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Differentiation and Tumor Progression

  • N. E. Fusenig
  • D. Breitkreutz
  • P. Boukamp
  • P. Tomakidi
  • H.-J. Stark
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 139)

Abstract

Clinical and experimental experience indicate that differentiation and malignancy are inversely correlated. However, more recent experimental studies using mouse and human keratinocyte systems have demonstrated that complete or even substantial loss in overall epithelial differentiation is not a prerequisite for malignant growth of cancer cells. Major defects in differentiation are also not a prerequisite for premalignant stages, in particular for cell immortalization, which is considered an early and essential step in the transformation process. Moreover, progressive dedifferentiation, often associated with advanced tumor stages, is also found in immortalized cell lines which are, however, nontumorigenic. On the other hand, malignant cell lines may have maintained a high degree of their normal differentiation program and sensitivity to differentiation modulators. However, to date no transformed keratinocyte cell lines with completely normal differentiation have been observed. Since epidermal keratinization is a very complex process involving many different parameters and is fully expressed only under in vivo conditions, an exact and quantitative comparison of such ill-defined phenomena (differentiation and malignancy) is still problematic.

Obviously, both phenomena are under separate control and not causally linked, Nevertheless, a better understanding of factors and mechanisms regulating differentiation and of their disturbance in carcinogenesis would offer new possibilities to design novel tumor therapeutic strategies in the held of differentiation therapy.

Keywords

HaCaT Cell Verrucous Carcinoma Stratify Epithelium Human Squamous Cell Carcinoma HaCaT Cell Line 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Auersperg N, Krug PA, MacLaren JA, Watt FM, Myrdal SE (1989) Heterogeneous expression of keratin, involucrin, and extracellular matrix among subpopulations of a poorly differentiated human cervical carcinoma: possibly relationship to pattern of invasion. Cancer Res 49:3007–3014PubMedGoogle Scholar
  2. Banks-Schlegel SP, Howley S (1983) Differentiation of human epidermal cells transformed by SV40. J Cell Biol 96:330–337PubMedCrossRefGoogle Scholar
  3. Bernard BA, Robinson SM, Semat A, Darmon M (1985) Reexpression of fetal characters in Simian virus 40-transformed human keratinocytes. Cancer Res 45: 1707–1716PubMedGoogle Scholar
  4. Boukamp P, Fusenig NE (1993) “Trans-differentiation” from epidermal to mesenchymal/myogenic phenotype is associated with a drastic change in cell-cell and cell-matrix adhesion molecules. J Cell Biol 120:981–993PubMedCrossRefGoogle Scholar
  5. Boukamp P, Tilgen W, Dzarliewa-Petrusevska RT, Breitkreutz D, Haag D, Riehl RK, Bohnert A, Fusenig NE (1982) Phenotypic and genotypic characteristics of a cell line from squamous cell carcinoma of human skin. J Natl Cancer Inst 68:415–427PubMedGoogle Scholar
  6. Boukamp P, Rupniak THR, Fusenig NE (1985) Environmental modulation of the expression of differentiation and malignancy in six human squamous cell carcinoma cell lines. Cancer Res 45:5582–5592PubMedGoogle Scholar
  7. Boukamp P, Dzarliewa-Petrusevska RT, Breitkreutz D, Hornung J, Markham A, Fusenig NE (1988) Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J Cell Biol 106:761–771PubMedCrossRefGoogle Scholar
  8. Boukamp P, Breitkreutz D, Stark H-J, Fusenig NE (1990a) Mesenchyme-mediated and endogeneous regulation of growth and differentiation of human skin kera-tinoytes derived from different body sites. Differentiation 44:150–161PubMedCrossRefGoogle Scholar
  9. Boukamp P, Stanbridge EJ, Foo DY, Cerutti PA, Fusenig NE (1990b) C-Ha-ras oncogene expression in immortalized human keratinocytes (HaCaT) alters growth potential in vivo but lacks correlation with malignancy. Cancer Res 50:2840–2847PubMedGoogle Scholar
  10. Boukamp P, Chen J, Gonzales F, Jones PA, Fusenig NE (1992) Progressive stages of “transdifferentiation” from epidermal to mesenchymal phenotype induced by MyoD1 transfection, 5-aza-2′-deoxycytidine treatment, and selection for reduced cell attachment in the human keratinocyte line HaCaT. J Cell Biol 116:1257–1271PubMedCrossRefGoogle Scholar
  11. Boukamp P, Breitkreutz D, Hülsen A, Altmeyer S, Tomakidi P, Fusenig NE (1993) In vitro transformation and tumor progression. In: Marks F, Hecker E, Jung EG, Tilgen W (eds) Skin carcinogenesis in man and in experimental models. Springer, Berlin Heidelberg New York (Recent results in cancer research, vol 128)Google Scholar
  12. Bowden PE, Stark H-J, Breitkreutz D, Fusenig NE (1987) Expression and modification of keratins during terminal differentiation of mammalian epidermis. Curr Top Dev Biol 22:35–68PubMedCrossRefGoogle Scholar
  13. Breitkreutz D, Tilgen W, Boukamp P, Fusenig NE (1981) Correlation of prekeratin peptides and ultrastructure in epithelial cells of human skin tumours in vivo and in vitro. Anticancer Res 1:323–328PubMedGoogle Scholar
  14. Breitkreutz D, Hornung J, Poehlmann J, Brown-Bierman L, Bohnert A, Bowden PE, Fusenig NE (1986) Environmental induction of differentiation-specific keratins in malignant mouse keratinocyte lines. Eur J Cell Biol 42:255–267PubMedGoogle Scholar
  15. Breitkreutz D, Boukamp P, Stark H-J, Ryle C, Fusenig NE (1989) Response of established keratinocyte lines to modulators of epidermal differentiation. In: Reichert U, Shroot B (eds) Pharmacology and the skin, vol 3. Karger, Basel, pp 8–14Google Scholar
  16. Breitkreutz D, Boukamp P, Ryle CM, Stark H-J, Roop DR, Fusenig NE (1991a) Epidermal morphogenesis and keratin expression in c-Ha-ras-transfected tumorigenic clones of the human HaCaT cell line. Cancer Res 51:4402–4409PubMedGoogle Scholar
  17. Breitkreutz D, Boukamp P, Hülsen A, Ryle C, Stark H-J, Smola H, Thiekötter G, Fusenig NE (1991b) Human keratinocyte cell lines. In: Wilson G, Davis SS, Ilium L (eds) Pharmaceutical applications of cell and tissue culture. Plenum, London, pp 283–296Google Scholar
  18. Breitkreutz D, Stark H-J, Plein P, Baur M, Fusenig NE (1993a) Differential modulation of epidermal keratinization in immortalized (HaCaT) and tumorigenic human skin keratinocytes (HaCaT-ras) by retinoic acid and extracellular Ca2+. Differentiation 54:201–217PubMedCrossRefGoogle Scholar
  19. Breitkreutz D, Stark H-J, Baur M, Thiekötter G, Smola H, Fusenig NE (1993b) Differenzielle Veränderungen epidermaler Integrinmuster in Modell-Epithelien transformierter benigner und maligner Keratinozyten (HaCaT-ras). In: Mahrle G, Krieg T (eds) Wundheilung und Wundverschluß. Springer, Berlin Heidelberg New YorkGoogle Scholar
  20. Broders AC (1932) Practical points on the microscopic grading of carcinoma. NY State J Med 32:667–671Google Scholar
  21. Carter WG, Kaur P, Gil SG, Gahr PG, Wayner EA (1990) Distinct functions for integrins α3β1 in focal adhesions and α6β4/bullous pemphigoid antigen in new stable anchoring contact (SAC) of keratinocytes: relation to hemidesmosomes. J Cell Biol 111:3141–3154PubMedCrossRefGoogle Scholar
  22. Chang SE (1986) In vitro transformation of human epithelial cells. Biochim Biophys Acta 823:161–194PubMedGoogle Scholar
  23. Coulomb B, Lebreton C, Dubertret L (1989) Influence of human dermal fibroblasts on epidermalization. Invest Dermatol 92:122–125CrossRefGoogle Scholar
  24. Dürst M, Dzarliewa-Petrusevska RT, Boukamp P, Fusenig NE, Gissmann L (1987) Molecular and cytogenetic analysis of immortalized human primary keratinocytes obtained after transfection with human papillomavirus type 16 DNA. Oncogene 1:251–256PubMedGoogle Scholar
  25. Easty DM, Easty GC, Baici A, Carter RL, Cederholm-Williams SA, Felix H, Gusterson B, Haemmerli G, Häuser-Urfer J, Heizmann CW, Marcel M, Stehrenberger B, Sträuli P (1986) Biological studies of ten human squamous carcinoma cell lines: an overview. Eur J Cancer 22:617–634CrossRefGoogle Scholar
  26. Eccles SA (1983) Differentiation and neoplasia. Invasion and metastasis; experimental systems. J Pathol 141:333–353PubMedCrossRefGoogle Scholar
  27. Fuchs E (1990) Epidermal differentiation: the bare essentials. J Cell Biol 111: 2807–2814PubMedCrossRefGoogle Scholar
  28. Fusenig NE (1994) Epithelial-mesenchymal interactions regulate keratinocyte growth and differentiation in vitro. In: Leigh I, Watt F, Lane B (eds) Keratinocyte handbook. Cambridge University Press, Cambridge (in press)Google Scholar
  29. Fusenig NE, Breitkreutz D, Dzarlieva RT, Boukamp P, Bohnert A, Tilgen W (1983) Growth and differentiation characteristics of transformed keratinocytes from mouse and human skin in vitro and in vivo. J Invest Dermatol 81:168–175CrossRefGoogle Scholar
  30. Fusenig NE, Boukamp P, Breitkreutz D, Karjetta S, Petrusevska RT (1987) Oncogenes and malignant transformation of human keratinocytes. In: Cerutti PA, Nyaard OF, Simic MG (eds) Anticarcinogenesis and radiation protection. Plenum, New York, pp 227–231Google Scholar
  31. Fusenig NE, Boukamp P, Breitkreutz D, Hülsen A, Karjetta S, Stanbridge E (1989) Transformation of human skin epithelial cells in vitro: concepts of stages of transformation. Paper presented at workshop on cell transformation systems relevant to radiation-induced cancer in man, Dublin, Chap. 3Google Scholar
  32. Fusenig NE, Breitkreutz D, Bohnert A et al. (1991a) Epithelial-mesenchymal interactions in tissue homeostasis and malignant transformation. In: Johnson NW (ed) Oral cancer. Cambridge University Press, Cambridge, pp 218–248Google Scholar
  33. Fusenig NE, Breitkreutz D, Boukamp P (1991b) Differentiation potential of cancer cells. In: Masters JRW (ed) Human cancer in primary culture, a handbook. Kluwer Academic, New York, pp 55–80CrossRefGoogle Scholar
  34. Gabbert H, Wagner R, Moll R, Gerharz C-D (1985) Tumor dedifferentiation: an important step in tumor invasion. Clin Exp Metastasis 3:257–279PubMedCrossRefGoogle Scholar
  35. Harris CC (1987) Human tissues and cells in carcinogenesis research. Cancer Res 47:1–10PubMedGoogle Scholar
  36. Heim S, Mandahl N, Mitelmann F (1988) Genetic convergence in tumour progression. Cancer Res 48:5911–5916PubMedGoogle Scholar
  37. Hornung J, Bohnert A, Phan-Than L, Krieg T, Fusenig NE (1987) Basement membrane formation by malignant mouse keratinocyte cell lines in organotypic culture and transplants: correlation with degree of morphologic differentiation. J Cancer Res Clin Oncol 113:325–341PubMedCrossRefGoogle Scholar
  38. Kartasova T, Roop DR, Yuspa SH (1992) Relationship between the expression of differentiation-specific keratins 1 and 10 and cell proliferation in epidermal tumors. Mol Carcinog 6:18–25PubMedCrossRefGoogle Scholar
  39. Knight J, Gusterson BA, Cowley G, Monaghan P (1984) Differentiation of normal and malignant human squamous epithelium in vivo and in vitro: a morphologic study. Ultrastruct Pathol 7:133–141PubMedCrossRefGoogle Scholar
  40. Levitt ML, Gazdar AF, Oie HK, Schüller H, Thacher SM (1990) Cross-linked envelope-related markers for squamous differentiation in human lung cancer cell lines. Cancer Res 50:120–128PubMedGoogle Scholar
  41. Lindberg K, Rheinwald JG (1989) Suprabasal 40 kd keratin (K19) expression as an immunohistologic marker of premalignancy in oral epithelium. Am J Pathol 134:98–98Google Scholar
  42. Mackenzie I, Rittman G, Bohnert A, Breitkreutz D, Fusenig NE (1993) Influence of connective tissues on the in vitro growth and differentiation of murine epidermis. Epith Cell Biol 2:107–119Google Scholar
  43. Mareel M, Bracke M, Van Roy F, Vakaet L (1993) Expression of E-cadherin in embryogenic ingression and cancer invasion. Int J Dev Biol 37:227–235PubMedGoogle Scholar
  44. Markey AC, Lane BE, Churchill LJ, MacDonald DM, Leigh LM (1991) Expression of simple epithelial keratins 8 and 18 in epidermal neoplasia. J Invest Dermatol 97:763–770PubMedCrossRefGoogle Scholar
  45. McCance DJ, Kopan R, Fuchs E, Laimins LA (1988) Human papillomavirus type 16 alters human epithelial cell differentiation in vitro. Proc Natl Acad Sci USA 85:7169–7173PubMedCrossRefGoogle Scholar
  46. Moll R, Franke WW, Schiller DL, Geiger B, Krepier R (1982) The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 31:11–34PubMedCrossRefGoogle Scholar
  47. Moll R, Moll I, Franke WW (1984) Differences of expression of cytokeratin polypeptides in various epithelial skin tumours. Arch Dermatol Res 276:349–363PubMedCrossRefGoogle Scholar
  48. Moll R, Achtstätter T, Becht E, Balcarova-Stäuder J, Ittensohn M, Franke WW (1988) Cytokeratins in normal and malignant transitional epithelium: maintenance of expression of urothelial differentiation features in transitional cell carcinomas and bladder carcinoma cell lines. Am J Pathol 132:123–144PubMedGoogle Scholar
  49. Morgan PR, Shirlaw PJ, Johnson NW, Leigh IM, Lane EB (1987) Potential application of anti-keratin antibodies on oral diagnosis. J Oral Pathol 16:212–222PubMedCrossRefGoogle Scholar
  50. Nischt R, Roop DR, Mehrel T, Yuspa SH, Rentrop M, Winter H, Schweizer J (1988) Aberrant expression during two-stage mouse skin carcinogenesis of a type I 47-kDA keratin, K13, normally associated with terminal differentiation of internal stratified epithelia. Mol Carcinog 1:96–108PubMedCrossRefGoogle Scholar
  51. Osborn M, Weber K (1983) Tumor diagnosis by intermediate filament typing: a novel tool for surgical pathology. Lab Invest 48:372–394PubMedGoogle Scholar
  52. Parkinson EK (1985) Defective responses of transformed keratinocytes to terminal differentiation stimuli. Their role in epidermal tumour promotion by phorbolesters and deep skin wounding. Br J Cancer 52:479–493PubMedCrossRefGoogle Scholar
  53. Rheinwald JG, Beckett M (1980) Defective terminal differentiation in culture as a consistent and selectable character of malignant human keratinocytes. Cell 22: 629–632PubMedCrossRefGoogle Scholar
  54. Rice RH, Green H (1979) Presence in human epidermal cells of a soluble protein precursor of the cross-linked envelope: activation of the cross-linking by calcium ions. Cell 18:681–694PubMedCrossRefGoogle Scholar
  55. Roop DR, Krieg TM, Mehrel T, Cheng CK, Yuspa SH (1988) Transcriptional control of high molecular weight keratin gene expression in multistage mouse skin carcinogenesis. Cancer Res 48:3245–3252PubMedGoogle Scholar
  56. Ryle CM, Breitkreutz D, Stark H-J, Leigh IM, Steinert PM, Roop D, Fusenig NE (1989) Density-dependent modulation of synthesis of keratins 1 and 10 in the human keratinocyte line HaCaT and in ras-transfected tumorigenic clones. Differentiation 40:42–54PubMedCrossRefGoogle Scholar
  57. Schwartz RA (1988) Skin cancer: recognition and management. Springer, Berlin Heidelberg New YorkCrossRefGoogle Scholar
  58. Smola H, Thiekötter G, Fusenig NE (1993) Mutual induction of growth factor gene expression by epidermal-dermal cell interaction. J Cell Biol 122:417–429PubMedCrossRefGoogle Scholar
  59. Sonnenberg A, Linders CJT (1990) The α6β1 (VLA-6) and α6β4 protein complexes: tissue distribution and biochemical properties. J Cell Sci 96:207–217PubMedGoogle Scholar
  60. Sonnenberg A, Calafat J, Janssen H, Daams H, Van der Raaij-Helmer LMH, Falcioni R, Kennel SJ, Aplin JD, Baker J, Loizidou M, Garrod D (1991) Integrin α6β4 complex is located in hemidesmosomes, suggesting a major role in epidermal cell-basement membrane adhesion. J Cell Biol 113:907–917PubMedCrossRefGoogle Scholar
  61. Steinert PM, Roop DR (1988) Molecular and cellular biology of intermediate filaments. Annu Rev Biochem 57:593–625PubMedCrossRefGoogle Scholar
  62. Stoler AB, Stenbäck F, Balmain A (1993) The conversion of mouse skin squamous cell carcinomas to spindle cell carcinomas is a recessive event. J Cell Biol 122: 1103–1117PubMedCrossRefGoogle Scholar
  63. Tennenbaum T, Yuspa SH, Grover A, Castronovo V, Sobel ME, Yamada Y, De Luca LM (1992) Extracellular matrix receptors and mouse skin carcinogenesis: altered expression linked to appearance of early markers of tumor progression. Cancer Res 52:2966–2976PubMedGoogle Scholar
  64. Tennenbaum T, Weiner AK, Belanger AJ, Glick AB, Hennings H, Yuspa SH (1993) The suprabasal expression of α6β4 integrin is associated with a high risk for malignant progression in mouse skin carcinogenesis. Cancer Res 53:4803–4810PubMedGoogle Scholar
  65. Tilgen W, Boukamp P, Breitkreutz D, Dzarliewa RT, Engstner M, Haag D, Fusenig NE (1983) Preservation of morphological, functional and karyotypic traits during long-term culture and in vivo passage of two human skin squamous cell carcinomas. Cancer Res 43:5995–6001PubMedGoogle Scholar
  66. Van Neste DJJ, Staquet M-J, Leroy BP, DeCoster WJ (1988) Distribution pattern of psoriatic keratoblasts: computer-assisted image-analysis for combined evaluation of DNA synthesis and expression of 67 kD keratin polypeptides in the epidermis of stable plaques of psoriasis. J Invest Dermatol 90:382–386PubMedCrossRefGoogle Scholar
  67. Wille JJ, Maercklein PB, Scott RE (1982) Neoplastic transformation and defective control of cell proliferation and differentiation. Cancer Res 42:4620–4628Google Scholar
  68. Woodworth CD, Bowden PE, Doninger J, Pirisi L, Barnes W, Lancaster WD, DiPaolo JA (1988) Characterization of normal human exocervical epithelial cells immortalized in vitro by papillomavirus types 16 and 18 DNA. Cancer Res 48:4620–4628PubMedGoogle Scholar
  69. Wu YJ, Rheinwald JG (1981) A new small (40 kd) keratin filament protein made by some human squamous cell carcinomas. Cell 25:627PubMedCrossRefGoogle Scholar
  70. Yuspa SH, Kilkenny AE, Stanley J, Lichti U (1985) Keratinocytes blocked in phorbol ester-responsive early stage of terminal differentiation by sarcoma viruses. Nature 314:459–462PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin · Heidelberg 1995

Authors and Affiliations

  • N. E. Fusenig
    • 1
  • D. Breitkreutz
    • 1
  • P. Boukamp
    • 1
  • P. Tomakidi
    • 1
  • H.-J. Stark
    • 1
  1. 1.Division of Carcinogenesis and DifferentiationGerman Cancer Research CenterHeidelbergGermany

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