髓母細胞瘤中相關信號通路與靶向抑制劑研究進展_《華西醫學》

作者：

田猛 , 方芳 , 李蹊 ,  游潮

四川大學華西醫院神經外科（成都，610041）;

關鍵詞：

髓母細胞瘤信號傳導靶向抑制劑綜述

DOI：

10.7507/1002-0179.20130197

視頻：

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髓母細胞瘤（MD）是一種高發于兒童的惡性腦腫瘤。雖然目前還沒有針對這一腫瘤的理想治療措施，但近來的研究表明在該腫瘤的發病機制中一些相關的信號通路扮演著十分重要的角色。深入研究這些信號傳導通路及其相互作用關系有助于對MD發病機制的進一步認識。在這些信號通路中，SHH（sonic hedgehog signaling pathway）對髓母細胞瘤的形成最具有特異性。因此針對SHH信號通路的靶向抑制劑的研究得到了深入地開展，并展現出良好的應用前景。現就MD發病機制中的信號通路和基于SHH信號通路靶向抑制劑的研究進展作一綜述，為探索更加有效的治療方法提供新的理論依據。

引用本文： 田猛,方芳,李蹊,游潮. 髓母細胞瘤中相關信號通路與靶向抑制劑研究進展. 華西醫學, 2013, 28(4): 623-626. doi: 10.7507/1002-0179.20130197 復制

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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.
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.
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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.

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. 　張紅梅. Wnt信號轉導途徑與MD[J]. 國際病理科學與臨床雜志, 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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髓母細胞瘤中相關信號通路與靶向抑制劑研究進展

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