Importance of Aberrantly Activated Hedgehog/Gli Pathway in Tumour Progression

Česká verzia

Authors: Kateřina Kreisingerová; Ubica Ondrušová; Pavel Horák; Jiří Vachtenheim
Authors place of work: Ústav lékařské biochemie a laboratorní diagnostiky, 1. LF UK a VFN Praha
Published in the journal: Klin Onkol 2020; 33(3): 177-183
Category: Přehled
doi: https://doi.org/10.14735/amko2020177

Summary

Background: Cancer is the second most common cause of death in the Czech Republic. The treatment of this disease is very exhausting for the patients and the treatment has often limited success only. The disease often relapses after a period of remission. Moreover, metastases often appear in lungs, liver or other organs and worsen patient’s prognosis and probability of survival. The Hedgehog (Hh) signaling pathway is one of the important pathways that affects initiation and maintenance of various types of tumours. When aberrantly activated, Hh signaling pathway helps cells escape apoptosis, disturbs cell energy metabolism, influences the process of epithelial-mesenchymal transition, helps to escape immune system, maintains cancer stem cells and supports metastasis. The role of Hh signaling cascade in tumour initiation, maintenance and progression is intensively studied. Several types of inhibitors of this pathway were developed. The most intensively studied were inhibitors of the receptor Smoothened. Due to commonly occurring resistance, the research of other groups of inhibitors is in the centre of interest. These new drugs do not target receptor Smoothened but proteins standing downstream of Smoothened (inhibition of final Gli transcription factors). The drugs could give new hope to patients whose treatment fails.

Purpose: This review summarizes the findings about the role of Hh signaling pathway in tumour development and describes the progress in the development of targeted inhibitors of this pathway.

Keywords:

molecular targeted therapy – apoptosis – epithelial-mesenchymal transition – metastasis – drug resistance – Hedgehog signaling pathway – Cancer stem cells

Zdroje

1. Nüsslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature 1980; 287 (5785): 795–801. doi: 10.1038/287795a0.

2. Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev 2001; 15 (23): 3059–3087. doi: 10.1101/gad.938601.

3. Machold R, Hayashi S, Rutlin M et al. Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron 2003; 39 (6): 937–950. doi: 10.1016/s0896-6273 (03) 00561-0.

4. Lowry WE, Richter L, Yachechko R et al. Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc Natl Acad Sci U S A 2008; 105 (8): 2883–2888. doi: 10.1073/pnas.0711983105.

5. Watkins DN, Berman DM, Burkholder SG et al. Hedgehog signaling within airway epithelial progenitors and in small-cell lung cancer. Nature 2003; 422 (6929): 313–317. doi: 10.1038/nature01493.

6. Hanna A, Shevde LA. Hedgehog signaling: modulation of cancer properties and tumor microenvironment. Mol Cancer 2016; 15: 24. doi: 10.1186/s12943-016-0509-3.

7. Skoda AM, Simovic D, Karin V et al. The role of the Hedgehog signaling pathway in cancer: A comprehensive review. Bosn J Basic Med Sci 2018; 18 (1): 8–20. doi: 10.17305/bjbms.2018.2756.

8. Katoh Y, Katoh M. Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant Hedgehog signaling activation. Curr Mol Med 2009; 9 (7): 873–886. doi: 10.2174/156652409789105570.

9. Milla LA, Gonzalez-Ramirez CN, Palma V. Sonic Hedgehog in cancer stem cells: a novel link with autophagy. Biol Res 2012; 45 (3): 223–230. doi: 10.4067/S0716-97602012000300004.

10. Vlčková K, Ondrušová L, Vachtenheim J et al. Survivin, a novel target of the Hedgehog/GLI signaling pathway in human tumor cells. Cell Death Dis 2016; 7: e2048. doi: 10.1038/cddis.2015.389.

11. Seto M, Ohta M, Asaoka Y et al. Regulation of the Hedgehog signaling by the mitogen-activated protein kinase cascade in gastric cancer. Mol Carcinog 2009; 48 (8): 703–712. doi: 10.1002/mc.20516.

12. Stecca B, Mas C, Clement V et al. Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proc Natl Acad Sci U S A 2007; 104 (14): 5895–5900. doi: 10.1073/pnas.0700776104.

13. Dennler S, Andre J, Alexaki I et al. 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 2007; 67 (14): 6981–6986. doi: 10.1158/0008-5472.CAN-07-0491.

14. Dennler S, Andre J, Verrecchia F et al. Cloning of the human GLI2 promoter: transcriptional activation by transforming growth factor-beta via SMAD3/beta-catenin cooperation. J Biol Chem 2009; 284 (46): 31523–31531. doi: 10.1074/jbc.M109.059964.

15. Riobo NA, Lu K, Ai X et al. Phosphoinositide 3-kinase and Akt are essential for sonic Hedgehog signaling. Proc Natl Acad Sci U S A 2006; 103 (12): 4505–4510. doi: 10.1073/pnas.0504337103.

16. Gu D, Xie J. Non-canonical Hh signaling in cancer-current understanding and future directions. Cancers (Basel) 2015; 7 (3): 1684–1698. doi: 10.3390/cancers7030857.

17. Pietrobono S, Gagliardi S, Stecca B. Non-canonical Hedgehog signaling pathway in cancer: activation of GLI transcription factors beyond Smoothened. Front Genet 2019; 10: 556. doi: 10.3389/fgene.2019.00556.

18. Archer TC, Weeraratne SD, Pomeroy SL. Hedgehog-GLI pathway in medulloblastoma. J Clin Oncol 2012; 30 (17): 2154–2156. doi: 10.1200/JCO.2011.41.1181.

19. Pellegrini C, Maturo MG, Di Nardo L et al. Understanding the molecular genetics of basal cell carcinoma. Int J Mol Sci 2017; 18 (11): E2485. doi: 10.3390/ijms18112485.

20. Thayer SP, di Magliano MP, Heiser PW et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003; 425 (6960): 851–856. doi: 10.1038/nature02009.

21. Abe Y, Tanaka N. The Hedgehog signaling networks in lung cancer: The mechanisms and roles in tumor progression and implications for cancer therapy. Biomed Res Int 2016; 2016: 7969286. doi: 10.1155/2016/7969286.

22. Bigelow RL, Chari NS, Unden AB et al. Transcriptional regulation of bcl-2 mediated by the sonic Hedgehog signaling pathway through Gli-1. J Biol Chem 2004; 279 (2): 1197–1205. doi: 10.1074/jbc.M310589200.

23. Regl G, Kasper M, Schnidar H et al. Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2. Cancer Res 2004; 64 (21): 7724–7731. doi: 10.1158/0008-5472.CAN-04-1085.

24. Kurita S, Mott JL, Cazanave SC et al. Hedgehog inhibition promotes a switch from Type II to Type I cell death receptor signaling in cancer cells. PLoS One 2011; 6 (3): e18330. doi: 10.1371/journal.pone.0018330.

25. Meister MT, Boedicker C, Klingebiel T et al. Hedgehog signaling negatively co-regulates BH3-only protein Noxa and TAp73 in TP53-mutated cells. Cancer Lett 2018; 429: 19–28. doi: 10.1016/j.canlet.2018.04.025.

26. Abe Y, Oda-Sato E, Tobiume K et al. Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2. Proc Natl Acad Sci U S A 2008; 105 (12): 4838–4843. doi: 10.1073/pnas.0712216105.

27. Matějka VM, Fínek J, Králíčková M. Epithelial-mesenchymal transition in tumor tissue and its role for metastatic spread of cancer. Klin Onkol 2017; 30 (1): 20–27. doi: 10.14735/amko201720.

28. Gonzalez DM, Medici D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal 2014; 7 (344): re8. doi: 10.1126/scisignal.2005189.

29. Riaz SK, Ke Y, Wang F et al. Influence of SHH/GLI1 axis on EMT mediated migration and invasion of breast cancer cells. Sci Rep 2019; 9 (1): 6620. doi: 10.1038/s41598-019-43093-x.

30. Wang L, Jin JQ, Zhou Y et al. Gli is activated and promotes epithelial-mesenchymal transition in human esophageal adenocarcinoma. Oncotarget 2018; 9 (1): 853–865. doi: 10.18632/oncotarget.22856.

31. Wang F, Ma L, Zhang Z et al. Hedgehog signaling regulates epithelial-mesenchymal transition in pancreatic cancer stem-like cells. J Cancer 2016; 7 (4): 408–417. doi: 10.7150/jca.13305.

32. Liu Q, Sheng W, Dong M et al. Gli1 promotes transforming growth factor-beta1- and epidermal growth factor-induced epithelial to mesenchymal transition in pancreatic cancer cells. Surgery 2015; 158 (1): 211–224. doi: 10.1016/j.surg.2015.03.016.

33. Maitah MY, Ali S, Ahmad A et al. Up-regulation of sonic Hedgehog contributes to TGF-beta1-induced epithelial to mesenchymal transition in NSCLC cells. PLoS One 2011; 6 (1): e16068. doi: 10.1371/journal.pone.0016068.

34. Neelakantan D, Zhou H, Oliphant MU et al. EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells. Nat Commun 2017; 8: 15773. doi: 10.1038/ncomms15773.

35. Yoo YA, Kang MH, Lee HJ et al. Sonic Hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT, and MMP-9 pathway in gastric cancer. Cancer Res 2011; 71 (22): 7061–7070. doi: 10.1158/0008-5472.

36. Fan HX, Wang S, Zhao H et al. Sonic Hedgehog signaling may promote invasion and metastasis of oral squamous cell carcinoma by activating MMP-9 and E-cadherin expression. Med Oncol 2014; 31 (7): 41. doi: 10.1007/s12032-014-0041-5.

37. Chen JS, Huang XH, Wang Q et al. Sonic Hedgehog signaling pathway induces cell migration and invasion through focal adhesion kinase/AKT signaling-mediated activation of matrix metalloproteinase (MMP) -2 and MMP-9 in liver cancer. Carcinogenesis 2013; 34 (1): 10–19. doi: 10.1093/carcin/bgs274.

38. Holčaková J, Nekulová M, Orzol P et al. Mechanisms of drug resistance and cancer stem cells. Klin Onkol 2014; 27 (Suppl 1): S34–S41. doi: 10.14735/amko20141s34.

39. Takebe N, Miele L, Harris PJ et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol 2015; 12 (8): 445–464. doi: 10.1038/nrclinonc.2015.61.

40. Po A, Ferretti E, Miele E et al. Hedgehog controls neural stem cells through p53-independent regulation of Nanog. EMBO J 2010; 29 (15): 2646–2658. doi: 10.1038/emboj.2010.131.

41. Gopinath S, Malla R, Alapati K et al. Cathepsin B and uPAR regulate self-renewal of glioma-initiating cells through GLI-regulated Sox2 and Bmi1 expression. Carcinogenesis 2013; 34 (3): 550–559. doi: 10.1038/emboj.2010.131.

42. Clement V, Sanchez P, de Tribolet N et al. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol 2007; 17 (2): 165–172. doi: 10.1016/j.cub.2006.11.033.

43. Cochrane CR, Szczepny A, Watkins DN et al. Hedgehog signaling in the maintenance of cancer stem cells. Cancers (Basel) 2015; 7 (3): 1554–1585. doi: 10.3390/cancers7030851.

44. Campbell V, Copland M. Hedgehog signaling in cancer stem cells: a focus on hematological cancers. Stem Cells Cloning 2015; 8: 27–38. doi: 10.2147/SCCAA.S58613.

45. Cooper MK, Porter JA, Young KE et al. Teratogen-mediated inhibition of target tissue response to Shh signaling. Science 1998; 280 (5369): 1603–1607. doi: 10.1126/science.280.5369.1603.

46. Xin M. Hedgehog inhibitors: a patent review (2013-present). Expert Opin Ther Pat 2015; 25 (5): 549–565. doi: 10.1517/13543776.2015.1019864.

47. Maughan BL, Suzman DL, Luber B et al. Pharmacodynamic study of the oral Hedgehog pathway inhibitor, vismodegib, in patients with metastatic castration-resistant prostate cancer. Cancer Chemother Pharmacol 2016; 78 (6): 1297–1304. doi: 10.1007/s00280-016-3191-7.

48. Berlin J, Bendell JC, Hart LL et al. A randomized phase II trial of vismodegib versus placebo with FOLFOX or FOLFIRI and bevacizumab in patients with previously untreated metastatic colorectal cancer. Clin Cancer Res 2013; 19 (1): 258–267. doi: 10.1158/1078-0432.CCR-12-1800.

49. National Library of Medicine, Bethesda (MD, US), c2000 [online]. Dostupné z: https: //clinicaltrials.gov/ct2/home.

50. Casey D, Demko S, Shord S et al. FDA approval summary: Sonidegib for locally advanced basal cell carcinoma. Clin Cancer Res 2017; 23 (10): 2377–2381. doi: 10.1158/1078-0432.CCR-16-2051.

51. Study of patidegib topical gel, 2%, for the reduction of disease burden of persistently developing basal cell carcinomas (BCCs) in subjects with basal cell nevus syndrome (Gorlin syndrome) [online]. Dostupné z: https: //clinicaltrials.gov/ct2/show/NCT03703310?term=patidegib&draw=2&rank=1.

52. Norsworthy KJ, By K, Subramaniam S et al. FDA approval summary: Glasdegib for newly diagnosed acute myeloid leukemia. Clin Cancer Res 2019; 25 (20): 6021–6025. doi: 10.1158/1078-0432.CCR-19-0365.

53. Stanton BZ, Peng LF. Small-molecule modulators of the sonic Hedgehog signaling pathway. Mol Biosyst 2010; 6 (1): 44–54. doi: 10.1039/b910196a.

54. Michaud NR, Wang Y, McEachern KA et al. Novel neutralizing Hedgehog antibody MEDI-5304 exhibits antitumor activity by inhibiting paracrine Hedgehog signaling. Mol Cancer Ther 2014; 13 (2): 386–398. doi: 10.1158/1535-7163.

55. Lauth M, Bergstrom A, Shimokawa T et al. Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc Natl Acad Sci U S A 2007; 104 (20): 8455–8460. doi: 10.1073/pnas.0609699104.

56. Reda J, Vachtenheim J, Vlckova K et al. Widespread expression of Hedgehog pathway components in a large panel of human tumor cells and inhibition of tumor growth by GANT61: Implications for cancer therapy. Int J Mol Sci 2018; 19 (9): E2682. doi: 10.3390/ijms19092682.

57. Pan D, Li Y, Li Z et al. Gli inhibitor GANT61 causes apoptosis in myeloid leukemia cells and acts in synergy with rapamycin. Leuk Res 2012; 36 (6): 742–748. doi: 10.1016/j.leukres.2012.02.012.

58. Tong W, Qiu L, Qi M et al. GANT-61 and GDC-0449 induce apoptosis of prostate cancer stem cells through a GLI-dependent mechanism. J Cell Biochem 2018; 119 (4): 3641–3652. doi: 10.1002/jcb.26572.

59. Vlčková K, Réda J, Ondrušová L et al. GLI inhibitor GANT61 kills melanoma cells and acts in synergy with obatoclax. Int J Oncol 2016; 49 (3): 953–960. doi: 10.3892/ijo.2016.3596.

60. Beauchamp EM, Ringer L, Bulut G et al. Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. J Clin Invest 2011; 121 (1): 148–160. doi: 10.1172/JCI42874.

61. Peer E, Tesanovic S, Aberger F. Next-generation Hedgehog/GLI pathway inhibitors for cancer therapy. Cancers (Basel) 2019; 11 (4): 538. doi: 10.3390/cancers11040538.

62. Kim J, Tang JY, Gong R et al. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell 2010; 17 (4): 388–399. doi: 10.1016/j.ccr.2010.02.027.

63. Kim J, Aftab BT, Tang JY et al. Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer Cell 2013; 23 (1): 23–34. doi: 10.1016/j.ccr.2012.11.017.

64. Gonnissen A, Isebaert S, McKee CM et al. The hedgehog inhibitor GANT61 sensitizes prostate cancer cells to ionizing radiation both in vitro and in vivo. Oncotarget 2016; 7 (51): 84286–84298. doi: 10.18632/oncotarget.12483.

65. Li J, Cai J, Zhao S et al. GANT61, a GLI inhibitor, sensitizes glioma cells to the temozolomide treatment. J Exp Clin Cancer Res 2016; 35 (1): 184. doi: 10.1186/s13046-016-0463-3.

66. Chen YJ, Lin CP, Hsu ML et al. Sonic Hedgehog signaling protects human hepatocellular carcinoma cells against ionizing radiation in an autocrine manner. Int J Radiat Oncol Biol Phys 2011; 80 (3): 851–859. doi: 10.1016/j.ijrobp.2011.01.003.

67. Sun W, Li L, Du Z et al. Combination of phospholipase Ce knockdown with GANT61 sensitizes castration-resistant prostate cancer cells to enzalutamide by suppressing the androgen receptor signaling pathway. Oncol Rep 2019; 41 (5): 2689–2702. doi: 10.3892/or.2019.7054.