Medulloblastoma tumorigenesis diverges from cerebellar granule cell differentiation in patched heterozygous mice
Medulloblastoma tumorigenesis diverges from cerebellar granule cell differentiation in patched heterozygous mice
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DOI：
10.1016/s0012-1606(03)00434-2
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发表时间：
2003-11-01
影响因子：
2.7
通讯作者：
Pomeroy, SL
中科院分区：
文献类型：
--
作者：
Kim, JYH;Nelson, AL;Pomeroy, SL
髓母细胞瘤是一种小脑肿瘤，可能是由于音刺猬 (Shh) 信号传导异常激活而引起，该信号通常调节小脑颗粒细胞增殖。 Shh 受体 PATCHED (PTCH) 的突变与髓母细胞瘤相关，但尚未发现髓母细胞瘤具有 PTCH 杂合性丧失。我们探讨了修补（Ptc）杂合性是否从根本上改变了颗粒细胞分化，并通过增加 Ptc+/- 小鼠的增殖和/或减少细胞凋亡来促进肿瘤发生。我们的数据表明，出生后 Ptc+/- 小鼠颗粒细胞前体生长并未发生全面改变。然而，许多老年 Ptc+/- 小鼠表现出异常的小脑区域，其中含有持续增殖的颗粒细胞前体。由于较少的 Ptc+/- 小鼠形成髓母细胞瘤，因此这些颗粒细胞代表了肿瘤发生的发育破坏但尚未确定的阶段。尽管 Ptc+/- 小鼠髓母细胞瘤表达神经发育基因，但它们与颗粒细胞分化不同，尽管它们持续生长，但有丝分裂后标记物的共表达不一致。与人类髓母细胞瘤一样，神经营养素 3 受体 trkC/Ntrk3 水平降低的小鼠肿瘤显示体内细胞凋亡减少，这说明了 TrkC 在调节肿瘤细胞存活中的作用。这些结果表明，Ptc 杂合性通过使颗粒细胞前体亚群易于形成增殖休息和随后的发育基因表达失调而促进肿瘤发生。 (C) 2003 Elsevier Inc. 保留所有权利。
Medulloblastoma is a cerebellar tumor that can arise through aberrant activation of Sonic hedgehog (Shh) signaling, which normally regulates cerebellar granule cell proliferation. Mutations of the Shh receptor PATCHED (PTCH) are associated with medulloblastomas, which have not been found to have loss of PTCH heterozygosity. We address whether patched (Ptc) heterozygosity fundamentally alters granule cell differentiation and contributes to tumorigenesis by increasing proliferation and/or decreasing apoptosis in Ptc+/- mice. Our data show that postnatal Ptc+/- mouse granule cell precursor growth is not globally altered. However, many older Ptc+/- mice display abnormal cerebellar regions containing persistently proliferating granule cell precursors. Since fewer Ptc+/- mice form medulloblastomas, these granule cell rests represent a developmentally disrupted, but uncommitted stage of tumorigenesis. Although Ptc+/- mouse medulloblastomas express neurodevelopmental genes, they diverge from granule cell differentiation in their discordant coexpression of postmitotic markers despite their ongoing growth. Like human medulloblastomas, mouse tumors with reduced levels of the neurotrophin-3 receptor, trkC/Ntrk3, display decreased apoptosis in vivo, illustrating the role of TrkC in regulating tumor cell survival. These results indicate that Ptc heterozygosity contributes to tumorigenesis by predisposing a subset of granule cell precursors to the formation of proliferative rests and subsequent dysregulation of developmental gene expression. (C) 2003 Elsevier Inc. All rights reserved.