Frizzled7 dictates embryonic morphogenesis: Implications for colorectal cancer progression

Frontiers in Bioscience

Volumn 12, Issue 12, 2007, Pages 4558-4567

  Vincan, Elizabeth ^a   Swain, Rajeeb Kumar ^b   Brabletz, Thomas ^c   Steinbeisser, Herbert ^b  

^a UNIVERSITY OF MELBOURNE   (Australia)

^b UNIVERSITY OF HEIDELBERG   (Germany)

^c UNIVERSITY OF FREIBURG   (Germany)

Author keywords

Colorectal cancer; Frizzled; Morphogenesis; Review; Wnt signalling

Indexed keywords

MAMMALIA;

FRIZZLED PROTEIN; FZD7 PROTEIN, HUMAN; G PROTEIN COUPLED RECEPTOR; UNCLASSIFIED DRUG;

COLORECTAL TUMOR; DISEASE COURSE; EMBRYO DEVELOPMENT; HUMAN; MORPHOGENESIS; PATHOLOGY; PHYSIOLOGY; REVIEW;

COLORECTAL NEOPLASMS; DISEASE PROGRESSION; EMBRYONIC DEVELOPMENT; FRIZZLED RECEPTORS; HUMANS; MORPHOGENESIS; RECEPTORS, G-PROTEIN-COUPLED;

EID: 34347269577     PISSN: 27686701     EISSN: 27686698     Source Type: Journal    
DOI: 10.2741/2410     Document Type: Article

References (91)

1. Wang H. Y., T. Liu and C. C. Malbon: Structure-function analysis of Frizzleds. Cell Signal 18, 934-941 (2006)
2. Carron C., A. Pascal, A. Djiane, J. C. Boucaut, D. L. Shi and M. Umbhauer: Frizzled receptor dimerization is sufficient to activate the Wnt/beta-catenin pathway. J Cell Sci 116, 2541-2550 (2003) (Pubitemid 36790135)
3. Kaykas A., J. Yang-Snyder, M. Heroux, K. V. Shah, M. Bouvier and R. T. Moon: Mutant Frizzled 4 associated with vitreoretinopathy traps wild-type Frizzled in the endoplasmic reticulum by oligomerization. Nat Cell Biol 6, 52-58 (2004) (Pubitemid 38425730)
4. Dann C. E., J. C. Hsieh, A. Rattner, D. Sharma, J. Nathans and D. J. Leahy: Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains. Nature 412, 86-90 (2001) (Pubitemid 32851515)
5. Wehrli M., S. T. Dougan, K. Caldwell, L. O'Keefe, S. Schwartz, D. Vaizel-Ohayon, E. Schejter, A. Tomlinson and S. DiNardo: arrow encodes an LDL-receptor-related protein essential for Wingless signalling. Nature 407, 527-530. (2000)
6. Pinson K. I., J. Brennan, S. Monkley, B. J. Avery and W. C. Skarnes: An LDL-receptor-related protein mediates Wnt signalling in mice. Nature 407, 535-538. (2000)
7. Tamai K., M. Semenov, Y. Kato, R. Spokony, C. Liu, Y. Katsuyama, F. Hess, J. P. Saint-Jeannet and X. He: LDL-receptor-related proteins in Wnt signal transduction. Nature 407, 530-535 (2000)
8. Hikasa H., M. Shibata, I. Hiratani and M. Taira: The Xenopus receptor tyrosine kinase Xror2 modulates morphogenetic movements of the axial mesoderm and neuroectoderm via Wnt signaling. Development 129, 5227-5239 (2002) (Pubitemid 35460686)
9. Yoshikawa S., R. D. McKinnon, M. Kokel and J. B. Thomas: Wnt-mediated axon guidance via the Drosophila Derailed receptor. Nature 422, 583-588 (2003) (Pubitemid 36460405)
10. Lu W., V. Yamamoto, B. Ortega and D. Baltimore: Mammalian Ryk is a Wnt coreceptor required for stimulation of neurite outgrowth. Cell 119, 97-108 (2004) (Pubitemid 39349323)
11. Cadigan K. M. and Y. I. Liu: Wnt signaling: complexity at the surface. J Cell Sci 119, 395-402 (2006)
12. Mikels A. J. and R. Nusse: Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context. PLoS Biol 4, e115 (2006)
13. Wu J., T. J. Klein and M. Mlodzik: Subcellular localization of frizzled receptors, mediated by their cytoplasmic tails, regulates signaling pathway specificity. PLoS Biol 2, E158 (2004)
14. Gordon M. D. and R. Nusse: Wnt signaling: Multiple pathways, multiple receptors and multiple transcription factors. J Biol Chem 281, 22429-22433 (2006)
15. Nusse R.: Wnt signaling in disease and in development. Cell Res 15, 28-32 (2005) (Pubitemid 41653961)
16. Moon R. T., A. D. Kohn, G. V. De Ferrari and A. Kaykas: WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet 5, 691-701 (2004) (Pubitemid 39150127)
17. Locascio A. and M. A. Nieto: Cell movements during vertebrate development: integrated tissue behaviour versus individual cell migration. Curr Opin Genet Dev 11, 464-469 (2001) (Pubitemid 32614207)
18. Thiery J. P. and J. P. Sleeman: Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7, 131-142 (2006) (Pubitemid 43278296)
19. Wallingford J. B., B. A. Rowning, K. M. Vogeli, U. Rothbacher, S. E. Fraser and R. M. Harland: Dishevelled controls cell polarity during Xenopus gastrulation. Nature 405, 81-85 (2000) (Pubitemid 30321819)
20. Wacker S., K. Grimm, T. Joos and R. Winklbauer: Development and control of tissue separation at gastrulation in Xenopus. Dev Biol 224, 428-439 (2000) (Pubitemid 30661022)
21. Kim H. J., J. R. Schleiffarth, J. Jessurun, S. Sumanas, A. Petryk, S. Lin and S. C. Ekker: Wnt5 signaling in vertebrate pancreas development. BMC Biol 3, 23 (2005)
22. Veeman M. T., J. D. Axelrod and R. T. Moon: A second canon. Functions and mechanisms of beta-cateninindependent Wnt signaling. Dev Cell 5, 367-377 (2003) (Pubitemid 37107667)
23. Willert K. and K. A. Jones: Wnt signaling: is the party in the nucleus? Genes Dev 20, 1394-1404 (2006) (Pubitemid 43830647)
24. Holstein T. W., E. Hobmayer and U. Technau: Cnidarians: an evolutionarily conserved model system for regeneration? Dev Dyn 226, 257-267 (2003) (Pubitemid 36158170)
25. Hobmayer B., F. Rentzsch, K. Kuhn, C. M. Happel, C. C. von Laue, P. Snyder, U. Rothbacher and T. W. Holstein: WNT signalling molecules act in axis formation in the diploblastic metazoan Hydra. Nature 407, 186-189 (2000)
26. Minobe S., K. Fei, L. Yan, M. Sarras Jr and M. Werle: Identification and characterization of the epithelial polarity receptor "Frizzled" in Hydra vulgaris. Dev Genes Evol 210, 258-262 (2000) (Pubitemid 30234963)
27. He X. and J. D. Axelrod: A WNTer wonderland in Snowbird. Development 133, 2597-2603 (2006) (Pubitemid 44177881)
28. Adamska M., K. Green, D. Koop, M. Adamski, D. Rokhsar and B. Degnan: Wnt Signalling at the onset of animal evolution: Lessons from Sponges. ComBio2006 Conference SYM-21-04, 57 (2006)
29. Larroux C., B. Fahey, D. Liubicich, V. F. Hinman, M. Gauthier, M. Gongora, K. Green, G. Worheide, S. P. Leys and B. M. Degnan: Developmental expression of transcription factor genes in a demosponge: insights into the origin of metazoan multicellularity. Evol Dev 8, 150-173 (2006)
30. Katoh M. and M. Katoh: Comparative integromics on FZD7 orthologs: conserved binding sites for PU.1, SP1, CCAAT-box and TCF/LEF/SOX transcription factors within 5'-promoter region of mammalian FZD7 orthologs. Int J Mol Med 19, 529-533 (2007)
31. Katoh M. and M. Katoh: Comparative genomics on Fzd7 orthologs. Int J Mol Med 15, 1051-1055 (2005)
32. Korinek V., N. Barker, P. Moerer, E. van Donselaar, G. Huls, P. J. Peters and H. Clevers: Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet 19, 379-383 (1998) (Pubitemid 28357912)
33. Gregorieff A., D. Pinto, H. Begthel, O. Destree, M. Kielman and H. Clevers: Expression pattern of Wnt signaling components in the adult intestine. Gastroenterology 129, 626-638 (2005) (Pubitemid 41096648)
34. Reya T. and H. Clevers: Wnt signalling in stem cells and cancer. Nature 434, 843-850 (2005) (Pubitemid 40558990)
35. Sato N., L. Meijer, L. Skaltsounis, P. Greengard and A. H. Brivanlou: Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 10, 55-63 (2004) (Pubitemid 38524699)
36. Assou S., T. Lecarrour, S. Tondeur, S. Strom, A. Gabell, S. Marty, L. Nadal, V. Pantesco, T. Reme, J. P. Hugnot, S. Gasca, O. Hovatta, S. Hamamah, B. J. Klein and J. De Vos: A meta-analysis of human embryonic stem cells transcriptome integrated into w web-based expression atlas. Stem cells Epub ahead of print, Jan 4 (2007)
37. Medina A., W. Reintsch and H. Steinbeisser: Xenopus frizzled 7 can act in canonical and non-canonical Wnt signaling pathways: implications on early patterning and morphogenesis. Mech Dev 92, 227-237 (2000) (Pubitemid 30155917)
38. Saburi S. and H. McNeill: Organising cells into tissues: new roles for cell adhesion molecules in planar cell polarity. Curr Opin Cell Biol 17, 482-488 (2005) (Pubitemid 41267162)
39. Witzel S., V. Zimyanin, F. Carreira-Barbosa, M. Tada and C. P. Heisenberg: Wnt11 controls cell contact persistence by local accumulation of Frizzled 7 at the plasma membrane. J Cell Biol 175, 791-802 (2006) (Pubitemid 44878511)
40. Song M. R., R. Shirasaki, C. L. Cai, E. C. Ruiz, S. M. Evans, S. K. Lee and S. L. Pfaff: T-Box transcription factor Tbx20 regulates a genetic program for cranial motor neuron cell body migration. Development 133, 4945-4955 (2006) (Pubitemid 46085060)
41. Winklbauer R., A. Medina, R. K. Swain and H. Steinbeisser: Frizzled-7 signalling controls tissue separation during Xenopus gastrulation. Nature 413, 856-860 (2001) (Pubitemid 33026854)
42. Wheeler G. N. and S. Hoppler: Two novel Xenopus frizzled genes expressed in developing heart and brain. Mech Dev 86, 203-207. (1999) (Pubitemid 29371761)
43. Djiane A., J. Riou, M. Umbhauer, J. Boucaut and D. Shi: Role of frizzled 7 in the regulation of convergent extension movements during gastrulation in Xenopus laevis. Development 127, 3091-3100 (2000) (Pubitemid 30611901)
44. Medina A. and H. Steinbeisser: Interaction of Frizzled 7 and Dishevelled in Xenopus. Dev Dyn 218, 671-680 (2000) (Pubitemid 30604919)
45. Sumanas S., P. Strege, J. Heasman and S. C. Ekker: The putative wnt receptor Xenopus frizzled-7 functions upstream of beta-catenin in vertebrate dorsoventral mesoderm patterning. Development 127, 1981-1990 (2000) (Pubitemid 30311801)
46. Swain R. K., A. Medina and H. Steinbeisser: Functional analysis of the Xenopus frizzled 7 protein domains using chimeric receptors. Int J Dev Biol 45, 259-264 (2001)
47. Medina A., R. K. Swain, K. M. Kuerner and H. Steinbeisser: Xenopus paraxial protocadherin has signaling functions and is involved in tissue separation. Embo J 23, 3249-3258 (2004) (Pubitemid 39209149)
48. Sumanas S., H. J. Kim, S. B. Hermanson and S. C. Ekker: Lateral line, nervous system, and maternal expression of Frizzled 7a during zebrafish embryogenesis. Mech Dev 115, 107-111 (2002) (Pubitemid 34615672)
49. Holmen S. L., A. Salic, C. R. Zylstra, M. W. Kirschner and B. O. Williams: A novel set of Wnt-Frizzled fusion proteins identifies receptor components that activate beta - catenin-dependent signaling. J Biol Chem 277, 34727-34735 (2002)
50. Tanaka S., T. Akiyoshi, M. Mori, J. R. Wands and K. Sugimachi: A novel frizzled gene identified in human esophageal carcinoma mediates APC/beta-catenin signals. Proc Natl Acad Sci U S A 95, 10164-10169 (1998) (Pubitemid 28415312)
51. Merle P., S. de la Monte, M. Kim, M. Herrmann, S. Tanaka, A. Von Dem Bussche, M. C. Kew, C. Trepo and J. R. Wands: Functional consequences of frizzled-7 receptor overexpression in human hepatocellular carcinoma. Gastroenterology 127, 1110-1122 (2004) (Pubitemid 39345880)
52. Vincan E., P. K. Darcy, C. A. Farrelly, M. C. Faux, T. Brabletz and R. Ramsay: Frizzled-7 dictates threedimensional organization of colorectal cancer cell carcinoids. Oncogene Epub Oct. 2 (2006)
53. Brown J. D., S. E. Hallagan, L. L. McGrew, J. R. Miller and R. T. Moo: The maternal Xenopus betacatenin signaling pathway, activated by frizzled homologs, induces goosecoid in a cell non-autonomous manner. Dev Growth Differ 42, 347-357 (2000) (Pubitemid 30662891)
54. Abu-Elmagd M., C. Garcia-Morales and G. N. Wheeler: Frizzled7 mediates canonical Wnt signaling in neural crest induction. Dev Biol 298, 285-298 (2006) (Pubitemid 44414812)
55. Burstyn-Cohen T., J. Stanleigh, D. Sela-Donenfeld and C. Kalcheim: Canonical Wnt activity regulates trunk neural crest delamination linking BMP/noggin signaling with G1/S transition. Development 131, 5327-5339 (2004) (Pubitemid 39562178)
56. Garcia-Castro M. I., C. Marcelle and M. Bronner-Fraser: Ectodermal Wnt function as a neural crest inducer. Science 297, 848-851 (2002) (Pubitemid 34839637)
57. Lewis J. L., J. Bonner, M. Modrell, J. W. Ragland, R. T. Moon, R. I. Dorsky and D. W. Raible: Reiterated Wnt signaling during zebrafish neural crest development. Development 131, 1299-1308 (2004) (Pubitemid 38443884)
58. Schubert F. R., R. C. Mootoosamy, E. H. Walters, A. Graham, L. Tumiotto, A. E. Munsterberg, A. Lumsden and S. Dietrich: Wnt6 marks sites of epithelial transformations in the chick embryo. Mech Dev 114, 143-148 (2002) (Pubitemid 34462964)
59. Schmidt C., M. Stoeckelhuber, I. McKinnell, R. Putz, B. Christ and K. Patel: Wnt 6 regulates the epithelialisation process of the segmental plate mesoderm leading to somite formation. Dev Biol 271, 198-209 (2004) (Pubitemid 38757786)
60. Borello U., V. Buffa, C. Sonnino, R. Melchionna, E. Vivarelli and G. Cossu: Differential expression of the Wnt putative receptors Frizzled during mouse somitogenesis. Mech Dev 89, 173-177 (1999) (Pubitemid 29528288)
61. Linker C., C. Lesbros, J. Gros, L. W. Burrus, A. Rawls and C. Marcelle: {beta}-Catenin-dependent Wnt signalling controls the epithelial organisation of somites through the activation of paraxis. Development 132, 3895-3905 (2005) (Pubitemid 41410254)
62. Stump R. J., S. Ang, Y. Chen, T. von Bahr, F. J. Lovicu, K. Pinson, R. U. de Iongh, T. P. Yamaguchi, D. A. Sassoon and J. W. McAvoy: A role for Wnt/betacatenin signaling in lens epithelial differentiation. Dev Biol 259, 48-61 (2003) (Pubitemid 36705527)
63. Carroll T. J., J. S. Park, S. Hayashi, A. Majumdar and A. P. McMahon: Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the Mammalian urogenital system. Dev Cell 9, 283-292 (2005) (Pubitemid 41051746)
64. De Calisto J., C. Araya, L. Marchant, C. F. Riaz and R. Mayor: Essential role of non-canonical Wnt signalling in neural crest migration. Development 132, 2587-2597 (2005) (Pubitemid 40883257)
65. Gregorieff A. and H. Clevers: Wnt signaling in the intestinal epithelium: from endoderm to cancer. Genes Dev 19, 877-890 (2005) (Pubitemid 40548056)
66. Giles R. H., J. H. van Es and H. Clevers: Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta 1653, 1-24 (2003) (Pubitemid 36627817)
67. Kirchner T. and T. Brabletz: Patterning and nuclear beta-catenin expression in the colonic adenoma-carcinoma sequence. Analogies with embryonic gastrulation. Am J Pathol 157, 1113-1121. (2000)
68. Brabletz T., A. Jung, S. Spaderna, F. Hlubek and T. Kirchner: Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression. Nat Rev Cancer 5, 744-749 (2005) (Pubitemid 41486367)
69. Thiery J. P.: Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2, 442-454 (2002)
70. Brabletz T., A. Jung, S. Reu, M. Porzner, F. Hlubek, L. A. Kunz-Schughart, R. Knuechel and T. Kirchner: Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc Natl Acad Sci U S A 98, 10356-10361 (2001) (Pubitemid 32803024)
71. Brabletz T., A. Jung, K. Hermann, K. Gunther, W. Hohenberger and T. Kirchner: Nuclear overexpression of the oncoprotein beta-catenin in colorectal cancer is localized predominantly at the invasion front. Pathol Res Pract 194, 701-704 (1998) (Pubitemid 28523944)
72. Yang J., S. A. Mani and R. A. Weinberg: Exploring a new twist on tumor metastasis. Cancer Res 66, 4549-4552 (2006)
73. Brabletz T., F. Hlubek, S. Spaderna, O. Schmalhofer, E. Hiendlmeyer, A. Jung and T. Kirchner: Invasion and metastasis in colorectal cancer: epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and beta-catenin. Cells Tissues Organs 179, 56-65 (2005) (Pubitemid 40976289)
74. Goto T., L. Davidson, M. Asashima and R. Keller: Planar cell polarity genes regulate polarized extracellular matrix deposition during frog gastrulation. Curr Biol 15, 787-793 (2005) (Pubitemid 40599936)
75. Munoz R., M. Moreno, C. Oliva, C. Orbenes and J. Larrain: Syndecan-4 regulates non-canonical Wnt signalling and is essential for convergent and extension movements in Xenopus embryos. Nat Cell Biol 8, 492-500 (2006)
76. Kaplan R. N., R. D. Riba, S. Zacharoulis, A. H. Bramley, L. Vincent, C. Costa, D. D. MacDonald, D. K. Jin, K. Shido, S. A. Kerns, Z. Zhu, D. Hicklin, Y. Wu, J. L. Port, N. Altorki, E. R. Port, D. Ruggero, S. V. Shmelkov, K. K. Jensen, S. Rafii and D. Lyden: VEGFR1-positive haematopoietic bone marrow progenitors initiate the premetastatic niche. Nature 438, 820-827 (2005) (Pubitemid 41753060)
77. Gradl D., M. Kuhl and D. Wedlich: The Wnt/Wg signal transducer beta-catenin controls fibronectin expression. Mol Cell Biol 19, 5576-5587 (1999) (Pubitemid 29339915)
78. Bissell M. J., A. Rizki and I. S. Mian: Tissue architecture: the ultimate regulator of breast epithelial function. Curr Opin Cell Biol 15, 753-762 (2003) (Pubitemid 37487969)
79. Whitehead R. H., J. K. Jones, A. Gabriel and R. E. Lukies: A new colon carcinoma cell line (LIM1863) that grows as organoids with spontaneous differentiation into crypt-like structures in vitro. Cancer Res 47, 2683-2689 (1987) (Pubitemid 17090078)
80. Hayward I. P., R. H. Whitehead, L. Ward, R. Gianello, P. Dempsey, R. Bates and G. F. Burns: Effect of TGF-beta on differentiated organoids of the colon carcinoma cell line LIM 1863. Immunol Cell Biol 73, 249-257 (1995)
81. Bates R. C. and A. M. Mercurio: Tumor necrosis factoralpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids. Mol Biol Cell 14, 1790-1800 (2003) (Pubitemid 36583533)
82. Bates R. C., D. I. Bellovin, C. Brown, E. Maynard, B. Wu, H. Kawakatsu, D. Sheppard, P. Oettgen and A. M. Mercurio: Transcriptional activation of integrin beta6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma. J Clin Invest 115, 339-347 (2005) (Pubitemid 40385475)
83. Vincan E., T. Brabletz, M. C. Faux and R. G. Ramsay: A human three-dimensional cell line model allows the study of dynamic and reversible epithelial-mesenchymal and mesenchymal-epithelial transition that underpins colorectal carcinogenesis. Cells Tissues Organs in press (2007)
84. Vincan E.: Frizzled/WNT signalling: the insidious promoter of tumour growth and progression. Front Biosci 9, 1023-1034 (2004) (Pubitemid 39060825)
85. Caldwell G. M., C. Jones, K. Gensberg, S. Jan, R. G. Hardy, P. Byrd, S. Chughtai, Y. Wallis, G. M. Matthews and D. G. Morton: The Wnt antagonist sFRP1 in colorectal tumorigenesis. Cancer Res 64, 883-888 (2004) (Pubitemid 38176888)
86. Suzuki H., D. N. Watkins, K. W. Jair, K. E. Schuebel, S. D. Markowitz, W. Dong Chen, T. P. Pretlow, B. Yang, Y. Akiyama, M. Van Engeland, M. Toyota, T. Tokino, Y. Hinoda, K. Imai, J. G. Herman and S. B. Baylin: Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet 36, 417-422 (2004) (Pubitemid 38437267)
87. Aguilera O., M. F. Fraga, E. Ballestar, M. F. Paz, M. Herranz, J. Espada, J. M. Garcia, A. Munoz, M. Esteller and J. M. Gonzalez-Sancho: Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer. Oncogene 25, 4116-4121 (2006) (Pubitemid 44024874)
88. Barker N. and H. Clevers: Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov 5, 997-1014 (2006) (Pubitemid 44835127)
89. He B., N. Reguart, L. You, J. Mazieres, Z. Xu, A. Y. Lee, I. Mikami, F. McCormick and D. M. Jablons: Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutations. Oncogene (2005)
90. Vincan E., P. K. Darcy, M. J. Smyth, E. W. Thompson, R. J. Thomas, W. A. Phillips and R. G. Ramsay: Frizzled-7 receptor ectodomain expression in a colon cancer cell line induces morphological change and attenuates tumor growth. Differentiation 73, 142-153 (2005) (Pubitemid 41632503)
91. Fujii N., L. You, Z. Xu, K. Uematsu, J. Shan, B. He, I. Mikami, L. R. Edmondson, G. Neale, J. Zheng, R. K. Guy and D. M. Jablons: An antagonist of dishevelled proteinprotein interaction suppresses beta-catenin-dependent tumor cell growth. Cancer Res 67, 573-579 (2007) (Pubitemid 46192194)