Key Points
-
The Sonic hedgehog (Shh) signal-transduction pathway is involved in the patterning, growth and survival of many cells and tissues, and its deregulation has been implicated in several cancers.
-
The pathway culminates in the activation of transcription factors of the Gli family. There are three such Gli proteins in vertebrates, with partially redundant functions, and Gli1 and Gli2 — both of which can mediate Hh signals — have been implicated in tumorigenesis.
-
The first hint that GLI1 activation might be involved in familial tumours came from the discovery that patched (PTCH, known as Ptc in mice), which inhibits the positive activation of GLI1, is mutated in basal-cell nevus syndrome (Gorlin's
-
a hereditary predisposition to basal-cell carcinomas, medulloblastomas and some other tumour types. This results in overexpression of positively activating GLI1 function.
-
The Shh–Gli pathway is also abnormally activated in sporadic cancers, including basal-cell carcinomas and medulloblastomas. Moreover, there is some evidence that Gli activation might be involved in the development of glioma and some other tumour types. Inhibition of Gli function might be a promising therapeutic target in these tumours.
-
In normal tissues, Gli is mainly active in precursor cells. This raises the possibility that tumours are derived from such cells, possibly even stem cells, which are unable to differentiate and/or to stop proliferating.
Abstract
Do tumours arise from stem cells, or are they derived from more differentiated cells that, for some reason, begin to recapitulate developmental programmes? Inappropriate activation of the Sonic hedgehog–Gli signalling pathway occurs in several types of tumour, including those of the brain and the skin. Studies in these and other systems suggest that inappropriate function of the Gli transcription factors in stem or precursor cells might lead to the onset of a tumorigenic programme and that these factors are prime targets for anticancer therapies.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ackerman, A. B. in Ackermans' Histologic Diagnosis of Neoplastic Skin Diseases: A Method by Pattern Analysis (Ardor Scribendi Publishers, Pennsylvania, 2001).
Ruiz i Altaba, A. Gli proteins and Hedgehog signaling: development and cancer. Trends Genet. 15, 418–425 (1999).
Corcoran, R. B. & Scott, M. P. A mouse model for medulloblastoma and basal cell nevus syndrome. J. Neurooncol. 53, 307–318 (2001).
Wechsler-Reya, R. & Scott, M. P. The developmental biology of brain tumors. Annu. Rev. Neurosci. 24, 385–428 (2001).
Ingham, P. W. & McMahon, A. P. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 15, 3059–3087 (2001).
Ruiz i Altaba, A., Palma, V. & Dahmane, N. Hedgehog–Gli signaling and the growth of the brain. Nature Rev. Neurosci. 3, 24–33 (2002).
Felsher, D. W. & Bishop, J. M. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol. Cell 4, 199–207 (1999).
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).
Chin, L. et al. Essential role for oncogenic Ras in tumor maintenance. Nature 400, 468–472 (1999).
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.
Dahmane, N. et al. The Shh–Gli pathway modulates the normal and abnormal growth of the dorsal brain. Development 128, 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.
Jackson, E. L. et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic Kras. Genes Dev. 15, 3243–3248 (2001).
Pathi, S. et al. Comparative biological responses to human Sonic, Indian, and Desert hedgehog. Mech. Dev. 106, 107–117 (2001).
Ruiz i Altaba, A. The works of GLI and the power of hedgehog. Nature Cell Biol. 1, E147–E148 (1999).
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.
Aza-Blanc, P., Lin, H. Y., Ruiz i Altaba, A. & Kornberg, T. B. Expression of the vertebrate Gli proteins in Drosophila 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.
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.
Roessler, E. et al. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nature Genet. 14, 357–360 (1996).
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).Evidence of Gli1 redundancy in mice.
von Mering, C. & Basler, K. Distinct regulated activities of human Gli proteins in Drosophila. Curr. Biol. 9, 1319–1322 (1999).
Ruiz i Altaba, A. Combinatorial Gli gene function in floor plate and neuronal inductions by Sonic hedgehog. Development 125, 2203–2212 (1998).
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).
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.
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. 17, 5891–5899 (1997).
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).
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).
Jessell, T. M. Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nature Rev. Genet. 1, 20–29 (2000).
Dahmane, N. & Ruiz i Altaba, A. Sonic hedgehog regulates the growth and patterning of the cerebellum. Development 126, 3089–3100 (1999).
Wechsler-Reya, R. J. & Scott, M. P. Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron 22, 103–114 (1999).
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.
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.
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).
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. 277, 5548–5555 (2002).
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 spinal-cord precursors.
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).
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).
Fan, H. & Khavari, P. A. Sonic hedgehog opposes epithelial cell cycle arrest. J. Cell Biol. 147, 71–76 (1999).
Gorlin, R. J. Nevoid basal cell carcinoma syndrome. Dermatol. Clin. 13, 113–125 (1995).
Johnson, R. L. et al. Human homolog of Patched, a candidate gene for basal cell nevus syndrome. Science 272, 1668–1671 (1996).
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 identify PTCH as the gene that is mutated in Gorlin's or basal-cell nevus syndrome.
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.
Hahn, H. et al. Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin's syndrome. Nature Med. 4, 619–622 (1998).Demonstration of the development of muscle tumours in Ptc+/− mice and the effects of radiation.
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.
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.
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).
Aszterbaum, M. et al. Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice. Nature Med. 5, 1285–1291 (1999).Study of the effects of radiation on the development of BCCs in Ptc+/− mice, establishing a model for environmental mutagens and skin cancer.
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.
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.
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.
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).
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 familial and sporadic basal cell carcinoma. Cancer Res. 57, 2336–2340 (1997).
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).
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).
Xie, J. et al. Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors. Cancer Res. 57, 2369–2372 (1997).
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.
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).
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).
Bonifas, J. M. et al. Activation of expression of hedgehog target genes in basal cell carcinomas. J. Invest. Dermatol. 116, 739–742 (2001).
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).
Kimonis, V. E. et al. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am. J. Med. Genet. 69, 299–308 (1997).
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).
St-Jacques, B. et al. Sonic hedgehog signaling is essential for hair development. Curr. Biol. 8, 1058–1068 (1998).
Chiang, C. et al. Essential role for Sonic hedgehog during hair follicle morphogenesis. Dev. Biol. 205, 1–9 (1999).
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).
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).
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.
Fuchs, E., Merrill, B. J., Jamora, C. & DasGupta, R. At the roots of a never-ending cycle. Dev. Cell 1, 13–25 (2001).
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.
Gao, W. O., Heintz, N. & Hatten, M. E. Cerebellar granule cell neurogenesis is regulated by cell–cell interactions. Neuron 6, 705–715 (1991).
Raffel, C. et al. Sporadic medulloblastomas contain PTCH mutations. Cancer Res. 57, 842–845 (1997).
Pietsch, T. et al. Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res. 57, 2085–2088 (1997).
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).
Zurawel, R. H. et al. Analysis of PTCH/SMO/SHH pathway genes in medulloblastoma. Genes Chromosom. Cancer 27, 44–51 (2000).
Pomeroy, S. L. et al. Prediction of central nervous system embryonal tumor outcome based on gene expression. Nature 415, 436–442 (2002).
Holland, E. C. Gliomagenesis: genetic alterations and mouse models. Nature Rev. Genet. 2, 120–129 (2001).
Maher, E. A. et al. Malignant glioma: genetics and biology of a grave matter. Genes Dev. 15, 1311–1333 (2001).
Kleihues, P. & Cavenee, W. K. Tumors of the Nervous System (International Agency for Research on Cancer, Lyon, 1997).
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).
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.
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).
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.
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).
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.
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).
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).
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).
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).
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.
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.
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).
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).
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).
Abate-Shen, C. & Shen, M. M. Molecular genetics of prostate cancer. Genes Dev. 14, 2410–2434 (2000).
Levanat, S., Pavelic, B., Crnic, I., Oreskovic, S. & Manojlovic, S. Involvement of PTCH gene in various noninflammatory cysts. J. Mol. Med. 78, 140–146 (2000).
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).
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).
Lewis, M. T. Hedgehog signalling in mouse mammary gland development and neoplasia. J. Mammary Gland Biol. Neoplasia 6, 53–66 (2001).
Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).
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).
Krishnan, V. et al. Mediation of Sonic hedgehog-induced expression of COUP-TFII by a protein phosphatase. Science 278, 1947–1950 (1997).
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).
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).
Kato, M. et al. Identification of sonic hedgehog-responsive genes using cDNA microarray. Biochem. Biophys. Res. Commun. 289, 472–478 (2001).
Malik, K. & Brown, K. W. Epigenetic gene deregulation in cancer. Br. J. Cancer 83, 1583–1588 (2000).
Bergstein, I. When is precancerous actually postcancerous? Mol. Carcinog. 29, 129–133 (2000).
Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).
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).
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.
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).
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).
Boerman, R. H. et al. The glial and mesenchymal elements of gliosarcomas share similar genetic alterations. J. Neuropathol. Exp. Neurol. 55, 973–981 (1996).
Mueller, W. et al. Clonal analysis in glioblastoma with epithelial differentiation. Brain Pathol. 11, 39–43 (2001).
Reis, R. M., Konu-Lebleblicioglu, D., Lopes, J. M., Kleihues, P. & Ohgaki, H. Genetic profile of gliosarcomas. Am. J. Pathol. 156, 425–432 (2000).
Dassule, H. R., Lewis, P., Bei, M., Maas, R. & McMahon, A. P. Sonic hedgehog regulates growth and morphogenesis of the tooth. Development 127, 4775–4785 (2000).
Mintz, B. & Fleischman, R. A. Teratocarcinomas and other neoplasms as developmental defects in gene expression. Adv. Cancer Res. 34, 211–278 (1981).
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.
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).
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).
Korinek, V. et al. Constitutive transcriptional activation by a β-catenin–TCF complex in APC−/− colon carcinoma. Science 275, 1784–1787 (1997).
Polakis, P. Wnt signaling and cancer. Genes Dev. 14, 1837–1851 (2000).
Alvarez-Buylla, A., Garcia-Verdugo, J. M. & Tramontin, A. D. A unified hypothesis on the lineage of neural stem cells. Nature Rev. Neurosci. 2, 287–293 (2001).
Brockes, J. P. Amphibian limb regeneration: rebuilding a complex structure. Science 276, 81–87 (1997).
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).
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.
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).
Xie, J. et al. A role of PDGFRα in basal cell carcinoma proliferation. Proc. Natl Acad. Sci. USA 98, 9255–9259 (2001).
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).
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).
Zumkeller, W. & Westphal, M. The IGF/IGFBP system in CNS malignancy. Mol. Pathol. 54, 227–229 (2001).
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.
Koch, A. et al. Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors. Int. J. Cancer 93, 445–449 (2001).
Ellisen, L. W. et al. TAN1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66, 649–661 (1991).
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).
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).
Varnum-Finney, B. et al. Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling. Nature Med. 6, 1278–1281 (2000).
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).
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.
Acknowledgements
We are grateful to J. L. Mullor, I. Carrera, A. Pellicer, M. Chao, V. Palma and Y. Gitton for comments. P.S. is a recipient of a Ramón Areces Foundation grant. N.D.'s laboratory is funded by an ATIPE grant from the Centre National de la Recherche Scientifique and grants from La Fondation pour la Recherche Médicale and L'Association pour la Recherche sur le Cancer. Our work described in this review was supported by grants from the March of Dimes, the Concern Foundation, the National Cancer Institute and National Institute of Neurological Disorders and Stroke, and a Pew Scholarship (to A.R.A.). Only a partial reference list is given due to journal restrictions.
Author information
Authors and Affiliations
Corresponding author
Related links
Related links
DATABASES
Cancer.gov
GenBank
LocusLink
OMIM
FURTHER INFORMATION
Encyclopedia of Life Sciences
Glossary
- ONTOGENY
-
The development of an organism from its earliest stages to maturity.
- HOLOPROSENCEPHALY
-
A defect in the forebrain that is caused by abnormal dorso–ventral patterning of the anterior neural tube.
- FLOOR PLATE
-
Part of the neural tube that comprises the ventral cells closest to the midline. They, and the underlying notochord, secrete Sonic hedgehog, setting up a ventral–dorsal gradient of this morphogen in the neural tube.
- MESODERM
-
The middle germ layer of the developing embryo. It gives rise to the musculoskeletal, vascular and urinogenital systems, and to connective tissue (including that of the dermis).
- PRIMITIVE NEUROECTODERMAL TUMOUR
-
(PNET). A tumour with cells that resemble those of the neuroectoderm — part of the dorsal ectoderm that gives rise to the central nervous system. Medulloblastoma — the most common form of childhood brain tumour — is classified by some as a PNET.
- PURKINJE NEURON
-
An output cell of the cerebellum, which has a large cell body with a characteristic mass of highly branched dendrites, and a single axon that sends inhibitory signals to the cerebral cortex. These cells coordinate the development of the cerebellar cortex.
- GRANULE NEURON
-
A small interneuron in the cerebellum, which relays excitatory signals to Purkinje neurons.
- VENTRICULAR ZONE
-
The layer of cells that immediately surrounds the cerebral ventricles.
- SUBVENTRICULAR ZONE
-
The layer of cells that is beneath the ventricular zone. Both the ventricular zone and the subventricular zone contain stem cells.
Rights and permissions
About this article
Cite this article
Ruiz i Altaba, A., Sánchez, P. & Dahmane, N. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer 2, 361–372 (2002). https://doi.org/10.1038/nrc796
Issue Date:
DOI: https://doi.org/10.1038/nrc796
This article is cited by
-
A clinicopathological exploration of Hedgehog signaling: implications in oral carcinogenesis
Journal of Cancer Research and Clinical Oncology (2023)
-
Cytoskeletal regulation of a transcription factor by DNA mimicry via coiled-coil interactions
Nature Cell Biology (2022)
-
GLI1 activates pro-fibrotic pathways in myelofibrosis fibrocytes
Cell Death & Disease (2022)
-
Association between cancer genes and germ layer specificity
Medical Oncology (2022)
-
Molecular interactions of miR-338 during tumor progression and metastasis
Cellular & Molecular Biology Letters (2021)