髓母细胞瘤中相关信号通路与靶向抑制剂研究进展_West China Medical Journal

Authors：

田猛 , 方芳 , 李蹊 ,  游潮

Corresponding author：

游潮, Email: tianmong007@gmail.com

Keywords：

髓母细胞瘤; 信号传导; 靶向抑制剂; 综述

DOI：

10.7507/1002-0179.20130197

Video：

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髓母细胞瘤（MD）是一种高发于儿童的恶性脑肿瘤。虽然目前还没有针对这一肿瘤的理想治疗措施，但近来的研究表明在该肿瘤的发病机制中一些相关的信号通路扮演着十分重要的角色。深入研究这些信号传导通路及其相互作用关系有助于对MD发病机制的进一步认识。在这些信号通路中，SHH（sonic hedgehog signaling pathway）对髓母细胞瘤的形成最具有特异性。因此针对SHH信号通路的靶向抑制剂的研究得到了深入地开展，并展现出良好的应用前景。现就MD发病机制中的信号通路和基于SHH信号通路靶向抑制剂的研究进展作一综述，为探索更加有效的治疗方法提供新的理论依据。

Citation： 田猛,方芳,李蹊,游潮. 髓母细胞瘤中相关信号通路与靶向抑制剂研究进展. West China Medical Journal, 2013, 28(4): 623-626. doi: 10.7507/1002-0179.20130197 Copy

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8.	Goodrich LV, Milenkovic L, Higgins KM, et al. Altered neural cell fates and medulloblastoma in mouse patched mutants[J]. Science, 1997, 277(5329): 1109-1113.
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17.	Fan X, Mikolaenko I, Elhassan I, et al. Notch1 and notch2 have opposite effects on embryonal brain tumor growth[J]. Cancer Res, 2004, 64(21): 7787-7793.
18.	Fan X, Matsui W, Khaki L, et al. Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors[J]. Cancer Res, 2006, 66(15): 7445-7452.
19.	Knoepfler PS, Kenney AM. Neural precursor cycling at sonic speed: N-Myc pedals, GSK-3 brakes[J]. Cell Cycle, 2006, 5(1): 47-52.
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28.	Wang Q, Li H, Liu N, et al. Correlative analyses of notch signaling with resveratrol-induced differentiation and apoptosis of human medulloblastoma cells[J]. Neurosci Lett, 2008, 438(2): 168-173.
29.	Wen S, Li H, Wu ML, et al. Inhibition of NF-κB signaling commits resveratrol-treated medulloblastoma cells to apoptosis without neuronal differentiation[J]. J Neurooncol, 2011, 104(1): 169-177.
30.	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]. J Clin Invest, 2011, 121(1): 148-160.
31.	Kim J, Lee JJ, Kim J, et al. Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector[J]. Proc Natl Acad Sci USA, 2010, 107(30): 13432-13437.
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33.	Favretto ME, Marouf S, Ioannou P. Arsonoliposomes for the Potential Treatment of Medulloblastoma[J]. Pharm Res, 2009, 26(10): 2237-2246.

1. 　Fan X, Eberhart CJ. Medulloblastoma stem cells [J]. J Clin Oncol, 2008, 26(17): 2821-2827.
2. 　Gibson P, Tong Y, Robinson G, et al. Subtypes of medulloblastoma have distinct developmental origins[J]. Nature, 2010, 468(7327): 1095-1099.
3. 　Visvader JE. Cells of origin in cancer[J]. Nature, 2011, 469(7330): 314-322.
4. 　Polkinghorn WR, Tarbell NJ. Medulloblastoma: tumorigenesis, current clinical paradigm, and efforts to improve risk stratification[J]. Nat Rev Clin Oncol, 2007, 4(5): 295-304.
5. 　Gailani MR, Bale SJ, Leffell DJ, et al. Developmental defects in Gorlin syndrome related to a putative tumor suppressor gene on chromosome 9[J]. Cell, 1992, 69(1): 111-117.
6. 　Kimonis VE, Goldstein AM, Pastakia B, et al. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome[J]. Am J Med Genet, 1997, 69(3): 299-308.
7. 　Raffel C, Jenkins RB, Frederick L, et al. Sporadic medulloblastomas contain PTCH mutations [J]. Cancer Res, 1997, 57(5): 842-845.
8. 　Goodrich LV, Milenkovic L, Higgins KM, et al. Altered neural cell fates and medulloblastoma in mouse patched mutants[J]. Science, 1997, 277(5329): 1109-1113.
9. 　Smyth I, Narang MA, Evans T, et al. Isolation and characterization of human patched 2 (PTCH2), a putative tumour suppressor gene inbasal cell carcinoma and medulloblastoma on chromosome 1p32 [J]. Hum Mol Genet, 1999, 8(2): 291-297.
10. 　Lee Y, Miller HL, Russell HR, et al. Patched2 modulates tumorigenesis in patched1 heterozygous mice[J]. Cancer Res, 2006, 66(14): 6964-6971.
11. 　Reifenberger J, Woher M, Weber RG, et a1. Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system [J]. Cancer Res, 1998, 58(9): 1798-1803.
12. 　Taylor MD, Liu L, Raffel C, et al. Mutations in SUFU predispose to medulloblastoma [J]. Nat Genet, 2002, 31(3): 306-310.
13. 　张红梅. Wnt信号转导途径与MD[J]. 国际病理科学与临床杂志, 2007, 27(1): 32-35.
14. 　Hamilton SR, Liu B, Parsons RE, et al. The molecular basis of Turcot’s syndrome [J]. N Engl J Med, 1995, 332(13): 839-847.
15. 　Baeza N, Masuoka J, Kleihues P, et al. AXIN1 mutations but not deletions in cerebellar medulloblastomas [J]. Oncogene, 2003, 22(4): 632-636.
16. 　Zhang P, Li H, WuM L, et al. c-Myc downregulation: a critical molecular event in resveratrol-induced cell cycle arrest and apoptosis of human medulloblastoma cells[J]. J Neurooncol, 2006, 80(2): 123-131.
17. 　Fan X, Mikolaenko I, Elhassan I, et al. Notch1 and notch2 have opposite effects on embryonal brain tumor growth[J]. Cancer Res, 2004, 64(21): 7787-7793.
18. 　Fan X, Matsui W, Khaki L, et al. Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors[J]. Cancer Res, 2006, 66(15): 7445-7452.
19. 　Knoepfler PS, Kenney AM. Neural precursor cycling at sonic speed: N-Myc pedals, GSK-3 brakes[J]. Cell Cycle, 2006, 5(1): 47-52.
20. 　Rao G, Pedone CA, Valle LD, et al. Sonic hedgehog and insulinlike growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice[J]. Oncogene, 2004, 23(36): 6156-6162.
21. 　Browd SR, Kenney AM, Gottfried ON, et al. N-myc can substitute for insulinlike growth factor signaling in a mouse model of sonic hedgehog-induced medulloblastoma[J]. Cancer Res, 2006, 66(5): 2666-2672.
22. 　Meng X, Poon R, Zhang X, et al. Suppressor of fused negatively regulates beta-catenin signaling[J]. J Biol Chem, 2001, 276(43): 40113-40119.
23. 　Taylor MD, Zhang X, Liu L, et al. Failure of a medulloblastoma derived mutant of SUFU to suppress WNT signaling[J]. Oncogene, 2004, 23(26): 4577-4583.
24. 　Stephan Teglund, Rune Toftgård. Hedgehog beyond medulloblastoma and basal cell carcinoma[J]. Biochimica Biophysica Acta, 2010, 1805(2): 181-208.
25. 　Jessica MY, Curran T. The Hedgehog’s tale: developing strategies for targeting cancer[J]. Nat Rev Cancer, 2011, 11(7): 493-501.
26. 　Rudin CM, Hann CL, Laterra J, et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449[J]. N Engl J Med, 2009, 361(12): 1173-1178.
27. 　Zhang P, Li H, Wu ML, et al. c-Myc downregulation: a critical molecular event in resveratrol-induced cell cycle arrest and apoptosis of human medulloblastoma cells[J]. J Neurooncol, 2006, 80(2): 123-131.
28. 　Wang Q, Li H, Liu N, et al. Correlative analyses of notch signaling with resveratrol-induced differentiation and apoptosis of human medulloblastoma cells[J]. Neurosci Lett, 2008, 438(2): 168-173.
29. 　Wen S, Li H, Wu ML, et al. Inhibition of NF-κB signaling commits resveratrol-treated medulloblastoma cells to apoptosis without neuronal differentiation[J]. J Neurooncol, 2011, 104(1): 169-177.
30. 　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]. J Clin Invest, 2011, 121(1): 148-160.
31. 　Kim J, Lee JJ, Kim J, et al. Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector[J]. Proc Natl Acad Sci USA, 2010, 107(30): 13432-13437.
32. 　Raju GP. Arsenic: a potentially useful poison for Hedgehog-driven cancers[J]. J Clin Invest, 2011, 121(1): 14-16.
33. 　Favretto ME, Marouf S, Ioannou P. Arsonoliposomes for the Potential Treatment of Medulloblastoma[J]. Pharm Res, 2009, 26(10): 2237-2246.

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