Differentiation and Tumor Progression
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.
KeywordsOncol Sarcoma Polypeptide Integrin Psoriasis
Unable to display preview. Download preview PDF.
- 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
- 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
- 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
- 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
- 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
- Broders AC (1932) Practical points on the microscopic grading of carcinoma. NY State J Med 32:667–671Google Scholar
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Wille JJ, Maercklein PB, Scott RE (1982) Neoplastic transformation and defective control of cell proliferation and differentiation. Cancer Res 42:4620–4628Google Scholar