Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-7479d7b7d-c9gpj Total loading time: 0 Render date: 2024-07-12T09:14:50.388Z Has data issue: false hasContentIssue false

7 - Hedgehog/GLI signaling in cancer

from SECTION III - TARGETING CANCER STEM CELL PATHWAYS

Published online by Cambridge University Press:  15 December 2009

By
Fritz Aberger
Edited by
William L. Farrar
Fritz Aberger
Affiliation:
University of Salzburg, Austria
Get access

Summary

Cancer is among the leading causes of death worldwide, and its incidence is continuously on the rise. Successful therapies of this disease are a major challenge and aim of this century. Understanding the molecular programs that control the malignant behavior of tumor cells, particularly of those that account for tumor initiation, growth, and metastasis, will be key to the development of targeted cancer therapies.

Cancer arises through the accumulation of genetic and epigenetic alterations that gradually endow the tumor cells with more aggressive growth properties, eventually leading to the spreading of cancer cells to form metastases. Over the past years, numerous studies have provided compelling evidence that many malignancies are driven by cancer stem cells, a small subpopulation of tumor cells with self-renewal and tumor-initiating capacity. Targeting the molecular signals that control self-renewal, survival, and proliferation of cancer stem cells is therefore considered a highly promising approach to tackle cancer at its very roots.

A series of recent studies has implicated the Hedgehog/GLI (HH/GLI) signaling cascade in the development of a variety of human malignancies, and there is increasing evidence that this developmental pathway plays a critical role in cancer stem cells, making it a primary target for novel and efficient cancer therapies. This review will give an overview on recent insights into the mechanisms of Hedgehog signal transduction, summarize key findings about the involvement of HH/GLI signaling in cancer development, and finally, concentrate on the role of HH/GLI in stem and cancer stem cells and its relevance to potential future therapies.

Type
Chapter
Information
Cancer Stem Cells , pp. 109 - 127
Publisher: Cambridge University Press
Print publication year: 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Ailles, L. E., and Weissman, I. L. (2007) Cancer stem cells in solid tumors. Curr Opin Biotechnol, 18(5), 460–6.CrossRefGoogle ScholarPubMed
Clarke, M. F., and Fuller, M. (2006) Stem cells and cancer: two faces of eve. Cell, 124(6), 1111–5.CrossRefGoogle ScholarPubMed
Wang, J. C., and Dick, J. E. (2005) Cancer stem cells: lessons from leukemia. Trends Cell Biol, 15(9), 494–501.CrossRefGoogle ScholarPubMed
Beachy, P. A., Karhadkar, S. S., and Berman, D. M. (2004) Tissue repair and stem cell renewal in carcinogenesis. Nature, 432(7015), 324–31.CrossRefGoogle ScholarPubMed
Rubin, L. L., and Sauvage, F. J. (2006) Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov, 5(12), 1026–33.CrossRefGoogle Scholar
Ruiz, I Altaba, Mas, C., and Stecca, B. (2007) The Gli code: an information nexus regulating cell fate, stemness and cancer. Trends Cell Biol, 17(9), 438–47.CrossRefGoogle Scholar
Ingham, P. W., and McMahon, A. P. (2001) Hedgehog signaling in animal development: paradigms and principles. Genes Dev, 15(23), 3059–87.CrossRefGoogle ScholarPubMed
Ahn, S., and Joyner, A. L. (2005) In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog. Nature, 437(7060), 894–7.CrossRefGoogle ScholarPubMed
Asai, J., Takenaka, H., Kusano, K. F., Ii, M., Luedemann, C., Curry, C., Eaton, E., Iwakura, A., Tsutsumi, Y., Hamada, H., Kishimoto, S., Thorne, T., Kishore, R., and Losordo, D. W. (2006) Topical Sonic hedgehog gene therapy accelerates wound healing in diabetes by enhancing endothelial progenitor cell-mediated microvascular remodeling. Circulation, 113(20), 2413–24.CrossRefGoogle ScholarPubMed
Chiang, C., Swan, R. Z., Grachtchouk, M., Bolinger, M., Litingtung, Y., Robertson, E. K., Cooper, M. K., Gaffield, W., Westphal, H., Beachy, P. A., and Dlugosz, A. A. (1999) Essential role for Sonic hedgehog during hair follicle morphogenesis. Dev Biol, 205(1), 1–9.CrossRefGoogle ScholarPubMed
Palma, V., Lim, D. A., Dahmane, N., Sanchez, P., Brionne, T. C., Herzberg, C. D., Gitton, Y., Carleton, A., Alvarez-Buylla, A., and Ruiz, I Altaba (2005) Sonic hedgehog controls stem cell behavior in the postnatal and adult brain. Development, 132(2), 335–44.CrossRefGoogle ScholarPubMed
St-Jacques, B., Dassule, H. R., Karavanova, I., Botchkarev, V. A., Li, J., Danielian, P. S., McMahon, J. A., Lewis, P. M., Paus, R., and McMahon, A. P. (1998) Sonic hedgehog signaling is essential for hair development. Curr Biol, 8(19), 1058–68.CrossRefGoogle ScholarPubMed
Oro, A. E., and Higgins, K. (2003) Hair cycle regulation of Hedgehog signal reception. Dev Biol, 255(2), 238–48.CrossRefGoogle ScholarPubMed
Jiang, J. (2006) Regulation of Hh/Gli signaling by dual ubiquitin pathways. Cell Cycle, 5(21), 2457–63.CrossRefGoogle ScholarPubMed
Wang, Y., McMahon, A. P., and Allen, B. L. (2007) Shifting paradigms in Hedgehog signaling. Curr Opin Cell Biol, 19(2), 159–65.CrossRefGoogle ScholarPubMed
Hooper, J. E., and Scott, M. P. (2005) Communicating with Hedgehogs. Nat Rev Mol Cell Biol, 6(4), 306–17.CrossRefGoogle ScholarPubMed
Varjosalo, M., Li, S. P., and Taipale, J. (2006) Divergence of Hedgehog signal transduction mechanism between Drosophila and mammals. Dev Cell, 10(2), 177–86.CrossRefGoogle ScholarPubMed
Taipale, J., Cooper, M. K., Maiti, T., and Beachy, P. A. (2002) Patched acts catalytically to suppress the activity of Smoothened. Nature, 418(6900), 892–7.CrossRefGoogle ScholarPubMed
Eggenschwiler, J. T., and Anderson, K. V. (2007) Cilia and developmental signaling. Annu Rev Cell Dev Biol, 23, 345–73.CrossRefGoogle ScholarPubMed
Huangfu, D., and Anderson, K. V. (2006) Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates. Development, 133(1), 3–14.CrossRefGoogle ScholarPubMed
Oro, A. E. (2007) The primary cilia, a “rab-id” transit system for Hedgehog signaling. Curr Opin Cell Biol, 19(6), 691–6.CrossRefGoogle ScholarPubMed
Scholey, J. M., and Anderson, K. V. (2006) Intraflagellar transport and cilium-based signaling. Cell, 125(3), 439–42.CrossRefGoogle ScholarPubMed
Haycraft, C. J., Banizs, B., Aydin-Son, Y., Zhang, Q., Michaud, E. J., and Yoder, B. K. (2005) Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet, 1(4), e53.CrossRefGoogle ScholarPubMed
Rohatgi, R., Milenkovic, L., and Scott, M. P. (2007) Patched1 regulates Hedgehog signaling at the primary cilium. Science, 317(5836), 372–6.CrossRefGoogle ScholarPubMed
Aza-Blanc, P., Ramirez-Weber, F. A., Laget, M. P., Schwartz, C., and Kornberg, T. B. (1997) Proteolysis that is inhibited by Hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor. Cell, 89(7), 1043–53.CrossRefGoogle ScholarPubMed
Kogerman, P., Grimm, T., Kogerman, L., Krause, D., Unden, A. B., Sandstedt, B., Toftgard, R., and Zaphiropoulos, P. G. (1999) Mammalian suppressor-of-Fused modulates nuclear-cytoplasmic shuttling of Gli-1. Nat Cell Biol, 1(5), 312–9.CrossRefGoogle ScholarPubMed
Methot, N., and Basler, K. (1999) Hedgehog controls limb development by regulating the activities of distinct transcriptional activator and repressor forms of Cubitus interruptus. Cell, 96(6), 819–31.CrossRefGoogle ScholarPubMed
Methot, N., and Basler, K. (2000) Suppressor of Fused opposes Hedgehog signal transduction by impeding nuclear accumulation of the activator form of Cubitus interruptus. Development, 127(18), 4001–10.Google ScholarPubMed
Pan, Y., Bai, C. B., Joyner, A. L., and Wang, B. (2006) Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. Mol Cell Biol, 26(9), 3365–77.CrossRefGoogle ScholarPubMed
Ruiz, I Altaba (1999) Gli proteins encode context-dependent positive and negative functions: implications for development and disease. Development, 126(14), 3205–16.Google Scholar
Wang, B., Fallon, J. F., and Beachy, P. A. (2000) Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell, 100(4), 423–34.CrossRefGoogle ScholarPubMed
Riobo, N. A., Saucy, B., Dilizio, C., and Manning, D. R. (2006) Activation of heterotrimeric G proteins by Smoothened. Proc Natl Acad Sci U S A, 103(33), 12607–12.CrossRefGoogle ScholarPubMed
Kasper, M., Regl, G., Frischauf, A. M., and Aberger, F. (2006) Gli transcription factors: mediators of oncogenic Hedgehog signalling. Eur J Cancer, 42(4), 437–45.CrossRefGoogle ScholarPubMed
Litingtung, Y., and Chiang, C. (2000) Specification of ventral neuron types is mediated by an antagonistic interaction between Shh and Gli3. Nat Neurosci, 3(10), 979–85.CrossRefGoogle ScholarPubMed
Litingtung, Y., Dahn, R. D., Li, Y., Fallon, J. F., and Chiang, C. (2002) Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature, 418(6901), 979–83.CrossRefGoogle ScholarPubMed
Jia, J., Zhang, L., Zhang, Q., Tong, C., Wang, B., Hou, F., Amanai, K., and Jiang, J. (2005) Phosphorylation by double-time/CKiepsilon and CKialpha targets Cubitus interruptus for Slimb/beta-TRCP-mediated proteolytic processing. Dev Cell, 9(6), 819–30.CrossRefGoogle ScholarPubMed
Price, M. A., and Kalderon, D. (2002) Proteolysis of the Hedgehog signaling effector Cubitus interruptus requires phosphorylation by glycogen synthase kinase 3 and casein kinase 1. Cell, 108(6), 823–35.CrossRefGoogle ScholarPubMed
Tempe, D., Casas, M., Karaz, S., Blanchet-Tournier, M. F., and Concordet, J. P. (2006) Multisite protein kinase A and glycogen synthase kinase 3beta phosphorylation leads to Gli3 ubiquitination by SCFbetaTrCP. Mol Cell Biol, 26(11), 4316–26.CrossRefGoogle ScholarPubMed
Wang, B., and Li, Y. (2006) Evidence for the direct involvement of {beta}TrCP in Gli3 protein processing. Proc Natl Acad Sci U S A, 103(1), 33–8.CrossRefGoogle ScholarPubMed
Bhatia, N., Thiyagarajan, S., Elcheva, I., Saleem, M., Dlugosz, A., Mukhtar, H., and Spiegelman, V. S. (2006) Gli2 is targeted for ubiquitination and degradation by beta-TrCP ubiquitin ligase. J Biol Chem, 281(28), 19320–6.CrossRefGoogle ScholarPubMed
Di Marcotullio, L., Ferretti, E., Greco, A., Smaele, E., Po, A., Sico, M. A., Alimandi, M., Giannini, G., Maroder, M., Screpanti, I., and Gulino, A. (2006) Numb is a suppressor of Hedgehog signalling and targets Gli1 for itch-dependent ubiquitination. Nat Cell Biol, 8(12), 1415–23.CrossRefGoogle ScholarPubMed
Huntzicker, E. G., Estay, I. S., Zhen, H., Lokteva, L. A., Jackson, P. K., and Oro, A. E. (2006) Dual degradation signals control Gli protein stability and tumor formation. Genes Dev, 20(3), 276–81.CrossRefGoogle ScholarPubMed
Callahan, C. A., Ofstad, T., Horng, L., Wang, J. K., Zhen, H. H., Coulombe, P. A., and Oro, A. E. (2004) Mim/beg4, a Sonic hedgehog-responsive gene that potentiates Gli-dependent transcription. Genes Dev, 18(22), 2724–9.CrossRefGoogle ScholarPubMed
Dai, P., Akimaru, H., Tanaka, Y., Maekawa, T., Nakafuku, M., and Ishii, S. (1999) Sonic hedgehog–induced activation of the Gli1 promoter is mediated by Gli3. J Biol Chem, 274(12), 8143–52.CrossRefGoogle ScholarPubMed
Mao, J., Maye, P., Kogerman, P., Tejedor, F. J., Toftgard, R., Xie, W., Wu, G., and Wu, D. (2002) Regulation of Gli1 transcriptional activity in the nucleus by Dyrk1. J Biol Chem, 277(38), 35156–61.CrossRefGoogle ScholarPubMed
Varjosalo, M., Bjorklund, M., Cheng, F., Syvanen, H., Kivioja, T., Kilpinen, S., Sun, Z., Kallioniemi, O., Stunnenberg, H. G., He, W. W., Ojala, P., and Taipale, J. (2008) Application of active and kinase-deficient kinome collection for identification of kinases regulating Hedgehog signaling. Cell, 133(3), 537–48.CrossRefGoogle ScholarPubMed
Dennler, S., Andre, J., Alexaki, I., Li, A., Magnaldo, T., Ten Dijke, P., Wang, X. J., Verrecchia, F., and Mauviel, A. (2007) Induction of Sonic hedgehog mediators by transforming growth factor-beta: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo. Cancer Res, 67(14), 6981–6.CrossRefGoogle ScholarPubMed
Kasper, M., Schnidar, H., Neill, G. W., Hanneder, M., Klingler, S., Blaas, L., Schmid, C., Hauser-Kronberger, C., Regl, G., Philpott, M. P., and Aberger, F. (2006) Selective modulation of Hedgehog/Gli target gene expression by epidermal growth factor signaling in human keratinocytes. Mol Cell Biol, 26(16), 6283–98.CrossRefGoogle ScholarPubMed
Lauth, M., Bergstrom, A., and Toftgard, R. (2007) Phorbol esters inhibit the Hedgehog signalling pathway downstream of Suppressor of Fused, but upstream of Gli. Oncogene, 26(35), 5163–8.CrossRefGoogle ScholarPubMed
Lauth, M., and Toftgard, R. (2007) Non-canonical activation of Gli transcription factors: implications for targeted anti-cancer therapy. Cell Cycle, 6(20), 2458–63.CrossRefGoogle ScholarPubMed
Riobo, N. A., Haines, G. M., and Emerson, C. P. (2006) Protein kinase c-delta and mitogen-activated protein/extracellular signal-regulated kinase-1 control Gli activation in Hedgehog signaling. Cancer Res, 66(2), 839–45.CrossRefGoogle ScholarPubMed
Riobo, N. A., Lu, K., Ai, X., Haines, G. M., and Emerson, C. P. (2006) Phosphoinositide 3-kinase and Akt are essential for Sonic hedgehog signaling. Proc Natl Acad Sci U S A, 103(12), 4505–10.CrossRefGoogle ScholarPubMed
Stecca, B., Mas, C., Clement, V., Zbinden, M., Correa, R., Piguet, V., Beermann, F., and Ruiz, I. A. A. (2007) Melanomas require Hedgehog-Gli signaling regulated by interactions between Gli1 and the Ras-Mek/Akt pathways. Proc Natl Acad Sci U S A, 104(14), 5895–900.CrossRefGoogle ScholarPubMed
Riobo, N. A., Lu, K., and Emerson, C. P. (2006) Hedgehog signal transduction: signal integration and cross talk in development and cancer. Cell Cycle, 5(15), 1612–5.CrossRefGoogle ScholarPubMed
Pasca Di Magliano, M., Sekine, S., Ermilov, A., Ferris, J., Dlugosz, A. A., and Hebrok, M. (2006) Hedgehog/Ras interactions regulate early stages of pancreatic cancer. Genes Dev, 20(22), 3161–73.CrossRefGoogle ScholarPubMed
Bigelow, R. L., Jen, E. Y., Delehedde, M., Chari, N. S., and McDonnell, T. J. (2005) Sonic hedgehog induces epidermal growth factor dependent matrix infiltration in HaCaT keratinocytes. J Invest Dermatol, 124(2), 457–65.CrossRefGoogle ScholarPubMed
Palma, V., and Ruiz, I Altaba (2004) Hedgehog-Gli signaling regulates the behavior of cells with stem cell properties in the developing neocortex. Development, 131(2), 337–45.CrossRefGoogle ScholarPubMed
Mimeault, M., Moore, E., Moniaux, N., Henichart, J. P., Depreux, P., Lin, M. F., and Batra, S. K. (2006) Cytotoxic effects induced by a combination of cyclopamine and gefitinib, the selective Hedgehog and epidermal growth factor receptor signaling inhibitors, in prostate cancer cells. Int J Cancer, 118(4), 1022–31.CrossRefGoogle ScholarPubMed
Gorlin, R. J. (1995) Nevoid basal cell carcinoma syndrome. Dermatol Clin, 13(1), 113–25.Google ScholarPubMed
Bale, A. E. (2002) Hedgehog signaling and human disease. Annu Rev Genomics Hum Genet, 3, 47–65.CrossRefGoogle ScholarPubMed
Gailani, M. R., Stahle-Backdahl, M., Leffell, D. J., Glynn, M., Zaphiropoulos, P. G., Pressman, C., Unden, A. B., Dean, M., Brash, D. E., Bale, A. E., and Toftgard, R. (1996) The role of the human homologue of Drosophila Patched in sporadic basal cell carcinomas. Nat Genet, 14(1), 78–81.CrossRefGoogle ScholarPubMed
Goodrich, L. V., and Scott, M. P. (1998) Hedgehog and Patched in neural development and disease. Neuron, 21(6), 1243–57.CrossRefGoogle ScholarPubMed
Hahn, H., Wojnowski, L., Miller, G., and Zimmer, A. (1999) The Patched signaling pathway in tumorigenesis and development: lessons from animal models. J Mol Med, 77(6), 459–68.CrossRefGoogle ScholarPubMed
Johnson, R. L., Rothman, A. L., Xie, J., Goodrich, L. V., Bare, J. W., Bonifas, J. M., Quinn, A. G., Myers, R. M., Cox, D. R., Epstein, E. H., and Scott, M. P. (1996) Human homolog of Patched, a candidate gene for the basal cell nevus syndrome. Science, 272(5268), 1668–71.CrossRefGoogle ScholarPubMed
Lam, C. W., Xie, J., To, K. F., Ng, H. K., Lee, K. C., Yuen, N. W., Lim, P. L., Chan, L. Y., Tong, S. F., and McCormick, F. (1999) A frequent activated Smoothened mutation in sporadic basal cell carcinomas. Oncogene, 18(3), 833–6.CrossRefGoogle ScholarPubMed
Xie, J., Murone, M., Luoh, S. M., Ryan, A., Gu, Q., Zhang, C., Bonifas, J. M., Lam, C. W., Hynes, M., Goddard, A., Rosenthal, A., Epstein, E. H., and Sauvage, F. J. (1998) Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature, 391(6662), 90–2.CrossRefGoogle ScholarPubMed
Aszterbaum, M., Epstein, J., Oro, A., Douglas, V., Leboit, P. E., Scott, M. P., and Epstein, E. H. (1999) Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in Patched heterozygous knockout mice. Nat Med, 5(11), 1285–91.CrossRefGoogle ScholarPubMed
Fan, H., Oro, A. E., Scott, M. P., and Khavari, P. A. (1997) Induction of basal cell carcinoma features in transgenic human skin expressing Sonic hedgehog. Nat Med, 3(7), 788–92.CrossRefGoogle ScholarPubMed
Goodrich, L. V., Milenkovic, L., Higgins, K. M., and Scott, M. P. (1997) Altered neural cell fates and medulloblastoma in mouse Patched mutants. Science, 277(5329), 1109–13.CrossRefGoogle ScholarPubMed
Grachtchouk, M., Mo, R., Yu, S., Zhang, X., Sasaki, H., Hui, C. C., and Dlugosz, A. A. (2000) Basal cell carcinomas in mice overexpressing Gli2 in skin. Nat Genet, 24(3), 216–7.CrossRefGoogle ScholarPubMed
Hallahan, A. R., Pritchard, J. I., Hansen, S., Benson, M., Stoeck, J., Hatton, B. A., Russell, T. L., Ellenbogen, R. G., Bernstein, I. D., Beachy, P. A., and Olson, J. M. (2004) The Smoal mouse model reveals that Notch signaling is critical for the growth and survival of Sonic hedgehog–induced medulloblastomas. Cancer Res, 64(21), 7794–800.CrossRefGoogle ScholarPubMed
Hatton, B. A., Villavicencio, E. H., Tsuchiya, K. D., Pritchard, J. I., Ditzler, S., Pullar, B., Hansen, S., Knoblaugh, S. E., Lee, D., Eberhart, C. G., Hallahan, A. R., and Olson, J. M. (2008) The Smo/Smo model: Hedgehog-induced medulloblastoma with 90% incidence and leptomeningeal spread. Cancer Res, 68(6), 1768–76.CrossRefGoogle ScholarPubMed
Kappler, R., Bauer, R., Calzada-Wack, J., Rosemann, M., Hemmerlein, B., and Hahn, H. (2004) Profiling the molecular difference between Patched- and p53-dependent rhabdomyosarcoma. Oncogene, 23(54), 8785–95.CrossRefGoogle ScholarPubMed
Nilsson, M., Unden, A. B., Krause, D., Malmqwist, U., Raza, K., Zaphiropoulos, P. G., and Toftgard, R. (2000) Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing Gli-1. Proc Natl Acad Sci U S A, 97(7), 3438–43.CrossRefGoogle ScholarPubMed
Oro, A. E., Higgins, K. M., Hu, Z., Bonifas, J. M., Epstein, E. H., and Scott, M. P. (1997) Basal cell carcinomas in mice overexpressing Sonic hedgehog. Science, 276(5313), 817–21.CrossRefGoogle ScholarPubMed
Wetmore, C., Eberhart, D. E., and Curran, T. (2000) The normal Patched allele is expressed in medulloblastomas from mice with heterozygous germ-line mutation of Patched. Cancer Res, 60(8), 2239–46.Google ScholarPubMed
Berman, D. M., Karhadkar, S. S., Maitra, A., Montes De Oca, R., Gerstenblith, M. R., Briggs, K., Parker, A. R., Shimada, Y., Eshleman, J. R., Watkins, D. N., and Beachy, P. A. (2003) Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature, 425(6960), 846–51.CrossRefGoogle ScholarPubMed
Hatsell, S., and Frost, A. R. (2007) Hedgehog signaling in mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia, 12(2–3), 163–73.CrossRefGoogle ScholarPubMed
Karhadkar, S. S., Bova, G. S., Abdallah, N., Dhara, S., Gardner, D., Maitra, A., Isaacs, J. T., Berman, D. M., and Beachy, P. A. (2004) Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature, 431(7009), 707–12.CrossRefGoogle ScholarPubMed
Kubo, M., Nakamura, M., Tasaki, A., Yamanaka, N., Nakashima, H., Nomura, M., Kuroki, S., and Katano, M. (2004) Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer. Cancer Res, 64(17), 6071–4.CrossRefGoogle ScholarPubMed
Sanchez, P., Hernandez, A. M., Stecca, B., Kahler, A. J., Degueme, A. M., Barrett, A., Beyna, M., Datta, M. W., Datta, S., and Ruiz, I Altaba (2004) Inhibition of prostate cancer proliferation by interference with Sonic hedgehog-Gli1 signaling. Proc Natl Acad Sci U S A, 101(34), 12561–6.CrossRefGoogle ScholarPubMed
Thayer, S. P., Di Magliano, M. P., Heiser, P. W., Nielsen, C. M., Roberts, D. J., Lauwers, G. Y., Qi, Y. P., Gysin, S., Fernandez-Del Castillo, C., Yajnik, V., Antoniu, B., McMahon, M., Warshaw, A. L., and Hebrok, M. (2003) Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature, 425(6960), 851–6.CrossRefGoogle ScholarPubMed
Watkins, D. N., Berman, D. M., Burkholder, S. G., Wang, B., Beachy, P. A., and Baylin, S. B. (2003) Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature, 422(6929), 313–7.CrossRefGoogle ScholarPubMed
Yuan, Z., Goetz, J. A., Singh, S., Ogden, S. K., Petty, W. J., Black, C. C., Memoli, V. A., Dmitrovsky, E., and Robbins, D. J. (2007) Frequent requirement of Hedgehog signaling in non-small cell lung carcinoma. Oncogene, 26(7), 1046–55.CrossRefGoogle ScholarPubMed
Athar, M., Li, C., Tang, X., Chi, S., Zhang, X., Kim, A. L., Tyring, S. K., Kopelovich, L., Hebert, J., Epstein, E. H., Bickers, D. R., and Xie, J. (2004) Inhibition of Smoothened signaling prevents ultraviolet b-induced basal cell carcinomas through regulation of Fas expression and apoptosis. Cancer Res, 64(20), 7545–52.CrossRefGoogle ScholarPubMed
Romer, J. T., Kimura, H., Magdaleno, S., Sasai, K., Fuller, C., Baines, H., Connelly, M., Stewart, C. F., Gould, S., Rubin, L. L., and Curran, T. (2004) Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/−)p53(−/−) mice. Cancer Cell, 6(3), 229–40.CrossRefGoogle ScholarPubMed
Sanchez, P., and Ruiz, I Altaba (2005) In vivo inhibition of endogenous brain tumors through systemic interference of Hedgehog signaling in mice. Mech Dev, 122(2), 223–30.CrossRefGoogle ScholarPubMed
Clement, V., Sanchez, P., Tribolet, N., Radovanovic, I., and Ruiz, I Altaba (2007) Hedgehog-Gli1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol, 17(2), 165–72.CrossRefGoogle ScholarPubMed
Lauth, M., Bergstrom, A., Shimokawa, T., and Toftgard, R. (2007) Inhibition of Gli-mediated transcription and tumor cell growth by small-molecule antagonists. Proc Natl Acad Sci U S A, 104(20), 8455–60.CrossRefGoogle ScholarPubMed
Tabs, S., and Avci, O. (2004) Induction of the differentiation and apoptosis of tumor cells in vivo with efficiency and selectivity. Eur J Dermatol, 14(2), 96–102.Google ScholarPubMed
Boman, B. M., and Wicha, M. S. (2008) Cancer stem cells: a step toward the cure. J Clin Oncol, 26(17), 2795–9.CrossRefGoogle ScholarPubMed
Reya, T., Morrison, S. J., Clarke, M. F., and Weissman, I. L. (2001) Stem cells, cancer, and cancer stem cells. Nature, 414(6859), 105–11.CrossRefGoogle ScholarPubMed
Bhardwaj, G., Murdoch, B., Wu, D., Baker, D. P., Williams, K. P., Chadwick, K., Ling, L. E., Karanu, F. N., and Bhatia, M. (2001) Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nat Immunol, 2(2), 172–80.CrossRefGoogle ScholarPubMed
Dahmane, N., and Ruiz, I Altaba (1999) Sonic hedgehog regulates the growth and patterning of the cerebellum. Development, 126(14), 3089–100.Google ScholarPubMed
Kenney, A. M., and Rowitch, D. H. (2000) Sonic hedgehog promotes G(1) cyclin expression and sustained cell cycle progression in mammalian neuronal precursors. Mol Cell Biol, 20(23), 9055–67.CrossRefGoogle Scholar
Trowbridge, J. J., Scott, M. P., and Bhatia, M. (2006) Hedgehog modulates cell cycle regulators in stem cells to control hematopoietic regeneration. Proc Natl Acad Sci U S A, 103(38), 14134–9.CrossRefGoogle ScholarPubMed
Wallace, V. A. (1999) Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr Biol, 9(8), 445–8.CrossRefGoogle ScholarPubMed
Wechsler-Reya, R. J., and Scott, M. P. (1999) Control of neuronal precursor proliferation in the cerebellum by Sonic hedgehog. Neuron, 22(1), 103–14.CrossRefGoogle ScholarPubMed
Paladini, R. D., Saleh, J., Qian, C., Xu, G. X., and Rubin, L. L. (2005) Modulation of hair growth with small molecule agonists of the Hedgehog signaling pathway. J Invest Dermatol, 125(4), 638–46.CrossRefGoogle ScholarPubMed
Jaks, V., Barker, N., Kasper, M., Es, J. H., Snippert, H. J., and Toftgard, R. (2009) Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nat Genet, in press.
Fan, X., and Eberhart, C. G. (2008) Medulloblastoma stem cells. J Clin Oncol, 26(17), 2821–7.CrossRefGoogle ScholarPubMed
Louis, D. N., Ohgaki, H., Wiestler, O. D., Cavenee, W. K., Burger, P. C., Jouvet, A., Scheithauer, B. W., and Kleihues, P. (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol, 114(2), 97–109.CrossRefGoogle ScholarPubMed
Di Marcotullio, L., Ferretti, E., Smaele, E., Argenti, B., Mincione, C., Zazzeroni, F., Gallo, R., Masuelli, L., Napolitano, M., Maroder, M., Modesti, A., Giangaspero, F., Screpanti, I., Alesse, E., and Gulino, A. (2004) Ren(kctd11) is a suppressor of Hedgehog signaling and is deleted in human medulloblastoma. Proc Natl Acad Sci U S A, 101(29), 10833–8.CrossRefGoogle ScholarPubMed
Taylor, M. D., Liu, L., Raffel, C., Hui, C. C., Mainprize, T. G., Zhang, X., Agatep, R., Chiappa, S., Gao, L., Lowrance, A., Hao, A., Goldstein, A. M., Stavrou, T., Scherer, S. W., Dura, W. T., Wainwright, B., Squire, J. A., Rutka, J. T., and Hogg, D. (2002) Mutations in SUFU predispose to medulloblastoma. Nat Genet, 31(3), 306–10.CrossRefGoogle ScholarPubMed
Eberhart, C. G. (2008) Even cancers want commitment: lineage identity and medulloblastoma formation. Cancer Cell, 14(2), 105–7.CrossRefGoogle ScholarPubMed
Schuller, U., Heine, V. M., Mao, J., Kho, A. T., Dillon, A. K., Han, Y. G., Huillard, E., Sun, T., Ligon, A. H., Qian, Y., Ma, Q., Alvarez-Buylla, A., McMahon, A. P., Rowitch, D. H., and Ligon, K. L. (2008) Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell, 14(2), 123–34.CrossRefGoogle ScholarPubMed
Yang, Z. J., Ellis, T., Markant, S. L., Read, T. A., Kessler, J. D., Bourboulas, M., Schuller, U., Machold, R., Fishell, G., Rowitch, D. H., Wainwright, B. J., and Wechsler-Reya, R. J. (2008) Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell, 14(2), 135–45.CrossRefGoogle ScholarPubMed
Berman, D. M., Karhadkar, S. S., Hallahan, A. R., Pritchard, J. I., Eberhart, C. G., Watkins, D. N., Chen, J. K., Cooper, M. K., Taipale, J., Olson, J. M., and Beachy, P. A. (2002) Medulloblastoma growth inhibition by Hedgehog pathway blockade. Science, 297(5586), 1559–61.CrossRefGoogle ScholarPubMed
Ehtesham, M., Sarangi, A., Valadez, J. G., Chanthaphaychith, S., Becher, M. W., Abel, T. W., Thompson, R. C., and Cooper, M. K. (2007) Ligand-dependent activation of the Hedgehog pathway in glioma progenitor cells. Oncogene, 26(39), 5752–61.CrossRefGoogle ScholarPubMed
Bar, E. E., Chaudhry, A., Lin, A., Fan, X., Schreck, K., Matsui, W., Piccirillo, S., Vescovi, A. L., Dimeco, F., Olivi, A., and Eberhart, C. G. (2007) Cyclopamine-mediated Hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells, 25(10), 2524–33.CrossRefGoogle ScholarPubMed
Matsui, W., Huff, C. A., Wang, Q., Malehorn, M. T., Barber, J., Tanhehco, Y., Smith, B. D., Civin, C. I., and Jones, R. J. (2004) Characterization of clonogenic multiple myeloma cells. Blood, 103(6), 2332–6.CrossRefGoogle ScholarPubMed
Peacock, C. D., Wang, Q., Gesell, G. S., Corcoran-Schwartz, I. M., Jones, E., Kim, J., Devereux, W. L., Rhodes, J. T., Huff, C. A., Beachy, P. A., Watkins, D. N., and Matsui, W. (2007) Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci U S A, 104(10), 4048–53.CrossRefGoogle ScholarPubMed
Liu, S., Dontu, G., Mantle, I. D., Patel, S., Ahn, N. S., Jackson, K. W., Suri, P., and Wicha, M. S. (2006) Hedgehog signaling and BMI-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res, 66(12), 6063–71.CrossRefGoogle ScholarPubMed
Hutchin, M. E., Kariapper, M. S., Grachtchouk, M., Wang, A., Wei, L., Cummings, D., Liu, J., Michael, L. E., Glick, A., and Dlugosz, A. A. (2005) Sustained Hedgehog signaling is required for basal cell carcinoma proliferation and survival: conditional skin tumorigenesis recapitulates the hair growth cycle. Genes Dev, 19(2), 214–23.CrossRefGoogle ScholarPubMed
Heuvel, M., and Ingham, P. W. (1996) Smoothened encodes a receptor-like serpentine protein required for Hedgehog signalling. Nature, 382(6591), 547–51.CrossRefGoogle ScholarPubMed
Zhang, X. M., Ramalho-Santos, M., and McMahon, A. P. (2001) Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R asymmetry by the mouse node. Cell, 105(6), 781–92.CrossRefGoogle ScholarPubMed
Lauth, M., and Toftgard, R. (2007) The Hedgehog pathway as a drug target in cancer therapy. Curr Opin Invest Drugs, 8(6), 457–61.Google ScholarPubMed
Ruiz, I Altaba, Sanchez, P., and Dahmane, N. (2002) Gli and Hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer, 2(5), 361–72.CrossRefGoogle Scholar
Xie, J. (2008) Hedgehog signaling pathway: development of antagonists for cancer therapy. Curr Oncol Rep, 10(2), 107–13.CrossRefGoogle ScholarPubMed
Chen, J. K., Taipale, J., Cooper, M. K., and Beachy, P. A. (2002) Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev, 16(21), 2743–8.CrossRefGoogle ScholarPubMed
Taipale, J., Chen, J. K., Cooper, M. K., Wang, B., Mann, R. K., Milenkovic, L., Scott, M. P., and Beachy, P. A. (2000) Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature, 406(6799), 1005–9.CrossRefGoogle ScholarPubMed
Corbit, K. C., Aanstad, P., Singla, V., Norman, A. R., Stainier, D. Y., and Reiter, J. F. (2005) Vertebrate Smoothened functions at the primary cilium. Nature, 437(7061), 1018–21.CrossRefGoogle ScholarPubMed
Chen, J. K., Taipale, J., Young, K. E., Maiti, T., and Beachy, P. A. (2002) Small molecule modulation of Smoothened activity. Proc Natl Acad Sci U S A, 99(22), 14071–6.CrossRefGoogle ScholarPubMed
Frank-Kamenetsky, M., Zhang, X. M., Bottega, S., Guicherit, O., Wichterle, H., Dudek, H., Bumcrot, D., Wang, F. Y., Jones, S., Shulok, J., Rubin, L. L., and Porter, J. A. (2002) Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. J Biol, 1(2), 10.CrossRefGoogle ScholarPubMed
Williams, J. A., Guicherit, O. M., Zaharian, B. I., Xu, Y., Chai, L., Wichterle, H., Kon, C., Gatchalian, C., Porter, J. A., Rubin, L. L., and Wang, F. Y. (2003) Identification of a small molecule inhibitor of the Hedgehog signaling pathway: effects on basal cell carcinoma-like lesions. Proc Natl Acad Sci U S A, 100(8), 4616–21.CrossRefGoogle ScholarPubMed
Bigelow, R. L., Chari, N. S., Unden, A. B., Spurgers, K. B., Lee, S., Roop, D. R., Toftgard, R., and Mcdonnell, T. J. (2004) Transcriptional regulation of BCL-2 mediated by the Sonic hedgehog signaling pathway through Gli-1. J Biol Chem, 279(2), 1197–205.CrossRefGoogle ScholarPubMed
Louro, I. D., Bailey, E. C., Li, X., South, L. S., McKie-Bell, P. R., Yoder, B. K., Huang, C. C., Johnson, M. R., Hill, A. E., Johnson, R. L., and Ruppert, J. M. (2002) Comparative gene expression profile analysis of Gli and c-MYC in an epithelial model of malignant transformation. Cancer Res, 62(20), 5867–73.Google Scholar
Regl, G., Kasper, M., Schnidar, H., Eichberger, T., Neill, G. W., Ikram, M. S., Quinn, A. G., Philpott, M. P., Frischauf, A. M., and Aberger, F. (2004) The zinc-finger transcription factor Gli2 antagonizes contact inhibition and differentiation of human epidermal cells. Oncogene, 23(6), 1263–74.CrossRefGoogle ScholarPubMed
Regl, G., Kasper, M., Schnidar, H., Eichberger, T., Neill, G. W., Philpott, M. P., Esterbauer, H., Hauser-Kronberger, C., Frischauf, A. M., and Aberger, F. (2004) Activation of the BCL2 promoter in response to Hedgehog/Gli signal transduction is predominantly mediated by Gli2. Cancer Res, 64(21), 7724–31.CrossRefGoogle ScholarPubMed
Hosoya, T., Arai, M. A., Koyano, T., Kowithayakorn, T., and Ishibashi, M. (2008) Naturally occurring small-molecule inhibitors of Hedgehog/Gli-mediated transcription. Chembiochem, 9(7), 1082–92.CrossRefGoogle ScholarPubMed
Mimeault, M., Johansson, S. L., Vankatraman, G., Moore, E., Henichart, J. P., Depreux, P., Lin, M. F., and Batra, S. K. (2007) Combined targeting of epidermal growth factor receptor and Hedgehog signaling by gefitinib and cyclopamine cooperatively improves the cytotoxic effects of docetaxel on metastatic prostate cancer cells. Mol Cancer Ther, 6(3), 967–78.CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×