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Sarcoma
Volume 2012, Article ID 406239, 13 pages
http://dx.doi.org/10.1155/2012/406239
Review Article

Embryonic Signaling Pathways and Rhabdomyosarcoma: Contributions to Cancer Development and Opportunities for Therapeutic Targeting

1Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA
2Department of Pediatrics, University of Virginia, Charlottesville, VA 22908, USA
3Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
4Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA

Received 15 October 2011; Accepted 17 January 2012

Academic Editor: Ivo Leuschner

Copyright © 2012 Brian Belyea et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. W. W. Huh and S. X. Skapek, “Childhood rhabdomyosarcoma: new insight on biology and treatment,” Current Oncology Reports, vol. 12, no. 6, pp. 402–410, 2010. View at Publisher · View at Google Scholar
  2. R. Saab, S. L. Spunt, and S. X. Skapek, “Myogenesis and rhabdomyosarcoma: the jekyll and hyde of skeletal muscle,” Current Topics in Developmental Biology, vol. 94, no. C, pp. 197–234, 2011. View at Publisher · View at Google Scholar
  3. C. M. Linardic, “PAX3-FOXO1 fusion gene in rhabdomyosarcoma,” Cancer Letters, vol. 270, no. 1, pp. 10–18, 2008. View at Publisher · View at Google Scholar · View at Scopus
  4. E. Davicioni, M. J. Anderson, F. G. Finckenstein et al., “Molecular classification of rhabdomyosarcoma—genotypic and phenotypic determinants of diagnosis: a report from the Children's Oncology Group,” American Journal of Pathology, vol. 174, no. 2, pp. 550–564, 2009. View at Publisher · View at Google Scholar · View at Scopus
  5. J. L. Meza, J. Anderson, A. S. Pappo, and W. H. Meyer, “Analysis of prognostic factors in patients with nonmetastatic rhabdomyosarcoma treated on intergroup rhabdomyosarcoma studies III and IV: the children's oncology group,” Journal of Clinical Oncology, vol. 24, no. 24, pp. 3844–3851, 2006. View at Publisher · View at Google Scholar · View at Scopus
  6. C. A. S. Arndt, J. A. Stoner, D. S. Hawkins et al., “Vincristine, actinomycin, and cyclophosphamide compared with vincristine, actinomycin, and cyclophosphamide alternating with vincristine, topotecan, and cyclophosphamide for intermediate-risk rhabdomyosarcoma: Children's Oncology Group Study D9803,” Journal of Clinical Oncology, vol. 27, no. 31, pp. 5182–5188, 2009. View at Publisher · View at Google Scholar · View at Scopus
  7. O. Oberlin, A. Rey, E. Lyden et al., “Prognostic factors in metastatic rhabdomyosarcomas: results of a pooled analysis from United States and European Cooperative Groups,” Journal of Clinical Oncology, vol. 26, no. 14, pp. 2384–2389, 2008. View at Publisher · View at Google Scholar · View at Scopus
  8. J. C. Breneman, E. Lyden, A. S. Pappo et al., “Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma–a report from the Intergroup Rhabdomyosarcoma Study IV,” Journal of Clinical Oncology, vol. 21, no. 1, pp. 78–84, 2003. View at Google Scholar · View at Scopus
  9. M. Carli, R. Colombatti, O. Oberlin et al., “European intergroup studies (MMT4-89 and MMT4-91) on childhood metastatic rhabdomyosarcoma: final results and analysis of prognostic factors,” Journal of Clinical Oncology, vol. 22, no. 23, pp. 4735–4742, 2004. View at Publisher · View at Google Scholar · View at Scopus
  10. A. S. Pappo, J. R. Anderson, W. M. Crist et al., “Survival after relapse in children and adolescents with rhabdomyosarcoma: a report from the intergroup rhabdomyosarcoma study group,” Journal of Clinical Oncology, vol. 17, no. 11, pp. 3487–3493, 1999. View at Google Scholar · View at Scopus
  11. N. Tiffin, R. D. Williams, J. Shipley, and K. Pritchard-Jones, “PAX7 expression in embryonal rhabdomyosarcoma suggests an origin in muscle satellite cells,” British Journal of Cancer, vol. 89, no. 2, pp. 327–332, 2003. View at Publisher · View at Google Scholar · View at Scopus
  12. S. Hettmer and A. J. Wagers, “Muscling in: uncovering the origins of rhabdomyosarcoma,” Nature Medicine, vol. 16, no. 2, pp. 171–173, 2010. View at Publisher · View at Google Scholar · View at Scopus
  13. C. Keller, B. R. Arenkiel, C. M. Coffin, N. El-Bardeesy, R. A. DePinho, and M. R. Capecchi, “Alveolar rhabdomyosarcomas in conditional Pax3:Fkhr mice: cooperativity of Ink4a/ARF and Trp53 loss of function,” Genes and Development, vol. 18, no. 21, pp. 2614–2626, 2004. View at Publisher · View at Google Scholar · View at Scopus
  14. M. Murphy and G. Kardon, “Origin of vertebrate limb muscle: the role of progenitor and myoblast populations,” Current Topics in Developmental Biology, vol. 96, pp. 1–32, 2011. View at Publisher · View at Google Scholar
  15. R. J. Bryson-Richardson and P. D. Currie, “The genetics of vertebrate myogenesis,” Nature Reviews Genetics, vol. 9, no. 8, pp. 632–646, 2008. View at Publisher · View at Google Scholar · View at Scopus
  16. S. Biressi, M. Molinaro, and G. Cossu, “Cellular heterogeneity during vertebrate skeletal muscle development,” Developmental Biology, vol. 308, no. 2, pp. 281–293, 2007. View at Publisher · View at Google Scholar · View at Scopus
  17. M. H. Parker, P. Seale, and M. A. Rudnicki, “Looking back to the embryo: defining transcriptional networks in adult myogenesis,” Nature Reviews Genetics, vol. 4, no. 7, pp. 497–507, 2003. View at Publisher · View at Google Scholar · View at Scopus
  18. L. Sang, H. A. Coller, and J. M. Roberts, “Control of the reversibility of cellular quiescence by the transcriptional repressor HES1,” Science, vol. 321, no. 5892, pp. 1095–1100, 2008. View at Publisher · View at Google Scholar · View at Scopus
  19. J. Roma, A. Masia, J. Reventos, J. Sanchez de Toledo, and S. Gallego, “A Human Protein with Sequence Similarity to Drosophila mastermind coordinates the nuclear form of notch and a CSL protein to build a transcriptional activator complex on target promoters,” Clinical Cancer Research, vol. 17, pp. 505–513, 2011. View at Google Scholar
  20. B. C. Belyea, S. Naini, R. C. Bentley, and C. M. Linardic, “Inhibition of the notch-hey1 axis blocks embryonal rhabdomyosarcoma tumorigenesis,” Clinical Cancer Research, vol. 17, no. 23, pp. 7324–7336, 2011. View at Publisher · View at Google Scholar
  21. S. Singh, C. Vinson, C. M. Gurley et al., “Impaired Wnt signaling in embryonal rhabdomyosarcoma cells from p53/c-fos double mutant mice,” American Journal of Pathology, vol. 177, no. 4, pp. 2055–2066, 2010. View at Publisher · View at Google Scholar · View at Scopus
  22. F. Y. Zeng, H. Dong, J. Cui, L. Liu, and T. Chen, “Glycogen synthase kinase 3 regulates PAX3-FKHR-mediated cell proliferation in human alveolar rhabdomyosarcoma cells,” Biochemical and Biophysical Research Communications, vol. 391, no. 1, pp. 1049–1055, 2010. View at Publisher · View at Google Scholar · View at Scopus
  23. U. Tostar, R. Toftgård, P. G. Zaphiropoulos, and T. Shimokawa, “Reduction of human embryonal rhabdomyosarcoma tumor growth by inhibition of the hedgehog signaling pathway,” Genes and Cancer, vol. 1, no. 9, pp. 941–951, 2010. View at Publisher · View at Google Scholar
  24. A. N. Gerber, C. W. Wilson, Y. J. Li, and P. T. Chuang, “The hedgehog regulated oncogenes Gli1 and Gli2 block myoblast differentiation by inhibiting MyoD-mediated transcriptional activation,” Oncogene, vol. 26, no. 8, pp. 1122–1136, 2007. View at Publisher · View at Google Scholar · View at Scopus
  25. R. Kopan, J. S. Nye, and H. Weintraub, “The intracellular domain of mouse Notch: a constitutively activated repressor of myogenesis directed at the basic helix-loop-helix region of MyoD,” Development, vol. 120, no. 9, pp. 2385–2396, 1994. View at Google Scholar · View at Scopus
  26. K. Kuroda, S. Tani, K. Tamura, S. Minoguchi, H. Kurooka, and T. Honjo, “Delta-induced Notch signaling mediated by RBP-J inhibits MyoD expression and myogenesis,” The Journal of Biological Chemistry, vol. 274, no. 11, pp. 7238–7244, 1999. View at Publisher · View at Google Scholar · View at Scopus
  27. M. F. Buas, S. Kabak, and T. Kadesch, “The notch effector Hey1 associates with myogenic target genes to repress myogenesis,” The Journal of Biological Chemistry, vol. 285, no. 2, pp. 1249–1258, 2010. View at Publisher · View at Google Scholar · View at Scopus
  28. J. Wilson-Rawls, J. D. Molkentin, B. L. Black, and E. N. Olson, “Activated Notch inhibits myogenic activity of the MADS-Box transcription factor myocyte enhancer factor 2C,” Molecular and Cellular Biology, vol. 19, no. 4, pp. 2853–2862, 1999. View at Google Scholar · View at Scopus
  29. I. M. Conboy and T. A. Rando, “The regulation of Notch signaling controls satellite cell activation and cell fate determination in postnatal myogenesis,” Developmental Cell, vol. 3, no. 3, pp. 397–409, 2002. View at Publisher · View at Google Scholar · View at Scopus
  30. E. Vasyutina, D. C. Lenhard, H. Wende, B. Erdmann, J. A. Epstein, and C. Birchmeier, “RBP-J (Rbpsuh) is essential to maintain muscle progenitor cells and to generate satellite cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 11, pp. 4443–4448, 2007. View at Publisher · View at Google Scholar · View at Scopus
  31. B. T. MacDonald, K. Tamai, and X. He, “Wnt/β-Catenin signaling: components, mechanisms, and diseases,” Developmental Cell, vol. 17, no. 1, pp. 9–26, 2009. View at Publisher · View at Google Scholar · View at Scopus
  32. H. Clevers, “Wnt/β-catenin signaling in development and disease,” Cell, vol. 127, no. 3, pp. 469–480, 2006. View at Publisher · View at Google Scholar · View at Scopus
  33. S. Brunelli, F. Relaix, S. Baesso, M. Buckingham, and G. Cossu, “Beta catenin-independent activation of MyoD in presomitic mesoderm requires PKC and depends on Pax3 transcriptional activity,” Developmental Biology, vol. 304, no. 2, pp. 604–614, 2007. View at Publisher · View at Google Scholar · View at Scopus
  34. U. Borello, B. Berarducci, P. Murphy et al., “The Wnt/β-catenin pathway regulates Gli-mediated Myf5 expression during somitogenesis,” Development, vol. 133, no. 18, pp. 3723–3732, 2006. View at Publisher · View at Google Scholar · View at Scopus
  35. S. Tajbakhsh, U. Borello, E. Vivarelli et al., “Differential activation of Myf5 and MyoD by different Wnts in explants of mouse paraxial mesoderm and the later activation of myogenesis in the absence of Myf5,” Development, vol. 125, no. 21, pp. 4155–4162, 1998. View at Google Scholar · View at Scopus
  36. D. A. Hutcheson, J. Zhao, A. Merrell, M. Haldar, and G. Kardon, “Embryonic and fetal limb myogenic cells are derived from developmentally distinct progenitors and have different requirements for β-catenin,” Genes and Development, vol. 23, no. 8, pp. 997–1013, 2009. View at Publisher · View at Google Scholar · View at Scopus
  37. A. S. Brack, I. M. Conboy, M. J. Conboy, J. Shen, and T. A. Rando, “A temporal switch from notch to Wnt signaling in muscle stem cells is necessary for normal adult myogenesis,” Cell Stem Cell, vol. 2, no. 1, pp. 50–59, 2008. View at Publisher · View at Google Scholar · View at Scopus
  38. A. Polesskaya, P. Seale, and M. A. Rudnicki, “Wnt signaling induces the myogenic specification of resident CD45+ adult stem cells during muscle regeneration,” Cell, vol. 113, no. 7, pp. 841–852, 2003. View at Publisher · View at Google Scholar · View at Scopus
  39. S. Descamps, H. Arzouk, F. Bacou et al., “Inhibition of myoblast differentiation by Sfrp1 and Sfrp2,” Cell and Tissue Research, vol. 332, no. 2, pp. 299–306, 2008. View at Publisher · View at Google Scholar · View at Scopus
  40. A. S. Brack, M. J. Conboy, S. Roy et al., “Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis,” Science, vol. 317, no. 5839, pp. 807–810, 2007. View at Publisher · View at Google Scholar · View at Scopus
  41. D. D. Armstrong, V. L. Wong, and K. A. Esser, “Expression of β-catenin is necessary for physiological growth of adult skeletal muscle,” American Journal of Physiology, vol. 291, no. 1, pp. C185–C188, 2006. View at Publisher · View at Google Scholar · View at Scopus
  42. A. Otto, C. Schmidt, G. Luke et al., “Canonical Wnt signalling induces satellite-cell proliferation during adult skeletal muscle regeneration,” Journal of Cell Science, vol. 121, no. 17, pp. 2939–2950, 2008. View at Publisher · View at Google Scholar · View at Scopus
  43. A. Perez-Ruiz, Y. Ono, V. F. Gnocchi, and P. S. Zammit, “β-catenin promotes self-renewal of skeletal-muscle satellite cells,” Journal of Cell Science, vol. 121, no. 9, pp. 1373–1382, 2008. View at Publisher · View at Google Scholar · View at Scopus
  44. P. Zhao and E. P. Hoffman, “Embryonic Myogenesis Pathways in Muscle Regeneration,” Developmental Dynamics, vol. 229, no. 2, pp. 380–392, 2004. View at Publisher · View at Google Scholar · View at Scopus
  45. P. W. Ingham, Y. Nakano, and C. Seger, “Mechanisms and functions of Hedgehog signalling across the metazoa,” Nature Reviews Genetics, vol. 12, no. 6, pp. 393–406, 2011. View at Publisher · View at Google Scholar
  46. J. J. Lee, S. C. Ekker, D. P. Von Kessler, J. A. Porter, B. I. Sun, and P. A. Beachy, “Autoproteolysis in hedgehog protein biogenesis,” Science, vol. 266, no. 5190, pp. 1528–1537, 1994. View at Google Scholar · View at Scopus
  47. R. Burke, D. Nellen, M. Bellotto et al., “Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified Hedgehog from signaling cells,” Cell, vol. 99, no. 7, pp. 803–815, 1999. View at Google Scholar · View at Scopus
  48. J. Taipale, M. K. Cooper, T. Maiti, and P. A. Beachy, “Patched acts catalytically to suppress the activity of smoothened,” Nature, vol. 418, no. 6900, pp. 892–897, 2002. View at Publisher · View at Google Scholar · View at Scopus
  49. H. Tukachinsky, L. V. Lopez, and A. Salic, “A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes,” Journal of Cell Biology, vol. 191, no. 2, pp. 415–428, 2010. View at Publisher · View at Google Scholar · View at Scopus
  50. H. Sasaki, Y. Nishizaki, C. C. Hui, M. Nakafuku, and H. Kondoh, “Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling,” Development, vol. 126, no. 17, pp. 3915–3924, 1999. View at Google Scholar · View at Scopus
  51. M. K. Gustafsson, H. Pan, D. F. Pinney et al., “Myf5 is a direct target of long-range Shh signaling and Gli regulation for muscle specification,” Genes and Development, vol. 16, no. 1, pp. 114–126, 2002. View at Publisher · View at Google Scholar · View at Scopus
  52. M. Krüger, D. Mennerich, S. Fees, R. Schäfer, S. Mundlos, and T. Braun, “Sonic hedgehog is a survival factor for hypaxial muscles during mouse development,” Development, vol. 128, no. 5, pp. 743–752, 2001. View at Google Scholar · View at Scopus
  53. G. Straface, T. Aprahamian, A. Flex et al., “Sonic hedgehog regulates angiogenesis and myogenesis during post-natal skeletal muscle regeneration,” Journal of Cellular and Molecular Medicine, vol. 13, no. 8, pp. 2424–2435, 2009. View at Publisher · View at Google Scholar · View at Scopus
  54. M. Koleva, R. Kappler, M. Vogler, A. Herwig, S. Fulda, and H. Hahn, “Pleiotropic effects of sonic hedgehog on muscle satellite cells,” Cellular and Molecular Life Sciences, vol. 62, no. 16, pp. 1863–1870, 2005. View at Publisher · View at Google Scholar · View at Scopus
  55. Y. Bren-Mattison and B. B. Olwin, “Sonic hedgehog inhibits the terminal differentiation of limb myoblasts committed to the slow muscle lineage,” Developmental Biology, vol. 242, no. 2, pp. 130–148, 2002. View at Publisher · View at Google Scholar · View at Scopus
  56. P. Mill, R. Mo, M. C. Hu, L. Dagnino, N. D. Rosenblum, and C. C. Hui, “Shh controls epithelial proliferation via independent pathways that converge on N-Myc,” Developmental Cell, vol. 9, no. 2, pp. 293–303, 2005. View at Publisher · View at Google Scholar · View at Scopus
  57. D. Walter, S. Satheesha, P. Albrecht et al., “CD133 positive embryonal rhabdomyosarcoma stem-like cell population is enriched in rhabdospheres,” PLoS ONE, vol. 6, no. 5, article e19506, 2011. View at Publisher · View at Google Scholar
  58. S. M. Powell, N. Zilz, Y. Beazer-Barclay et al., “APC mutations occur early during colorectal tumorigenesis,” Nature, vol. 359, no. 6392, pp. 235–237, 1992. View at Publisher · View at Google Scholar · View at Scopus
  59. Z. Wang, K. S. Smith, M. Murphy, O. Piloto, T. C. P. Somervaille, and M. L. Cleary, “Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy,” Nature, vol. 455, no. 7217, pp. 1205–1209, 2008. View at Publisher · View at Google Scholar · View at Scopus
  60. A. V. Ougolkov, M. E. Fernandez-Zapico, D. N. Savoy, R. A. Urrutia, and D. D. Billadeau, “Glycogen synthase kinase-3β participates in nuclear factor κB-mediated gene transcription and cell survival in pancreatic cancer cells,” Cancer Research, vol. 65, no. 6, pp. 2076–2081, 2005. View at Publisher · View at Google Scholar · View at Scopus
  61. J. Tan, L. Zhuang, H. S. Leong, N. G. Iyer, E. T. Liu, and Q. Yu, “Pharmacologic modulation of glycogen synthase kinase-3β promotes p53-dependent apoptosis through a direct bax-mediated mitochondrial pathway in colorectal cancer cells,” Cancer Research, vol. 65, no. 19, pp. 9012–9020, 2005. View at Publisher · View at Google Scholar · View at Scopus
  62. H. Hirata, Y. Hinoda, K. Ueno, S. Majid, S. Saini, and R. Dahiya, “Role of secreted frizzled-related protein 3 in human renal cell carcinoma,” Cancer Research, vol. 70, no. 5, pp. 1896–1905, 2010. View at Publisher · View at Google Scholar · View at Scopus
  63. D. B. D. Soglio, A. L. Rougemont, R. Absi et al., “Beta-catenin mutation does not seem to have an effect on the tumorigenesis of pediatric rhabdomyosarcomas,” Pediatric and Developmental Pathology, vol. 12, no. 5, pp. 371–373, 2009. View at Publisher · View at Google Scholar · View at Scopus
  64. T. L. Ng, A. M. Gown, T. S. Barry et al., “Nuclear beta-catenin in mesenchymal tumors,” Modern Pathology, vol. 18, no. 1, pp. 68–74, 2005. View at Publisher · View at Google Scholar · View at Scopus
  65. W. J. Fredericks, K. Ayyanathan, M. Herlyn, J. R. Friedman, and F. J. Rauscher III, “An engineered PAX3-KRAB transcriptional repressor inhibits the malignant phenotype of alveolar rhabdomyosarcoma cells harboring the endogenous PAX3- FKHR oncogene,” Molecular and Cellular Biology, vol. 20, no. 14, pp. 5019–5031, 2000. View at Publisher · View at Google Scholar · View at Scopus
  66. R. J. Gorlin, “Nevoid basal cell carcinoma (Gorlin) syndrome: unanswered issues,” Journal of Laboratory and Clinical Medicine, vol. 134, no. 6, pp. 551–552, 1999. View at Publisher · View at Google Scholar · View at Scopus
  67. H. Hahn, L. Wojnowski, A. M. Zimmer, J. Hall, G. Miller, and A. Zimmer, “Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome,” Nature Medicine, vol. 4, no. 5, pp. 619–622, 1998. View at Publisher · View at Google Scholar · View at Scopus
  68. H. Hahn, F. Nitzki, T. Schorban, B. Hemmerlein, D. Threadgill, and M. Rosemann, “Genetic mapping of a Ptch1-associated rhabdomyosarcoma susceptibility locus on mouse chromosome 2,” Genomics, vol. 84, no. 5, pp. 853–858, 2004. View at Publisher · View at Google Scholar · View at Scopus
  69. J. Calzada-Wack, U. Schnitzbauer, A. Walch et al., “Analysis of the PTCH coding region in human rhabdomyosarcoma,” Human mutation, vol. 20, no. 3, pp. 233–234, 2002. View at Google Scholar · View at Scopus
  70. J. A. Bridge, J. Liu, V. Weibolt et al., “Novel genomic imbalances in embryonal rhabdomyosarcoma revealed by comparative genomic hybridization and fluorescence in situ hybridization: an intergroup rhabdomyosarcoma study,” Genes Chromosomes and Cancer, vol. 27, no. 4, pp. 337–344, 2000. View at Publisher · View at Google Scholar · View at Scopus
  71. U. Tostar, C. J. Malm, J. M. Meis-Kindblom, L. G. Kindblom, R. Toftgård, and A. B. Undén, “Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development,” Journal of Pathology, vol. 208, no. 1, pp. 17–25, 2006. View at Publisher · View at Google Scholar
  72. H. Hahn, L. Wojnowski, A. M. Zimmer, J. Hall, G. Miller, and A. Zimmer, “Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome,” Nature Medicine, vol. 4, no. 5, pp. 619–622, 1998. View at Publisher · View at Google Scholar · View at Scopus
  73. P. M. LoRusso, C. M. Rudin, J. C. Reddy et al., “Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors,” Clinical Cancer Research, vol. 17, no. 8, pp. 2502–2511, 2011. View at Publisher · View at Google Scholar
  74. I. Ecke, A. Rosenberger, S. Obenauer et al., “Cyclopamine treatment of full-blown Hh/Ptch-associated RMS partially inhibits Hh/Ptch signaling, but not tumor growth,” Molecular Carcinogenesis, vol. 47, no. 5, pp. 361–372, 2008. View at Publisher · View at Google Scholar · View at Scopus
  75. B. P. Rubin, K. Nishijo, H. I. H. Chen et al., “Evidence for an unanticipated relationship between undifferentiated pleomorphic sarcoma and embryonal rhabdomyosarcoma,” Cancer Cell, vol. 19, no. 2, pp. 177–191, 2011. View at Publisher · View at Google Scholar
  76. J. G. Pressey, J. R. Anderson, D. K. Crossman, J. C. Lynch, and F. G. Barr, “Hedgehog pathway activity in pediatric embryonal rhabdomyosarcoma and undifferentiated sarcoma: a report from the Children's Oncology Group,” Pediatric Blood and Cancer, vol. 57, no. 6, pp. 930–938, 2011. View at Publisher · View at Google Scholar
  77. B. Purow, “Notch inhibitors as a new tool in the war on cancer: a pathway to watch,” Current Pharmaceutical Biotechnology, vol. 10, no. 2, pp. 154–160, 2009. View at Publisher · View at Google Scholar
  78. L. Luistro, W. He, M. Smith et al., “Preclinical profile of a potent γ-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties,” Cancer Research, vol. 69, no. 19, pp. 7672–7680, 2009. View at Publisher · View at Google Scholar · View at Scopus
  79. R. E. Moellering, M. Cornejo, T. N. Davis et al., “Direct inhibition of the Notch transcription factor complex,” Nature, vol. 462, no. 7270, pp. 182–188, 2009. View at Publisher · View at Google Scholar · View at Scopus
  80. N. Barker and H. Clevers, “Mining the Wnt pathway for cancer therapeutics,” Nature Reviews Drug Discovery, vol. 5, no. 12, pp. 997–1014, 2006. View at Publisher · View at Google Scholar · View at Scopus
  81. K. Watanabe and X. Dai, “Winning WNT: race to Wnt signaling inhibitors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 15, pp. 5929–5930, 2011. View at Publisher · View at Google Scholar
  82. S. M. A. Huang, Y. M. Mishina, S. Liu et al., “Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling,” Nature, vol. 461, no. 7264, pp. 614–620, 2009. View at Publisher · View at Google Scholar · View at Scopus
  83. F. C. Gonsalves, K. Klein, B. B. Carson et al., “An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 15, pp. 5954–5963, 2011. View at Publisher · View at Google Scholar
  84. P. S. Klein and D. A. Melton, “A molecular mechanism for the effect of lithium on development,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 16, pp. 8455–8459, 1996. View at Publisher · View at Google Scholar · View at Scopus
  85. T. Thomas, L. Stansifer, and R. L. Findling, “Psychopharmacology of pediatric bipolar disorders in children and adolescents,” Pediatric Clinics of North America, vol. 58, no. 1, pp. 173–187, 2011. View at Publisher · View at Google Scholar
  86. D. J. Newport, A. C. Viguera, A. J. Beach, J. C. Ritchie, L. S. Cohen, and Z. N. Stowe, “Lithium placental passage and obstetrical outcome: implications for clinical management during late pregnancy,” American Journal of Psychiatry, vol. 162, no. 11, pp. 2162–2170, 2005. View at Publisher · View at Google Scholar · View at Scopus
  87. T. Pearlstein, “Perinatal depression: treatment options and dilemmas,” Journal of Psychiatry and Neuroscience, vol. 33, no. 4, pp. 302–318, 2008. View at Google Scholar · View at Scopus
  88. S. J. Lubner, M. Kunnimalaiyaan, K. D. Holen et al., “A preclinical and clinical study of lithium in low-grade neuroendocrine tumors,” Oncologist, vol. 16, no. 4, pp. 452–457, 2011. View at Publisher · View at Google Scholar
  89. M. P. Coghlan, A. A. Culbert, D. A. E. Cross et al., “Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription,” Chemistry and Biology, vol. 7, no. 10, pp. 793–803, 2000. View at Publisher · View at Google Scholar · View at Scopus
  90. E. J. Park, S. J. Choi, Y. C. Kim, S. H. Lee, S. W. Park, and S. K. Lee, “Novel small molecule activators of β-catenin-mediated signaling pathway: structure-activity relationships of indirubins,” Bioorganic and Medicinal Chemistry Letters, vol. 19, no. 8, pp. 2282–2284, 2009. View at Publisher · View at Google Scholar
  91. P. V. N. Bodine, B. Stauffer, H. Ponce-de-Leon et al., “A small molecule inhibitor of the Wnt antagonist secreted frizzled-related protein-1 stimulates bone formation,” Bone, vol. 44, no. 6, pp. 1063–1068, 2009. View at Publisher · View at Google Scholar · View at Scopus
  92. J. K. Chen, J. Taipale, K. E. Young, T. Maiti, and P. A. Beachy, “Small molecule modulation of smoothened activity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 22, pp. 14071–14076, 2002. View at Publisher · View at Google Scholar · View at Scopus
  93. D. D. Von Hoff, P. M. LoRusso, C. M. Rudin et al., “Inhibition of the hedgehog pathway in advanced basal-cell carcinoma,” The New England Journal of Medicine, vol. 361, no. 12, pp. 1164–1172, 2009. View at Publisher · View at Google Scholar · View at Scopus
  94. T. Klingebiel, J. Boos, F. Beske et al., “Treatment of children with metastatic soft tissue sarcoma with oral maintenance compared to high dose chemotherapy: report of the HD CWS-96 trial,” Pediatric Blood and Cancer, vol. 50, no. 4, pp. 739–745, 2008. View at Publisher · View at Google Scholar · View at Scopus