Multicellular spheroids: A three-dimensional in vitro culture system to study tumour biology

International Journal of Experimental Pathology

Volumn 79, Issue 1, 1998, Pages 1-23

  Kunz Schughart, Leoni A ^a   Kreutz, Marina ^a   Knuechel, Ruth ^a  

^a UNIVERSITY OF REGENSBURG   (Germany)

Author keywords

in vitro; Multicellular spheroids; Three dimensional culture system; Tumour

Indexed keywords

CANCER CELL CULTURE; CELL INTERACTION; ENDOTHELIUM CELL; FIBROBLAST; HUMAN; IMMUNOCOMPETENT CELL; MALIGNANT NEOPLASTIC DISEASE; NONHUMAN; PRIORITY JOURNAL; REVIEW; SPHEROID CELL;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL COMMUNICATION; CELL CULTURE TECHNIQUES; COCULTURE TECHNIQUES; FIBROBLASTS; HUMANS; IMMUNITY, CELLULAR; MODELS, BIOLOGICAL; SPHEROIDS, CELLULAR;

EID: 0031883574     PISSN: 09599673     EISSN: None     Source Type: Journal    
DOI: 10.1046/j.1365-2613.1998.00051.x     Document Type: Review

References (222)

1. ACKER H. & CARLSSON J. (1992) The microenvironment in multicellular spheroids. In: Spheroid Culture in Cancer Research (Ed. Bjerkvig R.), Boca Raton: CRC Press pp. 135-157.
2. ACKER H., CARLSSON J., HOLTERMANN G., NEDERMAN T. & NYLÉN T. (1987a) Influence of glucose and buffer capacity in the culture medium on growth and pH in spheroids of human thyroid carcinoma and human glioma origin. Cancer Res. 47, 3504-3508.
3. 2 measurements in cell spheroids cultured with different techniques. Br. J. Cancer 56, 325-327.
4. ACKER H., PIETRUSCHKA F. & DEUTSCHER J. (1990) Endothelial cell mitogen released from HT29 tumour cells grown in monolayer or multicellular spheroid culture. Br. J. Cancer 62, 376-377.
5. ANDREESEN R., GADD S., BRUGGER W., LÖHR G.W. & ATKINS R.C. (1988) Activation of human monocyte-derived macrophages cultured on teflon: response to interferon-gamma during terminal maturation in vitro. Immunobiol. 177, 186-198.
6. ANDREESEN R., OSTERHOLZ J. & BROSS K.J. (1983) Cytotoxic effector cell function at different stages of human monocyte-macrophage maturation. Cancer Res. 43, 5931-5936.
7. AUDRAN R., DAZORD L. & TOUJAS L. (1994) Interactions between human macrophages and tumor cells in three-dimensional cultures. Cancer Immunol. Immunother. 39, 299-304.
8. BADER A., KNOP E., KERN A., BOKER K., FRUHAUF N., CROME O., ESSELMANN H., PAPE C., KEMPKA G. & SEWING K.F. (1996) 3-D coculture of hepatic sinusoidal cells with primary hepatocytes - design of an organotypical model. Exp. Cell Res. 226, 223-233.
9. BANKS S.D., WATERS K.A., BARRETT L.L., DICKERSON S., PENDERGAST W. & SMITH G.K. (1994) Destruction of WiDr multicellular tumour spheroids with the novel thymidylate synthase inhibitor 1843U89 at physiological thymidine concentrations. Cancer Chemother. Pharmacol. 33, 455-459.
10. BARDIËS M., THERDREZ P., GESTIN J.-F., MARCILLE B.-M., GUERREAU D., FAIVRE-CHAUVET A., MAHÈ M., SAI-MAUREL C. & CHATAL J.-F. (1992) Use of multi-cell spheroids of ovarian carcinoma as an intraperitoneal radio-immunotherapy model: Uptake, retention kinetics and dosimetric evaluation. Int. J. Cancer 50, 984-991.
11. BARNES R., MASOOD S., BARKER E., ROSENGARD A.M., COGGIN D.L., KING C.R., PORTER-JORDAN K., WARGOTZ E.S. & LIOTTA L.A. (1991) Low nm23 protein expression in infiltrating ductal breast carcinomas correlates with reduced patient survival. Am. J. Pathol. 139, 245-250.
12. BECKER I., BECKER K.F., ROHRL M.H., MINKUS G., SCHUETZE K. & HOFLER H. (1996) Single-cell mutation analysis of tumors from stained histologic sides. Lab. Invest. 75, 801-807.
13. BERGSTRAESSER L.M. & WEITZMAN S.A. (1993) 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.
14. BISSELL M.J. & HALL H.G. (1987) Form and function in the mammary gland: the role of extracellular matrix. In: The mammary gland. Eds Neville M.C. & Daniel C.W: New York: Plenum Publishing Corporation, pp. 97-146.
15. BJERKVIG R., HOSTMARK J., PEDERSEN P.-H. & LAERUM O. (1992) Tumor spheroids from biopsy specimens. In: Spheroid Culture in Cancer Research (Ed. by Bjerkvig R.), pp. 41-56, CRC Press Boca Raton.
16. BJERKVIG R., LAERUM O.D. & RUCKLIDGE G.J. (1989) Immunocytochemical characterization of extracellular matrix proteins expressed by cultured glioma cells. Cancer Res. 49, 5424-5428.
17. BJERKVIG R., TØNNESEN A., LAERUM O.D. & BACKLUND E.O. (1990) Multicellular tumor spheroids from human gliomas maintained in organ culture. J. Neurosurg. 72, 463-475.
18. BONTA I.L. & BEN-EFRAIM S. (1993) Involvement of inflammatory mediators in macrophage antitumor activity. J. Leukoc. Biol. 54, 613-626.
19. BOOTH C., HARNDEN P., THEJDOSIEWICZ L.K., SCRIVEN S., SELBY P.J. & SOUTHGATE J. (1997) Stromal and vascular invasion in an human in vitro bladder cancer model. Lab Invest. 76, 843-857.
20. BOSMAN F.T., DE BRUINE A., FLOHIL C., VAN DER WURFF A., TEN KATE J. & DINJENS W.W. (1993) Epidermal-stromal interactions in colon cancer. Int. J. Dev. Biol. 37, 203-211.
21. BOURRAT-FLOECK B., GROEBE K. & MUELLER-KLIESER W. (1991) Biological response of multicellular EMT6 spheroids to exogenous lactate. Int. J. Cancer 47, 792-799.
22. BRACKE M., ROMIJN H., VAKAET L., VYNCKE B., DE METS M. & MAREEL M. (1992) The use of spheroids in the study of invasion. In: Spheroid Culture in Cancer Research Ed. R. Bjerkvig, Boca Raton: CRC Press pp. 73-105.
23. BRACKE M.E., VYNCKE B.M., BRUYNEEL E.A., VERMEULEN S.J., DEBRUNYNE G.K., VANLAREBEKE N.A., VLEMINCK K., VANROY F.M. & MAREEL M.M. (1993) Insulin-like growth factor I activates the invasion suppressor function of E-cadherin in MCF-7 human mammary carcinoma cells in vitro. Br. J. Cancer 68, 282-289.
24. 3 on transformed C3H/10T1/2 fibroblasts grown as multicellular spheroids. Int. J. Cancer 62, 428-435.
25. BRADLEY C. & PITTS J. (1994) The use of genetic marking to assess the interaction of sensitive and multidrug-resistent cells in mixed culture. Br. J. Cancer 70, 795-798.
26. BREDEL-GEISSLER A., KARBACH U., WALENTA S., VOLLRATH L. & MUELLER-KLIESER W. (1992) Proliferation-associated oxygen consumption and morphology of tumour cells in monolayer and spheroid culture. J. Cell. Physiol. 153, 44-52.
27. BROUTY-BOYÈ D., MAINGUENE C., MAGNIEN V., ISRAEL L. & BEAUPAIN R. (1994) Fibroblast-mediated differentiation in human breast carcinoma cells (MCF-7) grown as nodules in vitro. Int. J. Cancer 56, 731-735.
28. BROUTY-BOYÈ D., RAUX H., AZZARONE B., TAMBOISE A., TAMBOISE E., BÈRANGER S., MAGNIEN V., PIHAN I., ZARDI L. & ISRAEL L. (1991) Fetal myofibroblast-like cells isolated from post-radiation fibrosis in human breast cancer. Int. J. Cancer 47, 697-702.
29. BUTTA A., NACLENNAN K., FLANDERS K.C., SACKS N.P., SMITH I., MCKINNA A., DOWSETT M., WAKEFIELD L.M., SPORN M.B. & BAUM M. (1992) Induction of transforming growth factor beta 1 in human breast cancer in vivo following tamoxifen treatment. Cancer Res. 52, 4261-4264.
30. BYERS S.W., SOMMERS C.L., HOXTER B., MERCURIO A.M. & TOZEREN A. (1995) Role of E-cadherin in the response of tumour cell aggregates to lymphatic, venous and arterial flow: Measurement of cell-cell adhesion strength. J. Cell Sci. 108, 2053-2064.
31. CARLSSON J. (1992) Tumor spheroids in studies of immunotherapy. In: Spheroid Culture in Cancer Research Ed. R. Bjerkvig, Boca Raton: CRC Press, pp. 277-306.
32. CARLSSON J. & ACKER H. (1988) Relations between pH, oxygen partial pressure and growth in cultured cell spheroids. Int. J. Cancer 42, 715-720.
33. CARLSSON J. & NEDERMAN T. (1989) Tumor spheroid technology in cancer therapy research. Eur. J. Cancer Clin. Oncol. 25, 1127-1133.
34. CARLSSON J. & NEDERMAN T. (1992) Tumor spheroids as a model in studies of drug effects. In: Spheroid Culture in Cancer Research (Ed. by Bjerkvig R.), pp. 199-216, CRC Press Boca Raton.
35. CHALFIE M. (1995) Green fluorescent protein. Photochem.-Photobiol. 62, 651-656.
36. CHAN W.S., WEST C.M.L., MORRE J.V. & HART I.R. (1991) Photo-cytotoxic efficacy of sulphonated species of aluminium phthalocyanine against cell monolayers, multicellular spheroids and in vivo tumours. Br. J. Cancer 64, 827-832.
37. CHIAVEGATO A., BOCHATON-PIALLAT M.L., D'AMORE E., SATORE S. & GABBIANI G. (1995) Expression of myosin heavy chain isoforms in mammary epithelial cells and in myofibroblasts from different fibrotic settings during neoplasia. Virchows Arch. 426, 77-86.
38. CHUNG L.W. (1991) Fibroblasts are critical determinants in prostatic cancer growth and dissemination. Cancer Metas. Rev. 10, 263-274.
39. CHUNG L.W., GLEAVE M.E., HSIEH J.T., HONG S.J. & ZHAU H.E. (1991) Reciprocal mesenchymal-epithelial interactions affecting prostate tumour growth and hormonal responsiveness. Cancer Surv. 11, 91-121.
40. COLLETTA A.A., WAKEFIELD L.M., HOWELL F.V., VAN ROOZENDAAL K.E., DANIELPOUR D., EBBS S.R., SPORN M.B. & BAUM M. (1990) Anti-oestrogens induce the secretion of active transforming growth factor β from human fetal fibroblasts. Br. J. Cancer 62, 405-409.
41. CUBITT A.B., HEIM R., ADAMS S.R., BOYD A.E., GROSS L.A. & TSIEN R.Y. (1995) Understanding, improving and using green fluorescent proteins. Trends Biochem. Sci. 20, 448-455.
42. CUNHA G.R., HAYASHI N. & WONG Y.C. (1991) Regulation of differentiation and growth of normal adult and neoplastic epithelia by inductive mesenchyme. Cancer Surv. 11, 73-90.
43. DJORDJEVIC B. & LANGE C.S. (1990) Clonogenicity of mammalian cells in hybrid spheroids: a new assay method. Radiat. Environ. Biophys. 29, 31-46.
44. DJORDJEVIC B. & LANGE C.S. (1991) Measurement of sensitivity to adriamycin in hybrid spheroids. Cancer Invest. 9, 505-512.
45. DONG-LE BOURHIS X., BERTHOIS Y., MILLOT G., DEGEORGES A., SYLVI M., MARTIN P.M. & CALVO F. (1997) Effect of stromal and epithelial cells derived from normal and tumourous breast tissue on the proliferation of human breast cell lines in co-culture. Int. J. Cancer 28, 42-48.
46. ELLIS M.J., SINGER C., HORNBY A., RASMUSSEN A. & CULLEN K.J. (1994) Insulin-like growth factor mediated stromal-epithelial interactions in human breast cancer. Breast Cancer Res. Treatment 31, 249-261.
47. ENDOH K., UENO K., MIYASHITA A. & SATOH T. (1993) An experimental model of acute liver injury using multicellular spheroids composed of rat parenchymal and non-parenchymal liver cells. Res. Commun. Chem. Pathol. Pharmacol. 82, 317-329.
48. ENGEBRAATEN O. (1992) Tumour cell invasion in vitro in syngeneic and heterologous systems. In: Spheroid Culture in Cancer Research Ed R. Bjerkvig, Boca Raton: CRC Press pp. 107-132.
49. 131I-labelled E4 antibodies on cells at different depth in DU 145 spheroids. Int. J. Cancer 63, 387-394.
50. FJELLBIRKELAND L., BJERKVIG R. & IAERUM O.D. (1995) Tumor fragment spheroids from human non-small-cell lung cancer maintained in organ culture. Virchows Arch. 426, 169-178.
51. FOIDART J.M., POLETTE M., BIREMBAUT P. & NOEL A. (1994) Breast cancer invasion: the key role of normal cells of host tissues. Bull. Acad. Natl. Med. 178, 533-544.
52. FOLKMAN J. (1990) What is the evidence that tumors are angiogenesis dependent? J. Natl. Cancer Inst. 82, 4-6.
53. FOLKMAN J. (1992) The role of angiogenesis in tumor growth. Semin. Cancer Biol. 3, 65-71.
54. FOLKMAN J. (1997) Angiogenesis and angiogenesis inhibition: an overview. Exs. 1-8.
55. FOSTER T.H., HARTLEY D.F., NICHOLS M.G. & HILF R. (1993) Fluence rate effects in photodynamic therapy of multicell tumor spheroids. Cancer Res. 53, 1249-1254.
56. FRANK C., WEBER K.J., FRITZ P. & FLENTJE M. (1993) Increased dose-rate effect in V79-multicellular aggregates (spheroids). Ralation to initial DNA lesions and repair. Radiother. Oncol. 26, 264-270.
57. FRENZEL K.R., SALLER R.M., KUMMERMEHR J. & SCHULTZ-HEKTOR S. (1995) Quantitative distinction of Cisplatin-sensitive and - resistant mouse fibrosarcoma cells grown in multicell tumor spheroids. Cancer Res. 55, 386-391.
58. FREYER J.P. (1992) Spheroids in Radiobiology research. In: Spheroid Culture in Cancer Research Ed. R. Bjerkvig, Boca Raton: CRC Press, pp. 217-275.
59. FREYER J.P. (1994) Rates of oxygen consumption for proliferating and quiescent cells isolated from multicellular spheroids. Adv. Exp. Med. Biol. 345, 335-342.
60. FREYER J.P., FINK N.H., SCHOR P.L., COULTER J.P., NEEMAN M. & SILLERUD L.O. (1990) A system for viably maintaining a stirred suspension of multicellular spheroids during NMR spectroscopy. NMR in Biomed. 3, 195-205.
61. FREYER J.P. & SCHOR P. (1989) Automated selective dissociation of cells from different regions of multicellular spheroids. In Vitro Cell. Dev. Biol. 25, 9-19.
62. FREYER J.P., SCHOR P.L., JARRETT K.A., NEEMAN M. & SILLERUD LO. (1991) Cellular energetics measured by phosphorous nuclear magnetic resonance spectroscopy are not correlated with chronic nutrient deficiency in multicellular tumour spheroids. Cancer Res. 51, 3831-3837.
63. FRITZ P., WEBER K.J., FRANK C. & FLENTJE M. (1996) Differential effects of dose rate and superf ractionation on survival and cell cycle of V79 cells from spheroid and monolayer culture. Radiother. Oncol. 39, 73-79.
64. FUJIWARA T., GRIMM E.A., MUKHOPADHYAY T., CAI D.W., OWEN SCHAUB L.B. & ROTH J.A. (1993) A retroviral wild-type p53 expression vector penetrates human lung cancer spheroids and inhibits growth by inducing apoptosis. Cancer Res. 53, 4129-4133.
65. FUJIWARA T., GRIMM E.A., MUKHOPADHYAY T., ZHANG W.W., OWEN SCHAUB L.B. & ROTH J.A. (1994) Induction of chemosensitivity in human lung cancer cells in vivo by adenovirus-mediated transfer of wild-type p53 gene. Cancer Res. 54, 2287-2291.
66. GABBIANI G. (1996) The cellular derivation and the life span of the myofibroblast. Pathol. Res. Pract. 192, 708-711.
67. 131I-meta-iodobenzylguanidine therapy in neuroblastoma spheroids of different sizes. Br. J. Cancer. 66, 1048-1052.
68. GERLACH J.C., SCHNOY N., ENCKE J., SMITH M.D., MUELLER C. & NEUHAUS P. (1995) Improved hepatocyte in vitro maintenance in a culture model with woven multicompartment capillary systems: electron microscopy studies. Hepatol. 22, 546-552.
69. GLEAVE M.E., HSIEH J.T., VON ESCHENBACH A.C. & CHUNG L.W. (1992) Prostate and bone fibroblasts induce human prostate cancer growth in vivo: implications for bidirectional tumor-stromal cell interactions in prostate carcinoma growth and metastasis. J. Urol. 147, 1151-1159.
70. GLIMELIUS B., NORLING B., NEDERMAN T. & CARLSSON J. (1988) Extracellular matrices in multicellular spheroids of human glioma origin: increased incorporation of proteoglycans and fibronectin as compared to monolayer. APMIS 96, 433-444.
71. GRAHAM C.H., KOBAYASHI H., STANKIEWICZ K.S., MAN S., KAPITAIN S.J. & KERBEL R.S. (1994) Rapid acquisition of multicellular drug resistance after single exposure of mammary tumour cells to antitumor alkylating agents. J. Natl. Cancer Inst. 86, 975-982.
72. GROEBE K. & MUELLER-KLIESER W. (1991) Distributions of oxygen, nutrient, and metabolic waste concentrations in multicellular spheroids and their dependence on spheroid parameters. Eur. Biophys. J. 19, 169-181.
73. GROEBE K. & MUELLER-KLIESER W. (1996) On the relation between size and diameter of human tumor spheroids. Int. J. Radiat. Oncol. Biol. Phys. 34, 395-401.
74. HAGGIE J.A., SELLWOOD R.A., HOWELL A., BIRCH J.M. & SCHOR S.L. (1987) Fibroblasts from relatives of patients with hereditary breast cancer show fetal-like behaviour in vitro. Lancet 1, 1455-1457.
75. HAUPTMANN S., DENKERT C., LOHRKE H., TIETZE L., OTT S., KLOSTERHALFEN B. & MITTERMAYER C. (1995) Integrin expression on colorectal tumor cells growing as monolayers, as multicellular tumour spheroids, or in nude mice. Int. J. Cancer 61, 819-825.
76. HAUPTMANN S., ZWADLO-KLARWASSER G., JANSEN M., KLOSTERHALFEN B. & KIRKPATRICK C.J. (1993) Macrophages and multicellular tumor spheroids:A three-dimensional model to study tumor-host interactions. Am. J. Pathol. 143, 1406-1415.
77. HEIM R. & TSIEN R.Y. (1996) Engineering green fluorescent protein for improved brightness, longer wavelengths and fluorescence resonance energy transfer. Curr. Biol. 6, 178-182.
78. HEPPNER G.H. & MILLER B.E. (1989) Therapeutic implications of tumour heterogeneity. Semin. Oncol. 16, 91-105.
79. HEWITT R.E., POWE D.G., CARTER G.I. & TURNER D.R. (1993) Desmoplasia and its relevance to colorectal tumor invasion. Int. J. Cancer 53, 62-69.
80. HLATKY L., TSIONOU C., HAHNFELDT P. & COLEMAN C.N. (1994) Mammary fibroblasts may influence breast tumor angiogenesis via hypoxia-induced vascular endothelial growth factor up-regulation and protein expression. Cancer Res. 54, 6083-6086.
81. HOFLAND L.J., VAN DER BURG B., VAN EIJCK C.H., SPRIJ D.M., VAN KOETSVELD P.M. & LAMBERTS S.W. (1995) Role of tumour-derived fibroblasts in the growth of primary cultures of human breast-cancer cells: effects of epidermal growth factor and the somatostatin analogue octreotide. Int. J. Cancer 60, 93-99.
82. HOFMANN-WELLENHOF R., FINK PUCHES R., SMOLLE J., HELIGE C., TRITTHART H.A. & KERL H. (1995) Correlation of melanoma cell motility and invasion in vitro. Melanoma Res. 5, 311-319.
83. HOWLETT A.R. & BISSELL M.J. (1993) The influence of tissue microenvironment (stroma and extracellular matrix) on the development and function of mammary epithelium. Epith. Cell Biol. 2, 79-89.
84. HOWLETT A.R., PETERSEN O.W., STEEG P.S. & BISSELL M.J. (1994) A novel function for the nm23-H1 gene: overexpression in human breast carcinoma cells leads to the formation of basement membrane and growth arrest. J. Natl. Cancer Inst. 86, 1838-1844.
85. HUELSER D.F. (1992) Intercellular communication in three-dimensional culture. In: Spheroid Culture in Cancer Research (Ed. by Bjerkvig R.), pp. 172-196, CRC Press Boca Raton.
86. INCH W.R., MCCREDIE J.A. & SUTHERLAND R.M. (1970) Growth of nodular carcinomas in rodents compared with multi-cell spheroids in tissue culture. Growth 34, 271-282.
87. IWASAKI K., KIKUCHI H., MIYATAKE S., AOKI T., YAMASAKI T. & ODA Y. (1990) Infiltrative and cytolytic activities of lymphokine-activated killer cells against a human glioma spheroid model. Cancer Res. 50, 2529-2436.
88. JÄÄSKELÄINEN J., KALLIOMÄKI P., PAETAU A. & TIMONEN T. (1989) Effect of LAK cells against three-dimensional tumor tissue. In vitro study using multi-cellular human glioma spheroids as targets. J. Immunol. 142, 1036-1045.
89. JÄÄSKELÄINEN J., LEHTONEN E., HEIKKILA P., KALLIOMAKI P. & TIMONEN T. (1990) Damage to multicellular human H-2 glioma sphera oids inkubated with LAK cells: an ultrastructural study. J. Natl. Cancer Inst. 82, 497-501.
90. JAMES N.H., MOLLOY C.A., SOAMES A.R., FRENCH N.J. & ROBERTS R.A. (1992) An in vitro model of rodent nongenotoxic hepato-carcinogenesis. Exp. Cell Res. 203, 407-419.
91. JANUSZ M.J. & HARE M. (1993) Cartilage degradation by cocultures of transformed macrophages and fibroblast cell lines. A model of metalloproteinase-mediated connective tissue degradation. J. Immunol. 150, 1922-1931.
92. JURIMA-ROMET M., CASLEY W.L., NEU J.M. & HUANG H.S. (1995) Induction of CYP3A and associated terenadine N-dealkylation in rat hepatocytes cocultured with 3T3 cells. Cell. Biol. Toxicol. 11, 313-327.
93. KAMMERER R. & VON KLEIST S. (1995) The influence of the local environment on tissue architecture of colorectal carcinoma (CRC) cell aggregates and its consequence for tumour attack by lymphocytes in vitro and in vivo. Eur. J. Cancer 31A, 2324-2329.
94. KARBACH U., GERHARZ C.D., GROEBE K., GABBERT H.E. & MUELLER-KLIESER W. (1992) Rhabdomyosarcoma spheroids with central proliferation and differentiation. Cancer Res. 52, 474-477.
95. KAWATA M., SEKIYA S., KERA K., KIMURA H. & TAKAMIZAWA H. (1991) Neural rosette formation within in vitro spheroids of a clonal teratocarcinoma cell line, PA-1/NR: role of extracellular matrix components in the morphogenesis. Cancer Res. 51, 2655-2669.
96. KLUENDER I. & HUELSER D.F. (1993) Beta galactosidase activity in transfected Ltk- cells is differentially regulated in monolayer and in spheroid cultures. Exp. Cell. Res. 207, 155-162.
97. KNUECHEL R., FEICHTINGER J., RECKTENWALD A., HOLLWEG H.G., FRANKE P., JAKSE G., RAMMAL E. & HOFSTAEDTER F. (1988) Interactions between bladder tumour cells as tumor spheroids from the cell line J82 and human endothelial cells in vitro. J.Urol. 139, 640-645.
98. KNUECHEL R., HOFSTADTER F., JENKINS W.E.A. & MASTERS J.R.W. (1989) Sensitivities of monolayers and spheroids of the human bladder cancer cell line MGH-U1 to the drugs used for intravesical chemotherapy. Cancer Res. 49, 1397-1401.
99. KNUECHEL R., KENG P., HOFSTAEDTER F., LANGMUIR V., SUTHERLAND R.M. & PENNEY D.P. (1990) Differentiation patterns in two- and three-dimensional culture systems of human squamous carcinoma cell lines. Am. J. Pathol. 137, 725-736.
100. KNUECHEL R., SIEBERT-WELLNHOFER A., TRAUB O. & DERMIETZEL R. (1996) Connexin expression and intercellular communication in two- and three-dimensional in vitro cultures of human bladder carcinoma. Am. J. Pathol. 4, 1321-1332.
101. KNUECHEL R. & SUTHERLAND R.M. (1990) Recent developments in research with human tumor spheroids. Cancer J. 3, 234-243.
102. KNUECHEL R. & SUTHERLAND R.M. (1992) Cell differentiation and heterogeneity in spheroid culture. In: Spheroid Culture in Cancer Research (Ed. by Bjerkvig R.), pp. 159-170, CRC Press Boca Raton.
103. KOBAYASHI H., MAN S., GRAHAM C.H., KAPITAIN S.J., TEICHER A. & KERBEL S. (1993) Acquired multicellular-mediated resistance to alkylating agents in cancer. Proc. Natl. Acad. Sci. USA 90, 3294-3298.
104. KOIDE N., SAKAGUCHI K., KOIDE Y., ASANO K., KAWAGUCHI M., MATSUSHIMA H., TAKENAMI T., SHINJI T., MORI M. & TSUJI T. (1990) Formation of multicellular spheroids composed of adult rat hepatocytes in dishes with positively charged surfaces and under other nonadherent environments. Exp. Cell Res. 186, 227-235.
105. KONUR A., KRAUSE S.W., REHLI M., KREUTZ M. & ANDREESEN R. (1996a) Human monocytes induce a carcinoma cell line to secrete high amounts of nitric oxide. J.Immunol. 157, 2109-2115.
106. KONUR A., KREUTZ M., KNUECHEL R., KRAUSE S.W. & ANDREESEN R. (1996b) Three-dimensional co-culture of human monocytes and macrophages with tumour cells: Analysis of macrophage differentiation and activation. Int. J. Cancer 66, 645-652.
107. KRISHNAN E.C., MENON C.D., KRISHNAN L. & JEWELL W.R. (1980) Deficiency in maturation process of macrophages in human cancer. J. Natl. Cancer Inst. 65, 273-276.
108. KUNZ-SCHUGHART L.A. & PREYER J.P. (1997) Adaptation of an automated selective dissociation procedure to multicellular spheroids of oncogene-transformed fibroblasts, In Vitro Cell. Dev. Biol. 33A, 73-76.
109. KUNZ-SCHUGHART L.A., GROEBE K. & MUELLER-KLIESER W. (1996) Three-dimensional cell culture induces novel proliferative and metabolic alterations associated with oncogenic transformation. Int. J. Cancer 66, 578-586.
110. KUNZ-SCHUGHART L.A., HABBERSETT R.C. & FREYER J.P. (1997) Mitochondrial function in oncogene transfected rat fibroblasts isolated from multicellular spheroids. Am. J. Physiol. (Cell Physiol.) 273, 42, 1487-1495
111. LADEROUTE K.R., MURPHY B.J., SHORT S.M., GRANT T.D., KNAPP A.M. & SUTHERLAND R.M. (1992) Enhancement of transforming growth factor-a synthesis in multicellular tumour spheroids of A431 squamous carcinoma cells. Br. J. Cancer 65, 157-162.
112. LAIRD A.K. (1964) Dynamics of tumour growth. Br. J. Cancer 18, 490-501.
113. LAIRD A.K. (1965) Dynamics of tumour growth. Comparison of growth rates and extrapolation of growth curve to one cell. Br. J. Cancer 19, 278-291.
114. LANGE C.S., DJORDJEVIC B. & BROCK W.A. (1992) The hybrid spheroid clonogenic assay for the intrinsic radio- and chemo-sensitivities of human tumors. Int. J. Radiat. Oncol. Biol. Phys. 24, 511-517.
115. LANIER L.L. & PHILLIPS J.H. (1992) Natural killer cells. Curr. Op. Immunol. 4, 38-42.
116. LAZAR A., MANN H.J., REMMEL R.P., SHATFORD R.A., CERRA F.B. & HU W.S. (1995) Extended liver-specific functions of porcine hepatocyte spheroids entrapped in collagen gel. In Vitro Cell. Dev. Biol. 31A, 340-346.
117. LEFEBVRE M.F., GUILLOT C., CREPIN M. & SAEZ S. (1995) Influence of tumor derived fibroblasts and 1,25 dihydroxyvitamin D3 on growth of breast cancer cell lines. Breast Cancer Res. Treat. 33, 189-197.
118. LEONE A., FLATOW U., VAN HOUTTE K. & STEEG P.S. (1993) Transfection of human nm23-H1 into the human MDA-MB-435 breast carcinoma cell line: effects on tumor metastatic potential, colonization, and enzymatic activity. Oncogene 8, 2325-2333.
119. LI A.P., COBURN S.M. & BECK D.J. (1992) A simplified method for the culturing of primary adult rat and human hepatocytes as multicellular spheroids. In Vitro Cell. Dev. Biol. 28A, 673-677.
120. LIN Q.C. & BISSELL M. (1993) Multi-faceted regulation of cell differentiation by extracellular matrix. FASEB J. 7, 737-743.
121. LIN K.H., MAEDA S. & SAITO T. (1995) Long-term maintainance of liver-specific functions in three-dimensional culture of adult rat hepatocytes with a porous gelatin sponge support. Biotechnol. Appl. Biochem. 21, 19-27.
122. LUND-JOHANSEN M., BJERKVIG R. & RUCKLIDGE G.J. (1992) Tumor spheroids from monolayer culture. In: Spheroid Culture in Cancer Research (Ed. by Bjerkvig R.), pp. 4-18, CRC Press Boca Raton.
123. LYBARGER L., DEMPSEY D., FRANEK K.J. & CHERVENAK R. (1996) Rapid generation and flow cytometric analysis of stable GFP-expressing cells. Cytometry 25, 211-220.
124. 131I]-meta-iodobenzylguanidine: Implications for the targeted radiotherapy of neuroblastoma. Eur. J. Cancer 31, 576-581.
125. MAKIYAMA N., MATSUI H., TSUJI H. & ICHIMURA K. (1991) Attachment and invasion of high- and low-metastatic clones of RCT sarcoma in a three-dimensional culture system. Clin. Exp. Metastasis 9, 411-425.
126. MANSBRIDGE J.N., AUSSERER W.A., KNAPP M.A. & SUTHERLAND R.M. (1994) Adaptation of EGF receptor signal transduction to three-dimensional culture conditions: changes in surface receptor expression and protein tyrosine phosphorylation. J. Cell. Physiol. 161, 374-382.
127. MANSBRIDGE J.N., KNUECHEL R., KNAPP A.M. & SUTHERLAND R.M. (1992) Importance of tyrosine phosphatases in the effects of cell-cell contact and microenvironment on EGF-stimulated tyrosine phosphorylation. J. Cell. Physiol. 151, 433-442.
128. MANTOVANI A., BOTTAZZI B., COLOTTA F., SOZZANI S. & RUCO L. (1992) The origin and function of tumor-associated macrophages. Immunol. Today 13, 265-270.
129. MAREEL M.M., VAN ROY F.M. & DE BAETSELIER P. (1990) The invasive phenotype. Cancer Metastasis Rev. 9, 45-62.
130. MARTIN M., PUJUGUET P. & MARTIN F. (1996) Role of stromal myofibroblasts infiltrating colon cancer in tumor invasion. Pathol. Res. Pract. 192, 712-717.
131. MARUSIC M., BAJZER Z., VUC-PAVLOVIC S. & FREYER J.P. (1994) Tumor growth in vivo and as multicellular spheroids compared by mathematical models. Bull. Math. Biol. 56, 617-631.
132. MATSUSHITA T., IJIMA H., KOIDE N. & FUNATSU K. (1991) High albumin production by multicellular spheroids of adult rat hepatocytes formed in the pores of polyurethane foam. Appl. Microbiol. Biotechnol. 36, 324-326.
133. MONZ B., KARBACH U., GROEBE K. & MUELLER-KLIESER W. (1996) Proliferation and oxygenation status of WiDr spheroids in different lactate and oxygen environments. Oncol. Rep. 1, 1177-1183.
134. MUELLER-KLIESER W. (1984) Microelectrode measurements of oxygen tension distributions in multicellular spheroids cultured in spinner flasks. In: Spheroids in Cancer Research: Methods and Perspectives, eds H. Acker, J. Carlsson, R. Durand, R.M. Sutherland, New York: Springer-Verlag. pp. 24-49.
135. MUELLER-KLIESER W. (1987) Multicellular spheroids. A review on cellular aggregates in cancer research. J. Cancer Res. Clin. Oncol. 113, 101-122.
136. MUELLER-KLIESER W. (1997) Three-dimensional cell cultures: from molecular mechanisms to clinical applications. Am. J. Physiol. in press.
137. 2 consumption of multicellular spheroids during development of necrosis. Adv. Exp. Med. Biol. 191, 775-784.
138. MUELLER-KLIESER W., FREYER J.P. & SUTHERLAND R.M. (1986) Influence of glucose and oxygen supply conditions on the oxygenation of multicellular spheroids. Br. J. Cancer 53, 345-353.
139. MURPHY B.J., LADEROUTE K.R., VREMAN H.J., GRANT T.D., GILL N.S., STEVENSON D.K. & SUTHERLAND R.M. (1993) Enhancement of heme oxygenase expression and activity in A431 squamous carcinoma multicellular tumor spheroids. Cancer Res. 53, 2700-2703.
140. NEEMAN M., JARRETT K.A., SILLERUD L.O. & FREYER J.P. (1991) Self-diffusion of water in multicellular spheroids measured by magnetic resonance microimaging. Cancer Res. 51, 4072-4079.
141. NEEMAN M., ABRAMOVITCH R., SCHIFFENBAUER Y.S. & TEMPEL C. (1997) Regulation of angiogenesis by hypoxic stress: from solid tumours to the ovarian follicle. Int. J. Exp. Path. 78, in press.
142. NEEMAN M., ABRAMOVITCH R., TEMPEL C., MEIR G., ITIN A., SHWEIKI D. & KESHET E. (1993) NMR microimaging of tumor angiogenesis: directed capillary growth into hypoxic regions of multicellular spheroids. Proc. Soc. Magn. Reson. Med. 1, 194 (extended abstract).
143. NEHLS V. & DRENCKHAHN D. (1995) A microcarrier-based cocultivation system for the investigation of factors and cells involved in angiogenesis in three-dimensional fibrin-matrices in vitro. Histochem. Cell. Biol. 104, 459-466.
144. NEMOTO N., SAKURAI J. & FUNAE Y. (1995) Maintenance of phenobarbital-inducibte Cyp2b gene expression in C57BU6 mouse hepatocytes in primary culture as spheroids. Arch. Biochem., Biophys. 316, 362-369.
145. NEUBER K., STEINRUCKE K., KOWALZICK L., KOHLER I. & RING J. (1995) Cytokine-mediated effects of peripheral blood mononuclear cells from patients with atopic eczema on keratinocytes (HaCaT) in a new coculture system. Br. J. Dermatol. 133, 750-756.
146. NISHIKAWA Y., TOKUSASHI Y., KADOHAMA T., NISHIMORI H. & OGAWA K. (1996) Hepatocytic cells form bile duct-like structures within a three-dimensional collagen matrix. Exp. Cell. Res. 223, 357-371.
147. NIWA T., KOIDE N., TSUJI T., IMAOKA S., ISHIBASHI F., FUNAE Y. & KATAGIRI M. (1996) Cytochrome P450s of isolated rat hepatocytes in spheroid and monolayer cultures. Res. Commun. Mol. Pathol. Pharmacol. 91, 372-378.
148. NOEL A., MUNAUT C., NUSGENS B., LAPIERE C.M. & FOIDARD J.M. (1993) Different mechanisms of extracellu-lar matrix remodeling by fibroblasts in response to human mammary neoplastic cells. Invas. Metast. 13, 72-81.
149. NYBERG S.L., PESHWA M.V., PAYNE W.D., HU W.S. & CERRA F.B. (1993) Evolution of the bioartificial liver: the need for randomized clinical trials. Am. J. Surg. 166, 512-521.
150. NYGAARD S.J., PEDERSEN P.H., MIKKELSEN T., TERZIS A.J., TYSNES O.B. & BJERKVIG R. (1995) Glioma cell invasion visualized by scanning confocal laser microscopy in an in vitro co-culture system. Invasion-Metastasis 15, 179-188.
151. OFFNER F.A., BIGALKE I., SCHIEFER J., WIRTZ H.-C., KLOSTERHALFEN B., FEICHTINGER H. & KIRKPATRICK C.J. (1993) Interaction of human malignant melanoma tumour spheroids with endothelium and reconstituted basement membrane: modulation by RGDS. Int.J. Cancer. 54, 506-512.
152. OFFNER F.A., WIRTZ H.-C., SCHIEFER J., BIGALKE I., KLOSTERHALFEN B., BITTINGER F., MITTERMAYER C. & KIRKPATRICK C.J. (1992) Interaction of human malignant melanoma (ST-ML12) tumour spheroids with endothelial cell monolayers: damage to endothelium by oxygen derived free radicals. Am. J. Pathol. 141, 601-610.
153. OLIVE P.L. & DURAND R.E. (1994) Drug and radiation resistance in spheroids: cell contact and kinetics. Cancer Metastasis Rev. 13, 121-138.
154. OTA K., SAITO S., HAMASAKI K., TANAKA N. & ORITA K. (1996) Transplantation of xenogeneic hepatocytes: three-dimensionally cultured hepatocytes (spheroid) transplantation into the spleen. Transplant. Proc. 28, 1430-1432.
155. PAULUS W., HUETTNER C. & TONN J.C. (1994) Collagens, integrins and the mesenchymal drift in glioblastomas: a comparison of cultures biopsy specimens, spheroids and early monolayer cultures. Int. J. Cancer 58, 841-846.
156. PERVEZ S., KIRKLAND S.C., EPENETOS A.A., MOOR W.J., EVANS D.J. & KRAUSZ T. (1989) Effect of polarity and differentiation on antibody localization in multicellular tumour spheroids and xenograft models and its potential importance for in vivo immunotargeting. Int. J. Cancer 44, 940-947.
157. PESHWA M.V., WU F.J., SHARP H.L., CERRA F.B. & HU W.S. (1996) Mechanistics of formation and ultrastructural evaluation of hepatocyte spheroids. In Vitro Cell. Dev. Biol. 32A, 197-203.
158. POWELL C.M., CRANOR M.L. & ROSEN P.P. (1995) Pseudoangiomatous stromal hyperplasia (PASH). A mammary stromal tumour with myofibroblastic differentiation. Am. J. Surg. Pathol. 19, 270-277.
159. RAJU U., CRISSMAN J.D., ZARBO R.J. & GOTTLIEB C. (1990) Epitheliosis of the breast. An immunohistochemical characterization and comparison to malignant intraductal proliferations of the breast. Am. J. Surg. Pathol. 14, 939-947.
160. RAK J., MITSUHASHI Y., ERDOS V., HUANG S.N., FILMUS J. & KERBEL R.S. (1995) Massive programmed cell death in intestinal epithelial cell induced by three-dimensional growth conditions: suppression by mutant c-H-ras oncogene expression. J. Cell. Biol. 131, 1587-1598.
161. REDDY N.M.S., CIEZKA K.A., ROZENBLYUM S. & LANGE C.S. (1994) Is there a cell-to-cell contact effect on the x-ray dose survival response of mammalian cells? Scanning Microscopy 8, 621-629.
162. ROMERO F.J., ZUKOWSKI D. & MUELLER-KLIESER W. (1997) Glutathione content of V79 cells in two- and three-dimensional culture. Am. J. Physiol., 272, C1507-C1512.
163. RONEN S.M., RUSHKIN E. & DEGANI H. (1992) Lipid metabolism in large T47D human breast cancer spheroids: 31P- and 13C-NMR studies of choline and ethanolamine uptake. Biochim. Biophys. Acta 1138, 203-212.
164. RØNNOV-JESSEN L. & PETERSEN O.W. (1993) Induction of alpha-smooth muscle actin by transforming growth factor-beta 1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia. Lab. Invest. 68, 696-707.
165. RØNNOV-JESSEN L., PETERSEN O.W. & BISSELL M.J. (1996) Cellular changes involved in conversion of normal to malignant breast: importance of stromal reaction. Physiol. Rev. 76, 69-125.
166. RØNNOV-JESSEN L., PETERSEN O.W., KOTELIANSKY V.E. & BISSELL M.J. (1995) The origin of myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. J. Clin. Invest. 95, 859-873.
167. RØNNOV-JESSEN L., VAN DEURS B., NIELSEN M. & PETERSEN O.W. (1992) Identification, paracrine generation, and possible function of human breast carcinoma myofibroblasts in culture. In Vitro Cell. Dev. Biol. 28A, 273-283.
168. ROSEN P.P. (1993) Proliferative breast 'disease'. An unresolved diagnostic dilemma. Cancer 71, 3798-3807.
169. ROSKELLEY C.D., SREBROW A. & BISSELL M. (1995) A hierarchy of ECM-mediated signalling regulates tissue specific gene expression. Curr. Opin. Cell Biol. 7, 736-747.
170. SACKS P.G., HARRIS D. & CHOU T.-C. (1995) Modulation of growth and proliferation in squameous carcinoma by retinoic acit: A rationale for combination therapy with chemotherapeutic agents. Int. J. Cancer 61, 409-415.
171. SCHEM B.-C. & DAHL O. (1992) Use of spheroids in hyperthermia research. In: Spheroid Culture in Cancer Research Ed. R. Bjerkvig, Boca Raton: CRC Press, pp. 307-320.
172. SCHMITTGEN T.D., AU J.L-S., WIENTJES M.G., BADALAMENT R.A. & DRAGO J.R. (1991a) Cultured human bladder tumors for pharmacodynamic studies. J. Urol. 145, 203-207.
173. SCHMITTGEN T.D., WIENTJES M.G., BADALAMENT R.A. & AU J.L.-S. (1991b) Pharmacodynamics of mitomycin C in cultured human bladder tumors. Cancer Res. 51, 3849-3856.
174. SCHUETZE K. & CLEMENT-SENGEWALD A. (1994) Catch and move -cut or fuse. Nature 368, 667-669.
175. SCHUSTER U., BÜTTNER R., HOFSTÄDTER F. & KNÜCHEL R. (1994) A heterologous in vitro coculture system to study interaction between human bladder cancer cells and fibroblasts. J. Urol. 151, 1707-1711.
176. SHIRAHA H., KOIDE N., HADA H., UJIKE K., NAKAMURA M., SHINJI T., GOTOH S. & TSUJI T. (1996) Improvement of serum amino acid profile in hepatic failure with the bioartificial liver using multicellular hepatocyte spheroids. Biotechnol. Bioeng. 50, 416-421.
177. SHWEIKI D., NEEMAN M., HIN A. & KESHET E. (1995) 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.
178. SILLERUD L.O., FREYER J.P., NEEMAN M. & MATTINGLY M.A. (1990) Proton NMR microscopy of multicellular spheroid morphology. Magn. Res. Med. 3, 195-205.
179. SIZIOPIKOU K.P., HARRIS J.E., CASEY L., NAWAS Y. & BRAUN D.P. (1991) Impaired tumouricidal function of alveolar macrophages from patients with non-small cell lung cancer. Cancer 68, 1035-1044.
180. STEINBACH P., KRIEGMAIR M., BAUMGARTNER R., HOFSTÄDTER F. & KNÜCHEL R. (1994) Intravesical instillation of 5-aminolevulinic acid: The fluorescent metabolite is limited to urothelial cells. Urol. 44, 676-681.
181. STEINBACH P., WEINGANDT H., BAUMGARTNER R., KRIEGMAIR M., HOFSTÄDTER F. & KNÜCHEL R. (1995) Cellular fluorescence of the endogenous photosensitizer protoporphyrin IX following exposure to 5-aminolevulinic acid. Photochem. Photobiol. 62, 887-895.
182. STUSCHKE M., BUDACH V., BUDACH W., FELDMANN H.-J. & SACK H. (1992a) Radioresponsiveness, sublethal damage repair and stem cell rate in spheroids from three human tumor cell lines: Comparison with xenograft data. Int. J. Rad. Oncol. Biol. 24, 119-126.
183. STUSCHKE M., BUDACH V., KLAES W. & SACK H. (1992b) Radioresponsiveness, repair capacity and stem cell fraction in human soft tissue tumors: An in vitro study using multicellular spheroids and the colony assay. Int. J. Rad. Oncol. Biol. 23, 69-80.
184. STUSCHKE M., BUDACH V. & SACK H. (1993a) Radioresponsiveness of human glioma, sarcoma, and breast cancer spheroids depends on tumor differentiation. Int. J. Rad. Oncol. Biol. 27, 627-636.
185. STUSCHKE M., BUDACH V., KALFF R.L., SACK H., BAMBERG M., REINHARDT V. & FELDMANN H.-J. (1993b) Spheroid control, of malignant glioma cell lines after fractionated irradiation: relation to the surviving fraction at 2 Gy and colony forming efficiencies in a soft agar clonogenic assay. Radiother. Oncol. 27, 245-251.
186. STUSCHKE M., BUDACH V., STRÜBEN G., STREFFER C. & SACK H. (1995) Heterogeneity in the fractionation sensitivities of human tumor cell lines: Studies in a three-dimensional model system. Int. J. Rad. Oncol. Biol. 32, 395-408.
187. SUTHERLAND R.M. (1988) Cell and environment interactions in tumour microregions: the multicell spheroid model. Sci. 240, 177-184.
188. SUTHERLAND R.M., INCH W.R. & MCCREDIE J.A. (1971) Phytohemagglutinin (PHA) -induced transformation of lymphocytes from patients with cancer. Cancer 27, 574-578.
189. SUTHERLAND R.M., INCH W.R., MCCREDIE J.A. & KRUUV J. (1970) A multi-component radiation survival curve using an in vitro tumor model. Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 18, 491-495.
190. SUTHERLAND R.M., MCCREDIE J.A. & INCH W.R. (1971) Growth of multicell spheroids in tissue culture as a model of nodular carcinomas. J. Natl. Cancer Inst. 46, 113-120.
191. TAKEZAWA T., YAMAZAKI M., MORI Y., YONAHA T. & YOSHIZATO K. (1992) Morphological and immuno-cytochemical characterization of a hetero-spheroid composed of fibroblasts and hepatocytes. J. Cell Sci. 101, 495-501.
192. TEARE G.F., HORAN P.K., SLEZAK S.E., SMITH C. & HAY J.B. (1991) Long-term tracking of lymphocytes in vivo: The migration of PKH-labeled lymphocytes. Cell. Immunol. 134, 157-170.
193. TEUTSCH H.F., GOELLNER A. & MUELLER-KLIESER W. (1995) Glucose levels and succinate and lactate dehydrogenase activity in EMT6/Ro tumor spheroids. Eur. J. Cell Biol. 66, 302-307.
194. THEODORESCU D., SHEEHAN C. & KERBEL R.S. (1993) TGF-β gene expression depends on tissue architecture. In Vitro Cell. Dev. Biol. 29A, 105-108.
195. THOMPSON T.C., TIMME T.L., KADMON D., PARK S.H., EGAWA S. & YOSHIDA K. (1993) Genetic predisposition and mesenchymal-epithelial interactions in ras+myc-induced carcinogenesis in reconstituted mouse prostate. Mol. Carcinog. 7, 165-179.
196. THOMSEN L.L., BAGULEY B.C. & WILSON W.R. (1992) Nitric oxide: its production in host-cell-infiltrated EMT6 spheroids and its role in tumour cell killing by flavone-8-acetic acid and 5,6-dimethylxanthenone-4-acetic acid. Cancer Chemother. Pharmacol. 31, 151-155.
197. TOFILON P.J., ARUNDEL C.M. & DEEN D.F. (1987) Response to BCNU of spheroids grown from mixtures of drug-sensitive and drug-resistant cells. Cancer Chemother. Pharmacol. 20, 89-95.
198. TOFILON P.J., BUCKLEY N. & DEEN D.F. (1984) Effect of cell-cell interactions on drug-sensitivity and growth of drug-sensitive and -resistant tumor cells in spheroids. Sci. 226, 862-864.
199. TONG J.Z., SARRAZIN S., CASSIO D., GAUTHIER F. & ALVAREZ F. (1994) Application of spheroid culture to human hepatocytes and maintainance of their differentiation. Biol. Cell 81, 77-81.
200. TSUJI T. & KARASEK M.A. (1985) A new method for obtaining scanning electron microscopic images of the reorganization process of human dermal microvascular endothelium in vitro. J. Microsc. 137, 75-83.
201. UENO K., KOBAYASHI A., TAKEGAWA N. & SATOH T. (1996) Rapid formation of multicellular spheroids composed of Propionibacterium acnes pretreated adult rat liver cells by rotary culture and their immunological properties. Res. Commun. Chem. Pathol. Pharmacol. 90, 373-387.
202. UENO K., MIYASHITA A., ENDOH E., TAKEZAWA T., YAMAZAKI M., MORI Y. & SATOH T. (1992) Formation of multicellular spheroids composed of rat hepatocytes. Res. Commun. Chem. Pathol. Pharmacol. 77, 107-120.
203. UTESCH D. & OESCH F. (1992) Dependency of the in vitro stabilization of differentiated functions in liver parenchymal cells on the type of cell line used for co-culture. In Vitro Cell. Dev. Biol. 28A, 193-198.
204. VAN ROOZENDAAL C.E., VAN OOIJEN B., KLIJN J.G., CLAASSEN C., EGGERMONT A.M., HENZEN-LOGMANS S.C. & FOEKENS J.A. (1992) Stromal influences on breast cancer cell growth. Br. J. Cancer 65, 77-81.
205. VERMEULEN S., VANMARCK V., VANHOORDE L., VANROY F., BRACKE M. & MAREEL M. (1996) Regulation of the invasion suppressor function of the cadherin/catenin complex. Pathol Res. Pract. 192, 694-707.
206. VILLASCHI S. & NICOSIA R.F. (1994) Paracrine interactions beween fibroblasts and endothelial cells in a serum-free coculture model. Modulation of angiogenesis and collagen gel contraction. Lab. Invest. 71, 291-299.
207. WALEH N.S., BRODY M.D., KNAPP M.A., MENDONCA H.L., LORD E.M., LADEROUTE R. & SUTHERLAND R.M. (1995) Mapping of vascular endothelial growth factor-producing hypoxic cells in multicellular tumor spheroids using a hypoxia specific marker. Cancer Res. 55, 6222-6226.
208. WALEH N.S., GALLO J., GRANT T.D., MURPHY B.J., KRAMER R.H. & SUTHERLAND R.M. (1994) Selective down-regulation of integrin receptors in spheroids of squamous cell carcinoma. Cancer Res. 54, 838-843.
209. WALENTA S., DOETSCH J. & MUELLER-KLIESER W. (1990) ATP concentrations in multicellular tumor spheroids assessed by single photon imaging and quantitative bioluminescence. Eur. J. Cell Biol. 52, 389-393.
210. WALKER K.A., MAIR R., MURRAY T., HILDITCH T.E., WHELDON T.E., GREGOR A. & HANN I.M. (1990) Tumour spheroid model for the biologically targeted radiotherapy of neuroblastoma micrometastases. Cancer Res. 50, 1000s-1002s.
211. WALKER K.A., MURRAY T., HILDITCH T.E., WHELDON T.E., GREGOR A. & HANN I.M. (1988) A tumour spheroid model for antibody-targeted therapy of micrometastases. Br. J. Cancer 58, 13-16.
212. WEAVER V.M., HOWLETT A.R., LANGTON-WEBSTER B., PETERSEN O.W. & BISSELL M.J. (1995) The development of a functionally relevant cell culture model of progressive human breast cancer. Semin. Cancer Biol. 6, 175-184.
213. WEST C.M.L. & MORRE J.V. (1992) Mechanism behind the resistance of spheroids to photodynamic treatment: A flow cytometry study. Photochem. Photobiol. 55, 425-430.
214. WHELDON T.E. (1994) Targeting radiation to tumours. Int. J. Radiat. Biol. 65, 109-116.
215. WILSON K.M. & LORD E.M. (1987) Specific (EMT6) and nonspecific (WEHI-164) cytolytic activity by host cells infiltrating tumour spheroids. Br. J. Cancer 55, 141-146.
216. WINSOR C.P. (1932) The Gompertz curve as a growth curve. Proc. Natl. Acad. Sci. USA 18, 1-7.
217. WU F.J., FRIEND J.R., HSIAO C.C., ZILLIOX M.J., KO F.B., CERRA F.B. & HU W.S. (1996) Efficient assembly of rat hepatocyte spheroids for tissue engineering applications. Biotechnol. Bioeng. 50, 404-415.
218. YAGI K., TSUDA K., SERADA M., YAMADA C., KONDOH A. & MIURA Y. (1993) Rapid formation of multicellular spheroids of adult rat hepatocytes by rotation culture and their immobilization within calcium alginate. Artif. Organs 17, 929-934.
219. YAGI K., YAMADA M., SERADA N., SUMIYOSHI N., MICHIBAYASHI Y., MIURA Y. & MIZOGUCHI T. (1995) Reciprocal regulation of prothrombin secretion and tyrosine aminotransferase induction in hepatocytes. Eur. J. Biochem. 227, 753-756.
220. YUASA C., TOMITA Y., SHONO M., ISHIMURA K. & ICHIHARA A. (1993) Importance of cell aggregation for expression of liver functions and regeneration demonstrated with primary cultured hepatocytes. J. Cell. Physiol. 156, 522-530.
221. ZEMBALA M., SIEDLAR M., MARCINKIEWICZ J. & PRYJMA J. (1994) Human monocytes are stimulated for nitric oxide release in vitro by some tumour cells but not by cytokines and lipopolysaccharide. Eur. J. Immunol. 24, 435-439.
222. ZWI L.J., BAGULEY B.C., GAVIN J.B. & WILSON W.R. (1990) The use of vascularised spheroids to investigate the action of flavone acetic acid on tumour blood vessels. Br. J. Cancer 62, 231-237.