The Caco-2 cell line as a model of the intestinal barrier: Influence of cell and culture-related factors on Caco-2 cell functional characteristics

Cell Biology and Toxicology

Volumn 21, Issue 1, 2005, Pages 1-26

  Sambuy, Y ^a   De Angelis, I ^b   Ranaldi, G ^a   Scarino, M L ^a   Stammati, A ^b   Zucco, F ^c  

^a ISTITUTO NAZIONALE DELLA NUTRIZIONE   (Italy)

^b ISTITUTO SUPERIORE DI SANITÀ   (Italy)

^c CNR   (Italy)

Author keywords

Biotransformation activities; Caco 2; Clonal cell lines; Culture conditions; Differentiation; Transporters

Indexed keywords

CELL ADHESION MOLECULE; SUCRASE ISOMALTASE;

AUTOCRINE EFFECT; BIOCHEMICAL COMPOSITION; BIOTRANSFORMATION; CELL CLONE; CELL CULTURE; CELL DENSITY; CELL DIFFERENTIATION; CELL FUNCTION; CELL GROWTH; CELL HETEROGENEITY; CELL ISOLATION; CELL MATURATION; CELL SELECTION; CELL STRAIN CACO 2; CELL STRUCTURE; CELL SUBPOPULATION; COLON ADENOCARCINOMA; ENZYME SUBSTRATE; EXTRACELLULAR MATRIX; GENE EXPRESSION; HUMAN; INTESTINE CELL; INTESTINE MUCOSA; LABORATORY; LITERATURE; MEMBRANE FILTER; METHODOLOGY; MONOLAYER CULTURE; MORPHOLOGICAL TRAIT; NUTRIENT; PARACRINE SIGNALING; PRIORITY JOURNAL; REVIEW; STANDARDIZATION;

AUTOCRINE COMMUNICATION; CACO-2 CELLS; CELL ADHESION; CELL COUNT; CELL CULTURE TECHNIQUES; CELL DIFFERENTIATION; CELL PHYSIOLOGY; CLONE CELLS; CULTURE MEDIA; ENTEROCYTES; EXTRACELLULAR MATRIX; HUMANS; INTESTINAL MUCOSA; MEMBRANE TRANSPORT PROTEINS; PARACRINE COMMUNICATION; SUCRASE-ISOMALTASE COMPLEX;

EID: 20044371666     PISSN: 07422091     EISSN: None     Source Type: Journal    
DOI: 10.1007/s10565-005-0085-6     Document Type: Review

References (115)

1. Anderle P, Rakhmanova V, Woodford K, Zerangue N, Sadee W. Messenger RNA expression of transporter and ion channel genes in undifferentiated and differentiated Caco-2 cells compared to human intestines. Pharm Res. 2003;20:3-15.
2. Artursson P. Epithelial transport of drugs in cell culture. I. A model for studying the passive diffusion of drugs over intestinal absorptive (Caco-2) cells. J Pharm Sci. 1990;79:476-82.
3. Artursson P, Borchardt RT. Intestinal drug absorption and metabolism in cell cultures: Caco-2 and beyond. Pharm Res. 1997;14:1655-8.
4. Artursson P, Palm K, Luthman K. Caco-2 monolayers in experimental and theoretical predictions of drug transport. Adv Drug Deliv Rev. 2001;46:27-43.
5. Ashford M, Horspool K, Keating K, Shaw M. Evaluation of an improved culturing protocol for producing Caco-2 monolayers. J Pharm Pharmacol. 2000;52:82.
6. Bai JPF, Hsu MJP, Shier WT. Insulin-degrading enzyme in a human colon adenocarcinoma cell line (Caco-2). Pharm Res. 1995;12:513-17.
7. Bareis P, Kallay E, Bischof MG, et al. Clonal differences in expression of 25-hydroxyvitamin D(3)-1alpha-hydroxylase, of 25-hydroxyvitamin D(3)-24-hydroxylase, and of the vitamin D receptor in human colon carcinoma cells: effects of epidermal growth factor and 1alpha,25-dihydroxyvitamin D(3). Exp Cell Res. 2002;276:320-7.
8. Basora N, Desloges N, Chang Q, et al. Expression of the alpha9beta1 integrin in human colonic epithelial cells: resurgence of the fetal phenotype in a subset of colon cancers and adenocarcinoma cell lines. Int J Cancer. 1998;75:738-43.
9. Basora N, Vachon PH, Herring-Gillam FE, Perreault N, Beaulieu JF. Relation between integrin alpha7Bbeta1 expression in human intestinal cells and enterocytic differentiation. Gastroenterology. 1997;113:1510-21.
10. Basson MD, Modlin IM, Madri JA. Human enterocyte (Caco-2) migration is modulated in vitro by extracellular matrix composition and epidermal growth factor. J Clin Invest. 1992;90:15-23.
11. Basson MD, Turowski G, Emenaker NJ. Regulation of human (Caco-2) intestinal epithelial cell differentiation by extracellular matrix proteins. Exp Cell Res. 1996;225:301-5.
12. Beaulieu JF. Extracellular matrix components and integrins in relationship to human intestinal epithelial cell differentiation. Prog Histochem Cytochem. 1997;31:1-78.
13. Beaulieu J-F, Quaroni A. Clonal analysis of sucrase-isomaltase expression in the human colon adenocarcinoma Caco-2 cells. Biochem J. 1991;280:599-608.
14. Behrens I, Kamm W, Dantzig AH, Kissel T. Variation of peptide transporter (PepT1 and HPT1) expression in Caco-2 cells as a function of cell origin. J Pharm Sci. 2004;93:1743-54.
15. Behrens I, Kissel T. Do cell culture conditions influence the carrier mediated transport of peptides in Caco-2 cell monolayers? Eur J Pharm Sci. 2003;19:433-42.
16. Bestwick CS, Milne L. Alteration of culture regime modifies antioxidant defenses independent of intracellular reactive oxygen levels and resistance to severe oxidative stress within confluent Caco-2 intestinal cells. Dig Dis Sci. 2001;46:417-23.
17. Borchardt G, Luessen H, de Boer A, Verhoef J, Lehr C, Junginger H. The potential of mucoadhesivs polymers in enhancing intestinal peptide drug absorption. III. Effects of chitosan-glutamate and carbomer on epithelial tight junctions in vitro. J Control Release. 1996;39:131-8.
18. Borst P, Elferink RO. Mammalian ABC transporters in health and disease. Ann Rev Biochem. 2002;71:537-92.
19. Bravo SA, Nielsen CU, Amstrup J, Frokjaer S, Bodin B. Indepth evaluation of Gly-Sar transport parameters as a function of culture time in the Caco-2 cell model. Eur J Pharm Sci. 2004;21:77-88.
20. Briske-Anderson MJ, Finley JW, Newman SM. The influence of culture time and passage number on the morphological and physiological development of Caco-2 cells. Proc Soc Exp Biol Med. 1997;214:248-57.
21. Caro I, Boulenc X, Rousset M, et al. Characterisation of a newly isolated Caco-2 clone (TC-7), as a model of transport processes and biotransformation of drugs. Int J Pharm. 1995;116:147-58.
22. Carriere V, Lesuffleur T, Barbat A, et al. Expression of cytochrome P-450 3A in HT29-MTX and Caco-2 clone TC7. FEBS Lett. 1994;355:247-50.
23. Chantret I, Barbat A, Dussaulx E, Brattain MG, Zweibaum A. Epithelial polarity, villin expression, and enterocytic differentiation of cultured human colon carcinoma cells: a survey of twenty cell lines. Cancer Res. 1988;48:1936-42.
24. Chantret I, Rodolosse A, Barbat A, et al. Differential expression of sucrase-isomaltase in clones isolated from early and late passages of the cell line Caco-2: evidence for glucose-dependent negative regulation. J Cell Sci. 1994;107(Pt 1):213-25.
25. Chateau D, Pauquai T, Delers F, Rousset M, Chambaz J, Demignot S. Lipid micelles stimulate the secretion of triglycerides-enriched apolipoprotein B48-containing lipo-proteins by Caco-2 cells. J Cell Physiol. Published on line 27 Aug 2004.
26. Chong S, Dando SA, Morrison RA. Evaluation of Biocoat® intestinal epithelium differentiation environment (3-day cultured Caco-2 cells) as an absorption screening model with improved productivity. Pharm Res. 1997;14:1835-7.
27. Crespi CL, Penman BW, Hu M. The development of Caco-2 cells expressing high levels of cDNA-derived cytochrome P4503A4. Pharm Res. 1996;13:1635-41.
28. Cummins CL, Mangravite LM, Benet LZ. Characterizing the expression of CYP3A4 and efflux transporters (P-gp, MRP1, and MRP2) in CYP3A4-transfected Caco-2 cells after induction with sodium butyrate and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate. Pharm Res. 2001;18:1102-9.
29. Darimont C, Gradoux N, Cumin F, Baum H-P, De Pover A. Differential regulation of intestinal and liver fatty acid-binding proteins in human intestinal cell line (Caco-2): role of collagen. Exp Cell Res. 1998;244:441-7.
30. Delie F, Rubas W. A human colonie cell line sharing similarities with enterocytes as a model to examine oral absorption: advantages and limitations of the Caco-2 model. Crit Rev Ther Drug Carrier Syst. 1997;14:221-86.
31. Ekmekcioglu C, Strauss-Blasche G, Marktl W. The plasma membrane Fe(+3) reductase activity of Caco-2 cells is modulated during differentiation. Biochem Mol Biol Int. 1998;46:951-61.
32. Engle MJ, Goetz GS, Alpers DH. Caco-2 cells express a combination of colonocyte and enterocyte phenotypes. J Cell Physiol. 1998;174:362-9.
33. Engman HA, Lennernas H, Taipalensuu J, Otter C, Leidvik B, Artursson P. CYP3A4, CYP3A5, and MDR1 in human small and large intestinal cell lines suitable for drug transport studies. J Pharm Sci. 2001;90:1736-51.
34. +-independent mechanisms on different plasma membrane domains. J Nutr. 1995;125:2577-85.
35. 3-modified Caco-2 cell monolayers. J Pharmacol Exp Ther. 1999;289:1134-42.
36. Fleet JC, Wang L, Vitek O, Craig BA, Edenberg HJ. Gene expression profiling of Caco-2 BBe cells suggests a role for specific signaling pathways during intestinal differentiation. Physiol Genom. 2003;13:57-68.
37. Fogh J, Fogh JM, Orfeo T. One hundred and twenty seven cultured human tumor cell lines producing tumors in nude mice. J Natl Cancer Inst. 1977;59:221-6.
38. Gangloff M, Lai C, Van Campen D, Miller D, Norvell W, Glahn R. Ferrous iron uptake but nor transfer is down-regulated in Caco-2 cells grown in high iron serum-free medium. J Nutr. 1996;126:118-27.
39. Gauthier R, Harnois C, Drolet JF, Reed JC, Vezina A, Vachon PH. Human intestinal epithelial cell survival: differentiation state-specific control mechanisms. Am J Physiol Cell Physiol. 2001;280:C1540-54.
40. Giuliano AR, Franceschi RT, Wood RJ. Characterization of the vitamin D receptor from the Caco-2 human colon carcinoma cell line: effect of cellular differentiation. Arch Biochem Biophys. 1991;285:261-9.
41. Goto M, Masuda S, Saito H, Inui K. Decreased expression of P-glycoprotein during differentiation in the human intestinal cell line Caco-2. Biochem Pharmacol. 2003;66:163-70.
42. Grasset E, Pinto M, Dussaulx E, Zweibaum A, Desjeux JF. Epithelial properties of human colonic carcinoma cell line Caco-2: electrical parameters. Am J Physiol. 1984;247:C260-7.
43. Grès M-C, Julian B, Bourrié M, et al. Correlation between oral drug absorption in humans, and apparent drug permeability in TC-7 cells, a human epithelial intestinal cell line: comparison with the parental Caco-2 cell line. Pharm Res. 1998;15:726-33.
44. Gunshin H, Mackenzie B, Berger U, et al. Cloning and characterization of a mammalian proton-coupled metalion transporter. Nature. 1997;338:482-8.
45. Halleux C, Schneider Y. Iron absorption by Caco-2 cells cultivated in serum-free medium as in vitro model of the human intestinal barrier. J Cell Physiol. 1994;158:17-28.
46. 3 on proliferation and differentiation of Caco-2 cells. Endocrinology. 1994;134:1710-17.
47. Han O, Wessling-Resnick M. Copper repletion enhances apical iron uptake and transepithelial iron transport by Caco-2 cells. Am J Physiol. 2002;282:G527-33.
48. Harris DS, Slot JW, Geuze HJ, James DE. Polarized distribution of glucose transporter isoforms in Caco-2 cells. Proc Natl Acad Sci USA. 1992;89:7556-60.
49. Hidalgo IJ, Li J. Carrier-mediated transport and efflux mechanisms in Caco-2 cells. Adv Drug Deliv Rev. 1996;22:53-66.
50. Hidalgo IJ, Raub TJ, Borchardt RT. Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology. 1989;96:736-49.
51. Hilgers AR, Conradi RA, Burton PS. Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa. Pharm Res. 1990;7:902-10.
52. Horie K, Tang F, Borchardt RT. Isolation and characterization of Caco-2 subclones expressing high levels of multidrug resistance protein efflux transporter. Pharm Res. 2003;20:161-8.
53. Hosoya KI, Kim KJ, Lee VH. Age-dependent expression of P-glycoprotein gp170 in Caco-2 cell monolayers. Pharm Res. 1996;13:885-90.
54. Hu M, Li Y, Davitt CM, et al. Transport and metabolic characterization of Caco-2 cells expressing CYP3A4 and CYP3A4 plus oxidoreductase. Pharm Res. 1999;16:1352-9.
55. Janecki AJ, Montrose MH, Tse CM, de Medina FS, Zweibaum A, Donowitz M. Development of an endogenous epithelial Na(+)/H(+) exchanger (NHE3) in three clones of Caco-2 cells. Am J Physiol. 1999;277:G292-305.
56. Jehle PM, Fussgaenger RD, Blum WF, et al. Differential autocrine regulation of intestine epithelial cell proliferation and differentiation by insulin-like growth factor (IGF) system components. Hormone Metab Res. 1999;31:97-102.
57. Jumarie C, Malo C. Caco-2 cells cultured in serum-free medium as a model for the study of enterocytic differentiation in vitro. J Cell Physiol. 1991;149:24-33.
58. Kuvada SK, Li XF, Damstrup L, Dempsey PJ, Coffey RJ, Wiley HS. The dynamic expression of the epidermal growth factor receptor and epidermal growth factor ligand family in a differentiating intestinal epithelial cell line. Growth Factors. 1999;17:139-53.
59. Le Bacquer O, Nazih H, Blottiere H, Meynial-Denis D, Laboisse C, Darmaun D. Effects of glutamine deprivation on protein synthesis in a model of human enterocytes in culture. Am J Physiol. 2001; 281:01340-7.
60. Le Beyec J, Delers F, Jourdant F, et al. A complete epithelial organization of Caco-2 cells induces I-FABP and potentializes apolipoprotein gene expression. Exp Cell Res. 1997;236:311-20.
61. Le Ferrec E, Chesne C, Artusson P, et al. In vitro models of the intestinal barrier. The report and recommendations of the ECVAM workshop 46. Altern Lab Anim. 2001;29:649-68.
62. Lentz KA, Hayashi J, Lucisano LJ, Polli JE. Development of a more rapid, reduced serum culture system for Caco-2 monolayers and application to the biopharmaceutics classification system. Int J Pharm. 2000;200:41-51.
63. Levy P, Loreal O, Munier A, et al. Enterocytic differentiation of the human Caco-2 cell line is correlated with down-regulation of fibronectin and laminin. FEBS Lett. 1994;338:272-6.
64. Levy P, Robin H, Kornprobst M, Capeau J, Cherqui G. Enterocytic differentiation of the human Caco-2 cell line correlates with alterations in integrin signaling. J Cell Physiol. 1998;177:618-27.
65. Li N, Lewis P, Samuelson D, Liboni K, Neu J. Glutamine regulates Caco-2 cell tight junction proteins. Am J Physiol. 2004;287:G726-33.
66. Li Q, Sai Y, Kato Y, Tamai I, Tsuji A. Influence of drugs and nutrients on transporter gene expression levels in Caco-2 and LS180 intestinal epithelial cell lines. Pharm Res. 2003;20:1119-24.
67. Liang E, Chessic K, Yazdanian M. Evaluation of an accelerated Caco-2 cell permeability model. J Pharm Sci. 1999;89:336-45.
68. Lu S, Gough AW, Bobrowski WF, Stewart BH. Transport properties are not altered across Caco-2 cells with heightened TEER despite underlying physiological and ultra-structural changes. J Pharm Sci. 1996;85:270-3.
69. Mahraoui L, Rodolosse A, Barbat A, et al. Presence and differential expression of SGLT1, GLUT1, GLUT2, GLUT3 and GLUT5 hexose-transporter mRNAs in Caco-2 clones in relation to cell growth and glucose consumption. Biochem J. 1994;298:629-33.
70. Mahraoui L, Rousset M, Dussaulx E, Darmoul D, Zweibaum A, Brot-Laroche E. Expression and localization of GLUT-5 in Caco-2 cells, human small intestine, and colon. Am J Physiol. 1992;263:G312-18.
71. +/glucose cotransporter and CFTR in Caco-2 cells: relevance to cystic fibrosis. J Cell Physiol. 1998;176:472-81.
72. Mariadason JM, Arango D, Corner GA, et al. A gene expression profile that defines colon cell maturation in vitro. Cancer Res. 2002;62:4791-804.
73. Matsumoto H, Erickson RH, Gum JR, Yoshioka M, Gum E, Kim YS. Biosynthesis of alkaline phosphatase during differentiation of the human colon cancer cell line Caco-2. Gastroenterology. 1990;98:1199-207.
74. Maulen NP, Henriquez EA, Kempe S, et al. Up-regulation and polarized expression of the sodium-ascorbic acid transporter SVCT1 in post-confluent differentiated CaCo-2 cells. J Biol Chem. 2003;278:9035-41.
75. + exchangers NHE2 and NHE3 in intestinal epithelial cell line C2/bbe. Am J Physiol. 1998;275:C693-701.
76. Mordrelle A, Jullian E, Costa C, et al. EAAT1 is involved in transport of L-glutamate during differentiation of the Caco-2 cell line. Am J Physiol. 2000;279:G366-73.
77. Murnin M, Kumar A, di Li G, Brown M, Sumpio BE, Basson MD. Effects of glutamine isomers on human (Caco-2) intestinal epithelial proliferation, strain-responsiveness and differentiation. J Gastroint Surg. 2000;4:435-42.
78. Nakamura T, Sakaeda T, Ohmoto N, et al. Gene expression profiles of ABC transporters and cytochrome P4503A in Caco-2 and human colorectal cancer cell lines. Pharm Res. 2003;20:324-7.
79. Nakamura T, Sakaeda T, Ohmoto N, et al. Real-time quantitative polymerase chain reaction for MDR1, MPR1, MPR2 and CYP3A-mRNA levels in Caco-2 cell lines, human duodenal enterocytes, normal colorectal tissues and colorectal adenocarcinoma. Drug Metab Dispos. 2002;30:4-6.
80. Oguchi S, Walker WA, Sanderson IR. Differentiation and polarity alter the binding of IGF-I to human intestinal epithelial (Caco-2) cells. J Ped Gastroent Nutr. 1995;20:148-55.
81. Pan M, Malandro M, Stevens BR. Regulation of system y+ arginine transport capacity in differentiating human intestinal Caco-2 cells. Am J Physiol. 1995;268:G578-85.
82. Pan M, Stevens BR. Differentiation- and protein kinase C-dependent regulation of alanine transport via system B. J Biol Chem. 1995;270:3582-7.
83. Papaconstantinou HT, Chung DH, Zhang W, et al. Prevention of mucosal atrophy: role of glutamine and caspases in apoptosis in intestinal epithelial cells. J Gastrointest Surg. 2000;4:416-23.
84. Perdikis DA, Davies R, Zhuravkov A, Brenner B, Etter L, Basson MD. Differential effects of mucosal pH on human (Caco-2) intestinal epithelial cell motility, proliferation and differentiation. Dig Dis Sci. 1998;43:1537-46.
85. Peterson MD, Mooseker MS. Characterization of the enterocyte-like brush border cytoskeleton of the C2BBe clones of the human intestinal cell line, Caco-2. J Cell Sci. 1992;102:581-600.
86. Pinto M, Robine-Leon S, Appay M-D, et al. Enterocyte-like differentiation and polarization of the human colon carcinoma cell line Caco-2 in culture. Biol Cell. 1983;47:323-30.
87. Pons V, Peres C, Teulie JM, et al. Enterophilin-1 interacts with focal adhesion kinase and decreases beta 1 integrins in intestinal Caco-2 cells. J Biol Chem. 2003;278:21155-61.
88. Raeissi S, Hidalgo I, Segura-Aguilar J, Artursson P. Interplay between CYP3A-mediated metabolism and polarized efflux of terfenadine and its metabolites in intestinal epithelial cells Caco-2(TC7) cell monolayers. Pharm Res. 1999;16:625-32.
89. Ranaldi G, Consalvo R, Sambuy Y, Scarino ML. Permeability characteristics of parental and clonal human intestinal Caco-2 cell lines differentiated in serum-supplemented and serum-free media. Toxicol in Vitro. 2003;17:761-7.
90. Ranaldi G, Marigliano I, Vespignani I, Perozzi G, Sambuy Y. The effect of chitosan and other polycations on tight junction permeability in the human intestinal Caco-2 cell line. J Nutr Biochem. 2002;13:157-67.
91. Rocha F, Musch MW, Lishanskiy L, et al. IFN-gamma down-regulates expression of Na(+)/H(+) exchangers NHE2 and NHE3 in rat intestine and human Caco-2/BBE cells. Am J Physiol. 2001;280:C1224-32.
92. Schinkel AH, Jonker JW. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv Drug Deliv Rev. 2003;55:3-29.
93. 3. Mol Pharmacol. 1997;51:741-54.
94. Schreider C, Peignon G, Thenet S, Chambaz J, Pincon-Raymond M. Integrin-mediated functional polarization of Caco-2 cells through E-cadherin-actin complexes. J Cell Sci. 2002;115:543-52.
95. Sergent-Engelen T, Delistrie V, Schneider Y-J. Phase I and II biotrasformations in living Caco-2 cells cultivated under serum free conditions. Biochem Pharmacol. 1993;46:1393-401.
96. Sharp P, Tandy S, Yamaji S, Tennant J, Williams M, Srai S. Rapid regulation of divalent metal transporter (DMT1) protein but not mRNA expression by non-haem iron in human intestinal Caco-2 cells. FEBS Lett. 2002;510:71-6.
97. Sood R, Bear C, Auerbach W, et al. Regulation of CFTR expression and function during differentiation of intestinal epithelial cells. EMBO J. 1992;11:2487-94.
98. Sterling KM Jr, Cutroneo KR. Differentiation-dependent induction of CYP1A1 in cultured rat small intestinal epithelial cells, colonocytes, and human colon carcinoma cells: basement membrane-mediated apoptosis. J Cell Biochem. 2002;86:440-50.
99. Stierum R, Gaspari M, Dommels Y, et al. Proteome analysis reveals novel proteins associated with proliferation and differentiation of the colorectal cancer cell line Caco-2. Biochim Biophys Acta. 2003;1650:73-91.
100. Tavelin S, Grasjo J, Taipalensuu J, Ocklind G, Artursson P. Applications of epithelial cell culture in studies of drug transport. Methods Mol Biol. 2002;188:233-72.
101. Thwaites DT, Ford D, Glanville M, Simmons NL. H(+)/solute-induced intracellular acidification leads to selective activation of apical Na(+)/H(+) exchange in human intestinal epithelial cells. J Clin Invest. 1999;104:629-35.
102. Thwaites DT, McEwan GT, Brown CD, Hirst BH, Simmons NL. Na(+)-independent, H(+)-coupled transepithelial beta-alanine absorption by human intestinal Caco-2 cell monolayers. J Biol Chem. 1993;268:18438-41.
103. Tran CDH, Timmins P, Conway BR, Irwin WJ. Investigation of the coordinate functional activities of cytochrome P450 3A4 and P-glycoprotein in limiting the absorption of xenobiotics in Caco-2 cells. J Pharm Sci. 2002;91:117-28.
104. Turowski GA, Rashid Z, Hong F, Madri JA, Basson MD. Glutamine modulates phenotype and stimulates proliferation in human colon cancer cell lines. Cancer Res. 1994;54:5974-80.
105. Vachon PH, Beaulieu JF. Extracellular heterotrimeric laminin promotes differentiation in human enterocytes. Am J Physiol. 1995;268:G857-67.
106. Vachon PH, Beaulieu J-F. Transient mosaic patterns of morphological and functional differentiation in the Caco-2 cell line. Gastroenterology. 1992;103:414-23.
107. Vachon PH, Perreault N, Magny P, Beaulieu JF. Uncoordinated, transient mosaic patterns of intestinal hydrolase expression in differentiating human enterocytes. J Cell Physiol. 1996;166:198-207.
108. Vachon PH, Simoneau A, Herring-Gillman FE, Beaulieu J-F. Cellular fibronectin expression is down regulated at the mRNA level in differentiating human intestinal epithelial cells. Exp Cell Res. 1995;216:30-4.
109. Varilek GW, Neil GA, Bishop WP, Lin J, Pantazis NJ. Nerve growth factor synthesis by intestinal epithelial cells. Am J Physiol. 1995;269:G445-52.
110. Walter E, Kissel T. Transepithelial transport and metabolism of thyrotropin-releasing hormone (TRH) in monolayers of a human intestinal cell line (Caco-2): evidence for an active transport component? Pharm Res. 1994;11:1575-80.
111. Walter E, Kissel T. Heterogeneity in the human intestinal cell line Caco-2 leads to differences in transepithelial transport. Eur J Pharm Sci. 1995;3:215-30.
112. Wilson G, Hassan IF, Dix CJ, et al. Transport and permeability properties of human Caco-2 cells: an in vitro model of the intestinal epithelial cell barrier. J Contr Rel. 1990;11:25-40.
113. Woodcock S, Williamson I, Hassan I, Mackay M. Isolation and characterisation of clones from the Caco-2 cell line displaying increased taurocholic acid transport. J Cell Sci. 1991;98:323-32.
114. Yamashita A, Konishi K, Yamazaki Y, et al. New and better protocols for a short-term Caco-2 cell culture systems. J Pharm Sci. 2002;91:669-679.
115. Yu H, Cook TJ, Sinko PJ. Evidence for diminished functional expression of intestinal transporters in Caco-2 cell monolayers at high passages. Pharm Res. 1997;14:757-62.