken embryo fibroblasts into a low molecular weight active beta-TGF under acidic conditions. Biochem Biophys Res Commun. 1985 Dec 31;133(3):1026–1034. doi: 10.1016/0006-291x(85)91239-2. [DOI] [PubMed] [Google Scholar]
  25. Lyons R. M., Keski-Oja J., Moses H. L. Proteolytic activation of latent transforming growth factor-beta from fibroblast-conditioned medium. J Cell Biol. 1988 May;106(5):1659–1665. doi: 10.1083/jcb.106.5.1659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Marquardt H., Hunkapiller M. W., Hood L. E., Todaro G. J. Rat transforming growth factor type 1: structure and relation to epidermal growth factor. Science. 1984 Mar 9;223(4640):1079–1082. doi: 10.1126/science.6320373. [DOI] [PubMed] [Google Scholar]
  27. Massagué J. Epidermal growth factor-like transforming growth factor. I. Isolation, chemical characterization, and potentiation by other transforming factors from feline sarcoma virus-transformed rat cells. J Biol Chem. 1983 Nov 25;258(22):13606–13613. [PubMed] [Google Scholar]
  28. Massagué J. Epidermal growth factor-like transforming growth factor. II. Interaction with epidermal growth factor receptors in human placenta membranes and A431 cells. J Biol Chem. 1983 Nov 25;258(22):13614–13620. [PubMed] [Google Scholar]
  29. Masui T., Wakefield L. M., Lechner J. F., LaVeck M. A., Sporn M. B., Harris C. C. Type beta transforming growth factor is the primary differentiation-inducing serum factor for normal human bronchial epithelial cells. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2438–2442. doi: 10.1073/pnas.83.8.2438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Nanney L. B., McKanna J. A., Stoscheck C. M., Carpenter G., King L. E. Visualization of epidermal growth factor receptors in human epidermis. J Invest Dermatol. 1984 Feb;82(2):165–169. doi: 10.1111/1523-1747.ep12259731. [DOI] [PubMed] [Google Scholar]
  31. O'Keefe E., Battin T., Payne R., Jr Epidermal growth factor receptor in human epidermal cells: direct demonstration in cultured cells. J Invest Dermatol. 1982 Jun;78(6):482–487. doi: 10.1111/1523-1747.ep12510246. [DOI] [PubMed] [Google Scholar]
  32. Ozanne B., Fulton R. J., Kaplan P. L. Kirsten murine sarcoma virus transformed cell lines and a spontaneously transformed rat cell-line produce transforming factors. J Cell Physiol. 1980 Oct;105(1):163–180. doi: 10.1002/jcp.1041050118. [DOI] [PubMed] [Google Scholar]
  33. Ozanne B., Richards C. S., Hendler F., Burns D., Gusterson B. Over-expression of the EGF receptor is a hallmark of squamous cell carcinomas. J Pathol. 1986 May;149(1):9–14. doi: 10.1002/path.1711490104. [DOI] [PubMed] [Google Scholar]
  34. Partridge M., Gullick W. J., Langdon J. D., Sherriff M. Expression of epidermal growth factor receptor on oral squamous cell carcinoma. Br J Oral Maxillofac Surg. 1988 Oct;26(5):381–389. doi: 10.1016/0266-4356(88)90090-3. [DOI] [PubMed] [Google Scholar]
  35. Reiss M., Sartorelli A. C. Regulation of growth and differentiation of human keratinocytes by type beta transforming growth factor and epidermal growth factor. Cancer Res. 1987 Dec 15;47(24 Pt 1):6705–6709. [PubMed] [Google Scholar]
  36. Rheinwald J. G., Green H. Epidermal growth factor and the multiplication of cultured human epidermal keratinocytes. Nature. 1977 Feb 3;265(5593):421–424. doi: 10.1038/265421a0. [DOI] [PubMed] [Google Scholar]
  37. Roberts A. B., Anzano M. A., Lamb L. C., Smith J. M., Sporn M. B. New class of transforming growth factors potentiated by epidermal growth factor: isolation from non-neoplastic tissues. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5339–5343. doi: 10.1073/pnas.78.9.5339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Roberts A. B., Lamb L. C., Newton D. L., Sporn M. B., De Larco J. E., Todaro G. J. Transforming growth factors: isolation of polypeptides from virally and chemically transformed cells by acid/ethanol extraction. Proc Natl Acad Sci U S A. 1980 Jun;77(6):3494–3498. doi: 10.1073/pnas.77.6.3494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Samsoondar J., Kobrin M. S., Kudlow J. E. Alpha-transforming growth factor secreted by untransformed bovine anterior pituitary cells in culture. I. Purification from conditioned medium. J Biol Chem. 1986 Nov 5;261(31):14408–14413. [PubMed] [Google Scholar]
  40. Schlessinger J., Shechter Y., Willingham M. C., Pastan I. Direct visualization of binding, aggregation, and internalization of insulin and epidermal growth factor on living fibroblastic cells. Proc Natl Acad Sci U S A. 1978 Jun;75(6):2659–2663. doi: 10.1073/pnas.75.6.2659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Seyedin S. M., Segarini P. R., Rosen D. M., Thompson A. Y., Bentz H., Graycar J. Cartilage-inducing factor-B is a unique protein structurally and functionally related to transforming growth factor-beta. J Biol Chem. 1987 Feb 15;262(5):1946–1949. [PubMed] [Google Scholar]
  42. Shipley G. D., Pittelkow M. R., Wille J. J., Jr, Scott R. E., Moses H. L. Reversible inhibition of normal human prokeratinocyte proliferation by type beta transforming growth factor-growth inhibitor in serum-free medium. Cancer Res. 1986 Apr;46(4 Pt 2):2068–2071. [PubMed] [Google Scholar]
  43. Silberstein G. B., Daniel C. W. Reversible inhibition of mammary gland growth by transforming growth factor-beta. Science. 1987 Jul 17;237(4812):291–293. doi: 10.1126/science.3474783. [DOI] [PubMed] [Google Scholar]
  44. Sporn M. B., Roberts A. B. Autocrine growth factors and cancer. 1985 Feb 28-Mar 6Nature. 313(6005):745–747. doi: 10.1038/313745a0. [DOI] [PubMed] [Google Scholar]
  45. Sporn M. B., Todaro G. J. Autocrine secretion and malignant transformation of cells. N Engl J Med. 1980 Oct 9;303(15):878–880. doi: 10.1056/NEJM198010093031511. [DOI] [PubMed] [Google Scholar]
  46. Sun T. T., Green H. Differentiation of the epidermal keratinocyte in cell culture: formation of the cornified envelope. Cell. 1976 Dec;9(4 Pt 1):511–521. doi: 10.1016/0092-8674(76)90033-7. [DOI] [PubMed] [Google Scholar]
  47. Todaro G. J., Fryling C., De Larco J. E. Transforming growth factors produced by certain human tumor cells: polypeptides that interact with epidermal growth factor receptors. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5258–5262. doi: 10.1073/pnas.77.9.5258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Tucker R. F., Volkenant M. E., Branum E. L., Moses H. L. Comparison of intra- and extracellular transforming growth factors from nontransformed and chemically transformed mouse embryo cells. Cancer Res. 1983 Apr;43(4):1581–1586. [PubMed] [Google Scholar]
  49. Waterfield M. D., Mayes E. L., Stroobant P., Bennet P. L., Young S., Goodfellow P. N., Banting G. S., Ozanne B. A monoclonal antibody to the human epidermal growth factor receptor. J Cell Biochem. 1982;20(2):149–161. doi: 10.1002/jcb.240200207. [DOI] [PubMed] [Google Scholar]
  50. Watt F. M., Green H. Stratification and terminal differentiation of cultured epidermal cells. Nature. 1982 Feb 4;295(5848):434–436. doi: 10.1038/295434a0. [DOI] [PubMed] [Google Scholar]
  51. de Larco J. E., Todaro G. J. Growth factors from murine sarcoma virus-transformed cells. Proc Natl Acad Sci U S A. 1978 Aug;75(8):4001–4005. doi: 10.1073/pnas.75.8.4001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. de Martin R., Haendler B., Hofer-Warbinek R., Gaugitsch H., Wrann M., Schlüsener H., Seifert J. M., Bodmer S., Fontana A., Hofer E. Complementary DNA for human glioblastoma-derived T cell suppressor factor, a novel member of the transforming growth factor-beta gene family. EMBO J. 1987 Dec 1;6(12):3673–3677. doi: 10.1002/j.1460-2075.1987.tb02700.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. ten Dijke P., Hansen P., Iwata K. K., Pieler C., Foulkes J. G. Identification of another member of the transforming growth factor type beta gene family. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4715–4719. doi: 10.1073/pnas.85.13.4715. [DOI] [PMC free article] [PubMed] [Google Scholar]

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