Conclusions
The above summarized findings of this laboratory on tumor-stroma interactions, together with a growing number of other reports contribute to the accumulating evidence that the stromal part of epithelial tumors plays a more active role in epithelial tumor development and progression than until recently recognized. The transplantation assay developed by us represents in in vivo system particularly suited to highlight early tumor-stroma interactions and to discriminate tumor stage-dependent characteristics in this interplay. Furthermore, by the unique assembly and geometry of this model the essential role of tumor-stroma interactions for tumor invasion has been documented unimbigously for the first time. Thus, the significance of extracellular matrix composition, stromal protease activity and growth factor interactions for modulating the tumor phenotype has been evidenced in different experimental settings. In addition to the transplantation assay comparable culture systems in vitro provide relevant models to study the mechanistic details of the complex interplay between tumor and stroma cells. These investigations will not only increase our knowledge on the important role of stromal cells in tumor biology, but may yield additional targets for novel therapeutic strategies aiming at genetically normal cells according to the principle of antiangiogenic therapy.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Bajou K, Noël, A, Gerard RD, Masson V, Brunner N, Holst-Hansen C, Skobe M, Fusenig NE, Carmeliet P, Collen D, Foidart JM. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nature Med 1998; 4: 923–928.
Bajou K, Masson V, Gerard RD, Schmitt PM, Albert, V, Lund, L.R, Frandsen, TL, Brunner N, Dano, K, Fusenig, NE, Loskutoff, D, Collen, D, Carmeliet P, Foidart JM, Noël A. The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin: implications for anti-angiogenic strategies. J Cell Biol 2000; in press.
Bleuel K, Popp S, Fusenig NE, Stanbridge EJ, Boukamp P. Tumor suppression in human skin carcinoma cells by chromosome 15 transfer or thrombospondin-1 overexpression through halted tumor vascularization. Proc Natl Acad Sci (USA) 1999; 96: 2065–2070.
Borchers AH, Powell MB, Fusenig NE, Bowden T. Paracrine factor and cell-cell contact-mediated induction of protease and c-ets gene expression in malignant keratinocyte/dermal fibroblast cocultures. Exp Cell Res 1994; 213: 143–147.
Borchers AH, Steinbauer H, Schafer BS, Kramer M, Bowden T. Fibroblast-directed expression and localization of 92-kDa type IV vollagenase along the tumor-stroma interface in an in vitro three-dimensional model of human squamous cell carcinoma. Molec Carcinog 1997; 19: 258–266.
Boukamp P, Dzarlieva-Petrusevska RT, Breitkreutz D, Hornung J, Markham A, Fusenig NE. Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J Cell Biol 1988; 106: 761–771.
Boukamp P, Stanbridge EJ, Foo DY, Cerutti PA, Fusenig NE. c-Ha-ras oncogene expression in immortalized human keratinocytes (HaCaT) alters growth potential in vivo but lacks correlation with malignancy. Cancer Res 1990; 50: 2840–2847.
Boukamp P, Popp S, Altmeyer S, Hülsen A, Fasching C, Cremer T, Fusenig NE. Sustained nontumorigenic phenotype correlates with a largely stable chromosome content during long-term culture of the human keratinocyte line HaCaT. Genes, Chromsomes & Cancer 1997; 19: 201–214.
Brauchle M, Angermeyer K, Hübner G, Werner S. Large induction of keratinocyte growth factor expression by serum growth factors and pro-inflammatory cytokines in cultured fibroblasts. Oncogene 1994; 9: 3199–3204.
Breitkreutz D, Boukamp P, Ryle CM, Stark HJ, Roop DR, Fusenig NE. Epidermal morphogenesis and keratin expression in c-Ha-ras-transfected tumorigenic clones of the human HaCaT cell line. Cancer Res 1991; 51: 4402–4409.
Breitkreutz D, Stark HJ, Plein P, Baur M, Fusenig NE. Differential modulation of epidermal keratinization in immortalized (HaCaT) and tumorigenic human skin keratinocytes (HaCaT-ras) by retinoic acid and extracellular Ca2+. Differentiation 1993; 5: 201–217.
Breitkreutz D, Stark HJ, Mirancea N, Tomakidi P, Steinbauer H, Fusenig NE. Integrin and basement membrane normalization in mouse grafts of human keratinocytes — implications for epidermal homeostasis. Differentiation 1997; 61: 195–209.
Breitkreutz D, Schoop VM, Mirancea N, Baur M, Stark HJ, Fusenig NE. Epidermal differentiation and basment membrane formation by HaCaT cells in surface transplants. Eur J Cell Biol 1998; 75: 273–286.
Cornil J, Theodorescu D, Man S, Herlin J, Jambrosic J, Kerbel RS. Fibroblast cell interactions with human melanoma cells affect tumor cell growth as a function of tumor progression. Proc Natl Acad Sci (USA) 1991; 88: 6028–6032.
Dingemans KP, Zeeman-Boeschoten IM, Keep RF, Pranab K. Transplantation of colon carcinoma into granulation tissue induces an invasive morphotype. Int J Cancer 1993; 54: 1010–1016.
Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. New Engl Med 1986; 315: 1650–1659.
Fidler IJ. Critical factors in the biology of human cancer metastasis: twenty-eight GHA Clowes memorial lecture. Cancer Res 1990; 50: 6130–6138.
Fusenig NE, Valentine EA, Worst PKM. Growth behaviour of normal and transformed mouse epidermal cells after reimplantation in vivo. In: Richards RJ, Rajan KT (eds), Tissue Culture in Medical Research (II). Pergamon Press, 1980, pp. 87–95.
Fusenig NE, Breitkreutz D, Dzarlieva RT, Boukamp P, Bohnert A, Tilgen W. Growth and differentiation characteristics of transformed keratinocytes from mouse and human skin in vitro and in vivo. J Invest Dermatol 1983; 81: 168–175.
Fusenig NE. Cell interaction and epithelial differentiation. In: Freshney RI (ed), Culture of Epithelial Cells. Wiley-Liss Inc, New York, 1992, pp. 25–57.
Fusenig NE. Epithelial-mesenchymal interactions regulate keratinocyte growth and differentiation in vitro. In: Leigh I, Lane B, Watt F (eds), The Keratinocyte Handbook. Cambridge University Press, 1994, pp. 71–94.
Fusenig NE, Boukamp P. Multiple stages and genetic alterations in immortalization, malignant transformation, and tumor progression of human skin keratinocytes. Molecular Carcinogenesis 1998; 23: 144–158.
Gregoire M, Lieubeau B. The role of fibroblasts in tumor behavior. Cancer Metastasis Rev 1995; 14: 339–350.
Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86: 353–364.
Hornung J, Bohnert A, Phan-Than L, Krieg T, Fusenig NE. 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 1987; 113: 325–341.
Maas-Szabowski N, Shimotoyodome A, Fusenig NE. Keratinocyte growth regulation in fibroblast cocultures via a double paracrine mechanism. J Cell Sci 1999; 112: 1843–1853.
Maas-Szabowski N, Stark HJ, Fusenig NE. Keratinocyte growth regulation in defined organotypic cultures through IL-1-induced keratinocyte growth factor expression in resting fibroblasts. J Invest Dermatol 2000; 114: 1075, 1084.
Montesano R, Pepper MS, Möhle-Steinlein U, Risau W, Wagner EF, Orci L. Increased proteolytic activity is responsible for the aberrant morphogenetic behavior of endothelial cells expressing the middle T oncogene. Cell 1990; 62: 435–445.
Morikawa K, Walker SM, Nakajima M, Pathak S, Jessup JM, Fidler IJ. Influence of organ environment on the growth, selection, and metastasis of human colon carcinoma cells in nude mice. Cancer Res 1988; 48: 6863–6871.
Mueller MM, Peter W, Mappes M, Huelsen A, Steinbauer H, Boukamp P, Vaccariello M, Garlick J, Fusenig. In vivo microenvironment promotes tumor progression of skin carcinomas by clonal selection and mutagenesis. Submitted.
Nakamura T, Matsumoto K, Kiritoshi A, Tano Y, Nakamura T. Induction of hepatocyte growth factor in fibroblasts by tumor-derived factors affects invasive growth of tumor cells: in vitro analysis of tumor-stromal interactions. Cancer Res 1997; 57: 3305–3313.
Noíl A, Gilles C, Bajou K, Devy L, Kebers F, Lewalle JM, Maquoi E, Munaut C, Remacle A, Foidart JM. Emerging roles for proteinases in cancer. Invasion Metastasis 1997; 17: 221–239.
Noser FK, Limat A. Organotypic culture of outer root sheath cells from human hair follicles using a new culture device. In Vitro Cell Develop Biol 1987; 23: 541–545.
Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tisty TD, Cunha GR. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 1999; 59: 5002–5011.
Pauli BU, Knudson W. Tumor invasion: a consequence of destructive and compositional matrix alterations. Hum Pathol 1988; 19: 628–639.
Ryle CM, Breitkreutz P, Stark HJ, Leigh IM, Steinert PM, Roop D, Fusenig NE. Density-dependent modulation of synthesis of keratins 1 and 10 in the human keratinocyte line HaCaT and in ras-transfected tumorigenic clones. Differentiation 1989; 40: 42–54.
Schoop V, Mirancea N, Fusenig NE. Epidermal organization and differentiation of HaCaT keratinocytes in organotypic coculture with human dermal fibroblasts. J Invest Dermatol 1999; 112: 343–353.
Schor SL, Schor AM, Grey AM, Rushton G. Foetal and cancer patient fibroblasts produce an autocrine migration-stimulating factor not made by normal adult cells. J Cell Sci 1988; 90: 391–399.
Skobe M. Mechanisms of tumor-stroma interactions with emphasis on angiogenesis and its significance for tumor growth and invasion, Doctoral Thesis, Technische Hochschule Darmstadt, Fachbereich Biologie, 1996.
Skobe M, Rockwell P, Goldstein N, Vosseler S, Fusenig NE. Halting angiogenesis suppresses carcinoma cell invasion. Nature Med 1997; 11: 1222–1227.
Skobe M, Fusenig NE. Tumorigenic conversion of immortal human keratinocytes through stromal cell activation. Proc Natl Acad Sci (USA) 1998; 95: 1050–1055.
Smith-McCune KK, Weidner N. Demonstration and characterization of the angiogenic properties of cervical dysplasia. Cancer Res 1994; 54: 800–809.
Smola H, Thiekötter G, Fusenig NE. Mutual induction of growth factor gene expression by epidermal-dermal cell interaction. J Cell Biol 1993; 122: 417–429.
Smola H, Stark HJ, Thiekötter G, Mirancea N, Krieg T, Fusenig NE. Dynamics of basement membrane formation by keratinocyte-fibroblast interactions in organotypic skin culture. Exp Cell Res 1998; 239: 399–410.
Stanbridge EJ, Boulger LR, Franks CR, Garrett JA, Reeson DE, Bischop D, Perkins FT. Optimal conditions for the growth of malignant human and animal cell populations in immunosuppressed mice. Cancer Res 1975; 35: 2203–2212.
Stark HJ, Baur M, Breitkreutz D, Mirancea N, Fusenig NE. Organotypic keratinocyte cocultures in defined medium with regular epidermal morphogenesis and differentiation. J Invest Dermatol 1999; 112: 681–691.
Strieth S, Hartschuh W, Pilz L, Fusenig NE. Angiogenic switch occurs late in squamous cell carcinomas of human skin. Br J Cancer 2000; 82: 591–600.
Szabowski A, Maas-Szabowski N, Andrecht S, Kolbus A, Schorpp-Kirstner M, Fusenig NE, Angel P. c-Jun and JunB antagonistically control cytokine-regulated mesenchymal-epidermal interaction in skin. Cell 2000, in press.
Tomakidi P, Mirancea N, Fusenig N, Herold-Mende C, Bosch FX, Breitkreutz D. Defects of basement membrane and hemidesmosome structure correlate with malignant phenotype and stromal interactions in HaCaT-ras xenografts. Differentiation 1999; 64: 263–275.
Tomakidi P, Baur M, Stark HJ, Herold-Mende C, Bosch FX, Steinbauer H, Fusenig NE, Breitkreutz D. Differential regulation of aberrant keratins and vimentin in transplants of benign and malignant human skin keratinocytes through stromal interactions (submitted).
Turner MA, Darragh T, Palefsky JM. Epithelial-stromal interactions modulating penetration of matrigel membranes by HPV 16-immortalized keratinocytes. J Invest Dermatol 1997; 109: 619–625.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2002 Kluwer Academic Publishers
About this chapter
Cite this chapter
Fusenig, N.E. et al. (2002). Tissue Models to Study Tumor-Stroma Interactions. In: Foidart, JM., Muschel, R.J. (eds) Proteases and Their Inhibitors in Cancer Metastasis. Cancer Metastasis — Biology and Treatment, vol 4. Springer, Dordrecht. https://doi.org/10.1007/1-4020-2008-2_11
Download citation
DOI: https://doi.org/10.1007/1-4020-2008-2_11
Publisher Name: Springer, Dordrecht
Print ISBN: 978-1-4020-0923-5
Online ISBN: 978-1-4020-2008-7
eBook Packages: Springer Book Archive