Gli and hedgehog in cancer: Tumours, embryos and stem cells

Nature Reviews Cancer

Volumn 2, Issue 5, 2002, Pages 361-372

  Ruiz i Altaba, Ariel ^a   Sánchez, Pilar ^a   Dahmane, Nadia ^a,b  

^a NEW YORK UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b CNRS   (France)

Author keywords

[No Author keywords available]

Indexed keywords

SONIC HEDGEHOG PROTEIN; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR GLI; UNCLASSIFIED DRUG; GLI PROTEIN; ONCOPROTEIN; SHH PROTEIN, HUMAN; TRANSACTIVATOR PROTEIN;

BASAL CELL CARCINOMA; BRAIN CANCER; CARCINOGENESIS; CELL DIFFERENTIATION; DISEASE ASSOCIATION; EMBRYO DEVELOPMENT; GLIOMA; MEDULLOBLASTOMA; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN SECRETION; REVIEW; SIGNAL TRANSDUCTION; SKIN CARCINOMA; STEM CELL; ANIMAL; CANCER STEM CELL; EMBRYO; HUMAN; METABOLISM; NEOPLASM;

ANIMALS; EMBRYO; HEDGEHOG PROTEINS; HUMANS; NEOPLASMS; ONCOGENE PROTEINS; SIGNAL TRANSDUCTION; TRANS-ACTIVATORS; TRANSCRIPTION FACTORS; TUMOR STEM CELLS;

EID: 0036559186     PISSN: 1474175X     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrc796     Document Type: Review

References (137)

1. Ackerman, A. B. in Ackermans' Histologic Diagnosis of Neoplastic Skin Diseases: A Method by Pattern Analysis (Ardor Scribendi Publishers, Pennsylvania, 2001).
2. Ruiz i Altaba, A. Gli proteins and Hedgehog signaling: development and cancer. Trends Genet. 15, 418-425 (1999).
3. Corcoran, R. B. & Scott, M. P. A mouse model for medulloblastoma and basal cell nevus syndrome. J. Neurooncol. 53, 307-318 (2001).
4. Wechsler-Reya, R. & Scott, M. P. The developmental biology of brain tumors. Annu. Rev. Neurosci. 24, 385-428 (2001).
5. Ingham, P. W. & McMahon, A. P. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 15, 3059-3087 (2001).
6. Ruiz i Altaba, A., Palma, V. & Dahmane, N. Hedgehog-Gli signaling and the growth of the brain. Nature Rev. Neurosci 3, 24-33 (2002).
7. Felsher, D. W. & Bishop, J. M. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol. Cell 4, 199-207 (1999).
8. Pelengaris, S., Littlewood, T., Khan, M., Elia, G. & Evan, G. Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion. Mol. Cell 3, 565-577 (1999).
9. Chin, L. et al. Essential role for oncogenic Ras in tumor maintenance. Nature 400, 468-472 (1999).
10. Fisher, G. H. et al. Induction and apoptotic regression of lung adenocarcinomas by regulation of a Kras transgene in the presence and absence of tumor suppressor genes. Genes Dev. 15, 3249-3262 (2001). References 7-10 and 12 show that the initiating event is required for tumour maintenance.
11. Dahmane, N. et al. The Shh-Gli pathway modulates the normal and abnormal growth of the dorsal brain. Development 238, 5201-5212 (2001). Demonstration of a common mechanism for the growth of the neocortex, tectum and cerebellum, and the role of Shh-Gli in various brain tumours, including gliomas.
12. Jackson, E. L. et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic. Kras. Genes Dev. 15, 3243-3248 (2001).
13. Pathi, S. et al. Comparative biological responses to human Sonic, Indian, and Desert hedgehog. Mech. Dev. 106, 107-117 (2001).
14. Ruiz i Altaba, A. The works of GLI and the power of hedgehog. Nature Cell Biol. 1, 147-148 (1999).
15. Aza-Blanc, P., Ramirez-Weber, F.-A., Laget, M.-P., Schwartz, C. & Kornberg, T. B. Proteolysis that is inhibited by hedgehog targets cubitus interuptus protein to the nucleus and converts it to a repressor. Cell 89, 1043-1053 (1997). Original discovery of repressor function in the Gli family.
16. Aza-Blane, P., Lin, H. Y., Ruiz i Altaba, A. & Kornberg, T. B. Expression of the vertebrate Gli proteins in Drasophila reveals a distribution of activator and repressor activities. Development 127, 4293-4301 (2000). Analysis of the vertebrate Gli proteins in transgenic flies confirms the existence of distinct functions for the Gli proteins, and shows that these can have different targets.
17. Chiang, C. et al. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383, 407-413 (1996). Knockout of Shh in mice.
18. Roessler, E. et al. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nature Genet. 14, 357-360 (1996).
19. Park, H. L. et al. Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation. Development 127, 1593-1605 (2000).
20. von Mering, C. & Basler, K. Distinct regulated activities of human Gli proteins in Drosophila. Curr. Biol. 9, 1319-1322 (1999).
21. Ruiz i Altaba, A. Combinatorial Gli gene function in floor plate and neuronal inductions by Sonic hedgehog. Development 125, 2203-2212 (1998).
22. Brewster, R. Lee J. & Ruiz i Altaba, A. Gli/Zic factors pattern the neural plate by defining domains of cell differentiation. Nature 393, 579-583 (1998).
23. Brewster, R., Mullor, J. L. & Ruiz i Altaba, A. Gli2 functions in Fgf signaling during antero-posterior patterning. Development 127, 4395-4405 (2000). Evidence for the regulation of Gli2 and Gli3 by Fgf signalling and their participation in non-hedgehog-dependent events.
24. Miao, N. et al. Sonic hedgehog promotes the survival of specific CNS neuron populations and protects these cells from toxic insult in vitro. J. Neurosci. 15, 5891-5899 (1997).
25. Ahlgren, S. C. & Bronner-Fraser, M. Inhibition of sonic hedgehog signaling in vivo results in craniofacial neural crest cell death. Curr. Biol. 9, 1304-1314 (1999).
26. Cobourne, M. T., Hardcastle, Z. & Sharpe, P. T. Sonic hedgehog regulates epithelial proliferation and cell survival in the developing tooth germ. J. Dent. Res. 80, 1974-1979 (2001).
27. Jessell, T. M. Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nature Rev. Genet. 1, 20-29 (2000).
28. Dahmane, N. & Ruiz i Altaba, A. Sonic hedgehog regulates the growth and patterning of the cerebellum. Development 126, 3089-3100 (1999).
29. Wechsler-Reya, R. J. & Scott, M. P. Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron 22, 103-114 (1999).
30. Wallace, V. A. Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr. Biol. 9, 445-448 (1999). References 28-30 discuss the role of Shh in the cerebellar cortex, providing a basis for the action of Purkinje neurons on granule-cell precursors and for the development of medulloblastoma.
31. Mullor, J. L., Dahmane, N., Sun, T. & Ruiz i Altaba, A. Wnt signals are targets and mediators of Gli function. Curr. Biol. 11, 769-773 (2001). Study of Gli function in mesoderm development and discovery of vertebrate Wnt proteins as targets of Gli proteins.
32. Kenney, A. M. & Rowitch, D. H. Sonic hedgehog promotes G(1) cyclin expression and sustained cell cycle progression in mammalian neuronal precursors. Mol. Cell Biol. 20, 9055-9067 (2000).
33. Yoon, J. W. et al. Gene expression profiling leads to identification of GLI1 binding elements in target genes and a role for multiple downstream pathways in GLI1 induced cell transformation. J. Biol. Chem. 21, 21 (2001).
34. Rowitch, D. H. et al. Sonic hedgehog regulates proliferation and inhibits differentiation of CNS precursor cells. J. Neurosci. 19, 8954-8965 (1999). Study of the effects of Shh misexpression on spinalcord precursors.
35. Ericson, J., Morton, S., Kawakami, A., Roelink, H. & Jessell, T. M. Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity. Cell 87, 661-673 (1996).
36. Barnes, E. A., Kong, M., Ollendorff, V. & Donoghue, D. J. Patched1 interacts with cyclin B1 to regulate cell cycle progression. EMBO J. 20, 2214-2223 (2001).
37. Fan, H. & Khavari, P. A. Sonic hedgehog opposes epithelial cell cycle arrest. J. Cell Biol. 147, 71-76 (1999).
38. Gorlin, R. J. Nevoid basal cell carcinoma syndrome. Dermatol. Clin. 13, 113-125 (1995).
39. Johnson, R. L. et al. Human homolog of Patched, a candidate gene for basal cell nevus syndrome. Science 272, 1668-1671 (1996).
40. Hahn, H. et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85, 841-851 (1996). References 39 and 40 identity PTCH as the gene that is mutated in Gorlin's or basal-cell nevus syndrome.
41. Goodrich, L. V. Milenkovic, L., Higgins, K. M. & Scott, M. P. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277, 1109-1113 (1997). Mouse model for medulloblastoma showing that these tumours develop in mice that lack a copy of Ptc, much like humans with Gorlin's syndrome.
42. +/- mice and the effects of radiation.
43. Wetmore, C., Eberhart, D. E. & Curran, T. Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. Cancer Res. 61, 513-516 (2001). Demonstration that medulloblastomas arise with high frequency in Ptc heterozygotes that lack p53.
44. Oro, A. E. et al. Basal cell carcinomas in mice overexpressing sonic hedgehog. Science 276, 817-821 (1997). Development of BCCs in the skin of mouse embryos that misexpress Shh.
45. Fan, H., Oro, A. E., Scott, M. P. & Khavari, P. A. Induction of basal cell carcinoma features in transgenic human skin expressing Sonic Hedgehog. Nature Med. 3, 788-792 (1997).
46. +/- mice, establishing a model for environmental mutagens and skin cancer.
47. Dahmane, N., Lee, J., Robins, P., Heller, P. & Ruiz i Altaba, A. Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours. Nature 389, 876-881 (1997). First evidence for a role of the Gli proteins and the Shh pathway in sporadic BCCs.
48. Nilsson, M. et al. Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing Gli1. Proc. Natl Acad. Sci. USA 97, 3438-3443 (2000). Development of BCCs in mice that misexpress Gli1 in the skin.
49. Grachtchouk, M. et al. Basal cell carcinomas in mice overexpressing Gli2 in skin. Nature Genet. 24, 216-217 (2000). Development of basal-cell carcinomas in mice through the misexpression of Gli2 in the epidermis.
50. Gailani, M.R. et al. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nature Genet. 14, 78-81 (1996).
51. Unden, A. B., Zaphiropoulos, P. G., Bruce, K., Toftgard, R. & Stahle-Backdahl, M. Human patched (PTCH) mRNA is overexpressed consistently in tumor cells of both familiar and sporadic basal cell carcinoma. Cancer Res. 57, 2336-2340 (1997).
52. Kalhassy, M. et al. Patched (PTCH)-associated preferential expression of smoothened (SMOH) in human basal cell carcinoma of the skin. Cancer Res. 57, 4731-4735 (1997).
53. Wolter, M., Reifenberger, J., Sommer, C., Ruzicka, T. & Reifenberger, G. Mutations in the human homologue of the Drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res. 57, 2581-2585 (1997).
54. Xie, J. et al. Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors. Cancer Res. 57, 2369-2372 (1997).
55. Xie, J. et al. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391, 90-92 (1998). Shows the potency of activated Smo mutants in instigating the Shh pathway.
56. Reifenberger, J. et al. Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res. 58, 1798-1803 (1998).
57. Ghali, L., Wong, S. T. Green, J., Tidman, N. & Quinn, A. G. Gli1 protein is expressed in basal cell carcinomas, outer root sheath keratinocytes and a subpopulation of mesenchymal cells in normal human skin. J. Invest. Dermatol. 113, 595-599 (1999).
58. Bonifas, J. M. et al. Activation of expression of hedgehog target genes in basal cell carcinomas. J. Invest. Dermatol. 116, 739-742 (2001).
59. Stein, U. et al. GLI gene expression in bone and soft tissue sarcomas of adult patients correlates with tumor grade. Cancer Res. 59, 1890-1895 (1999).
60. Kimonis, V. E. et al. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am. J. Med. Genet. 69, 299-308 (1997).
61. Callahan, C. A. & Oro, A. E. Monstrous attempts at adnexogenesis: regulating hair follicle progenitors through Sonic hedgehog signaling. Curr. Opin. Genet. Dev. 11, 541-546 (2001).
62. St-Jacques, B. et al. Sonic hedgehog signaling is essential for hair development. Curr. Biol. 8, 1058-1068 (1998).
63. Chiang, C. et al. Essential role for Sonic hedgehog during hair follicle morphogenesis. Dev. Biol. 205, 1-9 (1999).
64. Sato, N., Leopold, P. L. & Crystal, R. G. Induction of the hair growth phase in postnatal mice by localized transient expression of Sonic hedgehog. J. Clin. Invest. 104, 855-864 (1999).
65. Karlsson, L., Bondjers, C. & Betsholtz, C. Roles for PDGF-A and sonic hedgehog in development of mesenchymal components of the hair follicle. Development 126, 2611-2621 (1999).
66. Taylor, G., Lehrer, M. S., Jensen, P. J., Sun, T.-T. & Lavker, R. M. Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell 102, 451-461 (2000). Study of the potential of stem cells in the bulge region of the hair follicle.
67. Fuchs, E., Merrill, B. J., Jamora, C. & DasGupta, R. At the roots of a never-ending cycle. Dev. Cell 1, 13-25 (2001).
68. Marino, S., Vooijs, M., van Der Gulden, H., Jonkers, J. & Berns, A. Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Dev. 14, 994-1004 (2000). Unexpected development of medulloblastomas from lack of Trp53 and Rb in granule-cell precursors.
69. Gao, W. O., Heintz, N. & Hatten, M. E. Cerebellar granule cell neurogenesis is regulated by cell-cell interactions. Neuron 5, 705-715 (1991).
70. Raffel, C. et al. Sporadic medulloblastoma contain PTCH mutations. Cancer Res. 57, 842-845 (1997).
71. Pietsch. T. et al. Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res. 57, 2085-2088 (1997).
72. Vortmeyer, A. O. et al. Deletion analysis of the adenomatous polyposis coli and PTCH gene loci in patients with sporadic and nevoid basal cell carcinoma syndrome-associated medulloblastoma. Cancer 85, 2662-2667 (1999).
73. Zurawel, R. H. et al. Analysis of PTCH/SMO/SHH pathway genes in medulloblastoma. Genes Chromosom. Cancer 27, 44-51 (2000).
74. Pomeroy, S. L. et al. Prediction of central nervous system embryonal tumor outcome based on gene expression. Nature 415, 436-442 (2002).
75. Holland, E. C. Gliomagenesis: genetic alterations and mouse models. Nature Rev. Genet. 2, 120-129 (2001).
76. Maher, E. A. et al. Malignant glioma: genetics and biology of a grave matter. Genes Dev. 15, 1311-1333 (2001).
77. Kleihues, P. & Cavenee, W. K. Tumors of the Nervous System (International Agency for Research on Cancer, Lyon, 1997)
78. Nishikawa, R. et al. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc. Natl Acad. Sci. USA 91, 7727-7731 (1994).
79. Uhrbom, L., Hesselager, G., Nister, M. & Westermark, B. Induction of brain tumors in mice using a recombinant platelet-derived growth factor B-chain retrovirus. Cancer Res. 58, 5275-5279 (1998). Ability of Pdgf signalling to induce brain tumorigenesis.
80. Holland, E. C. et al. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nature Genet. 25, 55-57 (2000).
81. Dai, C. et al. PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev. 15, 1913-1925 (2001). Study of the ability of the Pdgf pathway to initiate gliomagenesis in mice.
82. Ding, H. et al. Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas. Cancer Res. 61, 3826-3836 (2001).
83. Kinzler, K. W. et al. Identification of an amplified, highly expressed gene in a human glioma. Science 236, 70-73 (1987). Original isolation and identification of Gli1.
84. Salgaller, M., Pearl, D. & Stephens, R. In situ hybridization with single-stranded RNA probes to demonstrate infrequently elevated Gli mRNA and no increased Ras mRNA levels in meningiomas and astrocytomas. Cancer Lett. 57, 243-253 (1991).
85. Xiao, H., Goldthwait, D. A. & Mapstone, T. A search for Gli expression in tumors of the central nervous system. Pediatr. Neurosurg. 20, 178-182 (1994).
86. Millen, K. J., Hui, C.-C. & Joyner, A. L. A role for En-2 and other murine homologues of Drosophila segment polarity genes in regulating positional information in the developing cerebellum. Development 121, 3935-3945 (1995).
87. Incardona, J. P., Gaffield, W., Kapur, R. P. & Roelink, H. The teratogenic Veratrum alkaloid cyclopamine inhibits Sonic hedgehog signal transduction. Development 125, 3553-3562 (1998).
88. Cooper, M. K., Porter, J. A., Young, K. E. & Beachy, P. A. Teratogen-mediated inhibition of target tissue response to Shh signaling. Science 280, 1603-1607 (1998). References 87 and 88 discuss the site of action of cyclopamine in the inhibition of Shh signalling.
89. Taipale, J. et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406, 1005-1009 (2000). Detailed study of the effects of cyclopamine on the Shh receptor complex.
90. Van Tuyl, M. & Post, M. From fruitflies to mammals: mechanisms of signaling via the Sonic hedgehog pathway in lung development. Resp. Res. 1, 30-35 (2001).
91. Miller, L. A., Wert, S. E. & Whitsett, J. A. Immunolocalization of sonic hedgehog (shh) in developing mouse lung. J. Histochem. Cytochem. 49, 1593-1604 (2001).
92. Podlasek, C. A., Barnett, D. H., Clemens, J. Q., Bak, P. M. & Bushman, W. Prostate development requires Sonic hedgehog expressed by the urogenital sinus epithelium. Dev. Biol. 209, 28-39 (1999).
93. Abate-Shen, C. & Shen, M. M. Molecular genetics of prostate cancer. Genes Dev. 14, 2410-2434 (2000).
94. Levanat, S., Pavelic, B., Crnic, I., Oreskovic, S. & Manojlovic, S. Involvement of PTCH gene in various noninflammatory cysts. J. Mol. Med. 76, 140-146 (2000).
95. Kwan, H. et al. Transgenes expressing the Wnt1 and Wnt2 proto-oncogenes cooperate during mammary carcinogenesis in doubly transgenic mice. Mol. Cell. Biol. 12, 147-154 (1992).
96. Shackleford, G. M., MacArthur, C. A., Kwan, H. C. & Varmus, H. E. Mouse mammary tumor virus infection accelerates mammary carcinogenesis in Wnt1 transgenic mice by insertional activation of Wnt2/Fgf3 and Hst/Fgf4. Proc. Natl Acad. Sci. USA 90, 740-744 (1993).
97. Lewis, M. T. Hedgehog signalling in mouse mammary gland development and neoplasia. J. Mammary Gland Biol. Neoplasia 6, 53-66 (2001).
98. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57-70 (2000).
99. Wetmore, C., Eberhart, D. E. & Curran, T. The normal patched allele is expressed in medulloblastomas from mice with heterozygous germ-line mutation of patched. Cancer Res. 60, 2239-2246 (2000).
100. Krishnan, V. et al. Mediation of Sonic hedgehog-induced expression of COUP-TFII by a protein phosphatase. Science 278, 1947-1950 (1997).
101. Apidianakis, Y., Grbavec, D. Stifani, S. & Delidakis, C. Groucho mediates a Ci-independent mechanism of hedgehog repression in the anterior wing pouch. Development 128, 4361-4370 (2001).
102. Ruppert, J. M., Vogelstein, B. & Kinzler, K. W. The zinc finger protein GLI transforms primary cells in cooperation with adenovirus E1A. Mol. Cell. Biol. 11, 1724-1728 (1991).
103. Kato, M. et al. Identification of sonic hedgehog-responsive genes using cDNA microarray. Biochem. Biophys. Res. Commun. 289, 472-478 (2001).
104. Malik, K. & Brown, K. W. Epigenetic gene deregulation in Cancer. Br. J. Cancer 83, 1583-1588 (2000).
105. Bergstein, I. When is precancerous actually postcancerous? Mol. Carcinog. 29, 129-133 (2000).
106. Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105-111 (2001).
107. Bonnet, D. & Dick, J. E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Med. 3, 730-737 (1997).
108. Bhardwaj, G. et al. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nature Immunol. 2, 172-180 (2001). Study of the role of the Shh pathway in the haematopoietic system.
109. Detmer, K. Walker, A. N. Jenkins, T. M., Steele, T. A. & Dannawi, H. Erythroid differentiation in vitro is blocked by cyclopamine, an inhibitor of hedgehog signaling. Blood Cells Mol. Dis. 26, 360-372 (2000).
110. Biernat, W. et al. Identical mutations of the p53 tumor suppressor gene in the gliomatous and the sarcomatous component soft gliosarcomas suggest a common origin from glial cells. J. Neuropathol. Exp. Neurol. 54, 651-656 (1995).
111. Boerman, R. H. et al. The glial and mesenchymal elements of gliosarcomas share similar genetic alterations. J. Neuropathol. Exp. Neurol. 55, 973-981 (1996).
112. Mueller, W. et al. Clonal analysis in glioblastoma with epithelial differentiation. Brain Pathol. 11, 39-43 (2001).
113. Reis, R. M., Konu-Lebleblicioglu, D., Lopes, J. M., Kleihues, P. & Ohgaki, H. Genetic profile of gliosarcomas. Am. J. Pathol. 156, 425-432 (2000).
114. Dassule, H. R., Lewis, P., Bel, M., Maas, R. & McMahon, A. P. Sonic hedgehog regulates grown and morphogenesis of the tooth. Development 127, 4775-4785 (2000).
115. Mintz, B. & Fleischman, R. A. Teratocarcinomas and other neoplasms as developmental defects in gene expression. Adv. Cancer Res. 34, 211-278 (1981).
116. Cano, A. et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nature Cell Biol. 2, 76-83 (2000). Study of the role of Snail family genes in cell shape and position changes in development and cancer.
117. Lu, Q. R. et al. Oligodendrocyte lineage genes (OLIG) as molecular markers for human glial brain tumors. Proc. Natl Acad. Sci. USA 98, 10851-10856 (2001).
118. Morin, P. J. et al. Activation of β-catenin-TCF signaling in colon cancer by mutations in β-catenin or APC. Science 275, 1787-1790 (1997).
119. -/- colon carcinoma. Science 275, 1784-1787 (1997).
120. Polakis, P. Wnt signaling and cancer. Genes Dev. 14, 1837-1851 (2000).
121. Alvarez-Buylla, A., Garcia-Verdugo, J. M. & Tramontin, A. D. A unified hypothesis on the lineage of neural stem cells. Nature Res. Neurosci. 2, 287-293 (2001).
122. Brockes, J. P. Amphibian limb regeneration: rebuilding a complex structure. Science 276, 81-87 (1997).
123. Kalyani, A., Hobson, K. & Rao, M. S. Neuroepithelial stem cells from the embryonic spinal cord: isolation, characterization, and clonal analysis. Dev. Biol. 186, 202-223 (1997).
124. Groszer, M. et al. Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science 294, 2186-2189 (2001). Genetic analysis of PTEN function, revealing an unsuspected role in the control of progenitor-cell numbers.
125. MacDonald, T. J. et al. Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease. Nature Genet. 29, 143-152 (2001).
126. Xie, J. et al. A role of PDGFRα in basal cell carcinoma proliferation. Proc. Natl Acad. Sci. USA 98, 9255-9259 (2001).
127. Uhrbom, L., Hesselager G., Ostman, A., Nister, M. & Westermark, B. Dependence of autocrine growth factor stimulation in platelet-derived growth factor-B-induced mouse brain tumor cells. Int. J. Cancer 85, 398-406 (2000).
128. Trojan, J., Johnson, T. R., Rudin, S. D., Ilan, J. & Tykocinski, M. L. Treatment and prevention of rat glioblastoma by immunogenic C6 cells expressing antisense insulin-like growth factor 1 RNA. Science 259, 94-97 (1993).
129. Zumkeller, W. & Westphal, M. The IGF/IGFBP system in CNS malignancy. Mol. Pathol. 54, 227-229 (2001).
130. Hahn, H. et al. Patched target Igf2 is indispensable for the formation of medulloblastoma and rhabdomyosarcoma. J. Biol. Chem 275, 28341-28344 (2000). Identification of the Igf signalling pathway as a target of Shh-Gli function.
131. Koch, A. et al. Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors. Int. J. Cancer 93, 445-449 (2001).
132. Ellisen, L. W. et al. TAN1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocation in T lymphoblastic neoplasms. Cell 66, 649-661 (1991).
133. Pear, W. S. et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J. Exp. Med. 183, 2283-2291 (1996).
134. Karanu, F. N. et al. The notch ligand jagged-1 represents a novel growth factor of human hematopoietic stem cells. J. Exp. Med. 192, 1365-1372 (2000).
135. Varnum-Finney, B. et al. Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling. Nature Med. 6, 1278-1281 (2000).
136. Gaiano, N., Nye, J. S. & Fishell, G. Radial glia identity is promoted by Notch 1 signaling in the murine forebrain. Neuron 26, 395-404 (2000).
137. Solecki, D. J., Liu, X. L., Tomoda, T., Fang, Y. & Hatten, M. E. Activated Notch2 signaling inhibits differentiation of cerebellar granule neuron precursors by maintaining proliferation. Neuron 31, 557-568 (2001). Involvement of Notch signalling in the process of granule-neuron precursor proliferation. An interesting potential link with Shh signalling.