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Three-dimensional in vitro tissue culture models of breast cancer — a review

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Abstract

Three-dimensional (3D) in vitro breast tumour models have an invaluable role in tumour biology today providing some very important insights into breast cancer. As well as increasing our understanding of homeostasis, cellular differentiation and tissue organization they provide a well defined environment for cancer research in contrast to the complex host environment of an in vivo model. With the recent availability of relevant stromal elements together with the vast array of extracellular matrix constituents available, in vivo like microenvironments can be recreated. These tissue like structures more realistically model the structural architecture and differentiated function of breast cancer than a cellular monolayer providing in vivo like responses to therapeutic agents. Three dimensional in vitro models allow the study of cell—cell and cell—extracellular matrix interactions, in addition to the influence of the microenvironment on cellular differentiation, proliferation, apoptosis and gene expression. Due to their enormous potential 3D cultures are currently being exploited by many other branches of biomedical science with therapeutically orientated studies becoming the major focus of research. In return great progress in 3D culture techniques have been made, largely due to this greater interaction. At present they are being used in studies ranging from investigating the role of adhesion molecules (e.g., E-cadherin) in invasion/metastasis; VEGF and angiogenesis, to tissue modelling and remodelling. Progress in the development of complex 3D culture systems is more productive than ever, however further research is vital.

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References

  1. Freuer EJ, Wun LM, Boring CC, Flanders WD, Timmel JJ, Tong T: The lifetime risk of developing breast cancer. J Natl Cancer Inst 85: 892–897, 1993

    Google Scholar 

  2. Wolff MS, Collman GW, Barret JC, Huff J: Breast cancer and environmental risk factors: epidemiological and experimental findings. Ann Rev Pharmacol Toxicol 36: 573–596, 1996

    Google Scholar 

  3. Smith SH, Wolman SR, Hackett AJ: The biology of breast cancer at the cellular level. Biochem Biophys Acta 783: 103–123, 1984

    Google Scholar 

  4. Drife JO: Breast development in puberty, in Annals of the New York Academy of Sciences, In: Angeli A, Bradlow HL, Dogliotti L (eds) Endocrinology of the Breast: Basic and Clinical Aspects. The New York Academy of Sciences, New York, 1996, pp 58-66

    Google Scholar 

  5. Bissell MJ: The differentiated state of normal and malignant cells or how to define a normal cell culture. Int Rev Cytol 70: 27–100, 1981

    Google Scholar 

  6. Petersen OW, R?nnov-Jessen L, Howlett AR, Bissell MJ: Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells. Proc Natl Acad Sci USA 89: 9064–9068, 1992

    Google Scholar 

  7. Stoker AW, Streuli CH, Martins-Green M, Bissell MJ: Designer environments for the analysis of cell and tissue function. Curr Opin Cell Biol 2: 864–874, 1990

    Google Scholar 

  8. Jones JL, Critchley DR, Walker RA: Alteration of stromal protein and integrin expression in breast-a marker of premalignant change. J Pathol 167: 399–406, 1992

    Google Scholar 

  9. Howlett AR, Bailey N, Damsky C, Petersen OW, Bissell MJ: Cellular growth and survival are mediated by B1 integrins in normal human breast epithelium but not in breast carcinoma. J Cell Sci 108: 1945–1957, 1995

    Google Scholar 

  10. Kleinman HK, Luckenbill-Edds FW, Cannon FW, Sephel GC: Use of extracellular matrix components for cell culture. Anal Biochem 166: 1–13, 1987

    Google Scholar 

  11. Bergstraesser LM, Weitzman SA: Culture of normal and malignant primary epithelial cells in a physiological manner simulates in vivo patterns and allows discrimination of cell type. Cancer Res 53: 2644–2654, 1993

    Google Scholar 

  12. Alford D, Taylor-Papadimitrou J: Cell adhesion, molecules in the normal and cancerous mammary gland. J Mam Gland Biol Neoplasia 1: 207–218, 1996

    Google Scholar 

  13. Ohmori T, Yang JL, Price JO, Arteaga CL: Blockade of tumor cell transforming growth factor-betas enhances cell cycle progression and sensitizes human breast carcinoma cells to cytotoxic chemotherapy. Exp Cell Res 245(2): 350–359, 1998

    Google Scholar 

  14. Rak J, Mitsuhashi Y, Erdos V, Huang SN, Filmus J, Kerbel RS: Massive programmed cell death in intestinal epithelial cells induced by three-dimensional growth conditions: suppression by mutant c-H-ras oncogene expression. J Cell Biol 131(6 Pt 1): 1587–1598, 1995

    Google Scholar 

  15. Bissell MJ, Hall HG, Parry G: How does the extracellular matrix direct gene expression. J Theor Biol 99: 31–68, 1982

    Google Scholar 

  16. R?nnov-Jessen L, Petersen OW, Bissell MJ: Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol Rev 76: 25–69, 1996

    Google Scholar 

  17. Martin GR: Teratocarcinomas and mammalian embryogenesis. Science 209(4458): 768–776, 1980

    Google Scholar 

  18. Ronnov-Jessen L, Petersen OW, Koteliansky VE, Bissell MJ: The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. J Clin Invest95: 859–873, 1995

    Google Scholar 

  19. Tlsty TD, Hein PW: Know thy neighbor: stromal cells can contribute oncogenic signals. Curr Opin Genet Dev 11(1): 54–59, 2001 (review)

    Google Scholar 

  20. Kunz-Schughart LA, Heyder P, Schroeder J, Knuechel R: A heterologous 3D co-culture model of breast tumor cells and fibroblasts to study tumor-associated fibroblast differentiation. Exp Cell Res 266: 74–86, 2001

    Google Scholar 

  21. Barcellos-Hoff M, Ravani S: Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. Cancer Res 60: 1254–1260, 2000

    Google Scholar 

  22. Koukoulis GK, Virtanen I, Korhonen M, Litinen L, Quaranta V, Gould VE: Immunohistochemical localization of integrins in the normal, hyperplastic and neoplastic breast: correlations with their function as receptors and cell adhesion molecules. Am J Pathol 139: 787–799, 1991

    Google Scholar 

  23. Zutter M, Mazoujian GM, Santoro SA: Decreased expression of integrin adhesive protein receptors in adenocarcinoma of the breast. Am J Pathol 137: 863–870, 1990

    Google Scholar 

  24. Umbas R, Schalken JA, Aalders TW, Carter BS, Karthaus HFM, Schaafsma HE, Debruyne FMJ, Issacs WB: Expression of the cellular adhesion molecule E-cadherin is reduced or absent in high grade-prostate cancer. Cancer Res 52: 5104–5109, 1992

    Google Scholar 

  25. Christofori G, Semb H: The role of the cell-adhesion molecule E-cadherin as a tumour-suppressor gene. Trends Biochem Sci 24(2): 73–76, 1999

    Google Scholar 

  26. Wang F, Weaver VM, Petersen OW, Larabell CA, Dedhar S, Briand P, Lupu R, Bissell MJ: Reciprocal interactions between ?1-integrin and epidermal growth factor receptor in three-dimensional basement membrane breast cultures: a different perspective in epithelial biology. Proc Natl Acad Sci USA 95: 14821–14826, 1998

    Google Scholar 

  27. Cukierman E, Pankov R, Stevens DR, Yamada KM: Taking cell-matrix adhesions to the third dimension. Science 294(5547): 1708–1712, 2001

    Google Scholar 

  28. Miller BE, Miller FR, Heppner GH: Factors affecting growth and drug sensitivity of mammary tumor lines in collagen gel cultures. Cancer Res 45: 4200–4205, 1985

    Google Scholar 

  29. Glinsky VV, Huflejt ME, Glinsky GV, Deutscher SL, Quinn TP: Effects of Thomsen-Friedenreich antigen-specific peptide P-30 on ?-galactoside-mediated homotypic aggregation and adhesion to the endothelium of MDA-MB-435 human breast carcinoma cells. Cancer Res 16: 2588–3584, 2000

    Google Scholar 

  30. Langlois AJ, Holder Jr WD, Iglehart JD, Nelson-Rees WA, Wells Jr SA, Bolognesi DP: Morphological and biochemical properties of a new human breast cancer cell line. Cancer Res 39: 2604–2613, 1979

    Google Scholar 

  31. Glinsky GV, Glinsky VV: Apoptosis and metastasis: a superior resistance of metastatic cells to programmed cell death. Cancer Lett 101: 43–51, 1996

    Google Scholar 

  32. Fidler IJ: The relationship of embolic homogeneity, number, size, and viability to the incidence of experimental metastasis. Eur J Cancer 9: 223–227, 1975

    Google Scholar 

  33. Sutherland RM: Cell and environment interactions in tumor microregions: the multicell spheroid model. Science 240: 177–184, 1988

    Google Scholar 

  34. Yuhas JM, Li AP, Martinez AO, Ladman AJ: A simplified method for production and growth of multicellular tumor spheroids. Cancer Res 37: 3639–3643, 1977

    Google Scholar 

  35. Ellis MJ, Singer C, Hornby A, Rasmussen, Cullen KJ: Insulin-like growth factor mediated stromal-epithelial interactions in human breast cancer. Breast Cancer Res Treat 31: 249–261, 1994

    Google Scholar 

  36. Hewitt RE, Powe DG, Carter GI, Turner DR: Desmoplasia and its relevance to colorectal tumour invasion. Int J Cancer 53(1): 62–69, 1993

    Google Scholar 

  37. Noel A, Munaut C, Nusgens B, Lapiere CM, Foidart JM: Different mechanisms of extracellular matrix remodeling by fibroblasts in response to human mammary neoplastic cells. Invas Metast 13: 72–81, 1993

    Google Scholar 

  38. Sutherland RM, Inch WR, McCredie JA, Kruuv J: A multi-component radiation survival curve using an in vitro tumour model. Int J Radiat Biol Relat Stud Phys Chem Med 18: 491–495, 1970

    Google Scholar 

  39. Sourla A, Doillon C, Koutsilieris M: Three dimensional type I collagen gel system containing MG-63 osteoblasts-like cells as model for studying local bone reaction caused by metastatic cancer cells. Anticancer Res 16: 2773–2780, 1996

    Google Scholar 

  40. Bell E: Strategy for the selection of scaffolds for tissue engineering. Tissue Eng 1: 163–179, 1995

    Google Scholar 

  41. Jacquot J, Spilmont C, Burlet H, Fuchey C, Buisson AC, Tournier JM, Gaillard D, Puchelle E: Glandular-like morphogenesis and secretory activity of human tracheal gland cells in a three-dimensional collagen gel matrix. J Cell Physiol 161: 407–418, 1994

    Google Scholar 

  42. Tan W, Krishnaraj R, Desai TA: Evaluation of nanostructured composite collagen-chitosan matrices for tissue engineering. Tissue Eng 7: 203, 2001

    Google Scholar 

  43. Goodwin TJ, Prewett TL, Wolf DA, Spaulding GF: Reduced shear stress: a major component in the ability of mammalian tissue to form three-dimensional assemblies in simulated microgravity. J Cell Biochem 51: 301–311, 1993

    Google Scholar 

  44. Sheffield LG: Organization and growth of mammary epithelia in the mammary gland fat pad. J Dairy Sci 71: 2855–2874, 1988

    Google Scholar 

  45. O'Hare MJ, Bond J, Clarke C, Takeuchi Y, Atherton AJ, Berry C, Moody J, Silver AR, Davies DC, Alsop AE, Neville AM, Jat PS: Conditional immortalization of freshly isolated human mammary fibroblasts and endothelial cells. Proc Natl Acad Sci USA98: 646–651, 2001

    Google Scholar 

  46. Shweiki D, Neeman M, Itin AE, Keshet E: Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency in multicell spheroids: implications for tumor angiogenesis. Proc Natl Acad Sci USA 92: 768–772, 1995

    Google Scholar 

  47. Gudjonsson T, Villadsen R, Nielsen HL, Ronnov-Jessen L, Bissell MJ, Petersen OW: Isolation, immortalization, and characterization of a human breast epithelial cell line with stem cell properties. Genes Dev 16(6): 693–706, 2002

    Google Scholar 

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Kim, J.B., Stein, R. & O'Hare, M.J. Three-dimensional in vitro tissue culture models of breast cancer — a review. Breast Cancer Res Treat 85, 281–291 (2004). https://doi.org/10.1023/B:BREA.0000025418.88785.2b

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