Pazzaglia S, Tanori M, Mancuso M, Gessi M, Pasquali E, Leonardi S, Oliva M A, Rebessi S, Di Majo V, Covelli V, Giangaspero F, Saran A
Biotechnology Unit, ENEA CR-Casaccia, Rome, Italy.
Oncogene. 2006 Sep 7;25(40):5575-80. doi: 10.1038/sj.onc.1209544. Epub 2006 Apr 24.
Inactivation of one Ptc1 allele predisposes humans and mice to spontaneous medulloblastoma development, and irradiation of newborn Ptc1 heterozygous mice results in dramatic increase of medulloblastoma incidence. While a role for loss of wild-type (wt) Ptc1 (LOH) in radiation-induced medulloblastomas from Ptc1(neo67/+) mice is well established, the importance of this event in spontaneous medulloblastomas is still unclear. Here, we demonstrate that biallelic Ptc1 loss plays a crucial role in spontaneous medulloblastomas, as shown by high rate of wt Ptc1 loss in spontaneous tumors. In addition, remarkable differences in chromosomal events involving the Ptc1 locus in spontaneous and radiation-induced medulloblastomas suggest distinct mechanisms for Ptc1 loss. To assess when, during tumorigenesis, Ptc1 loss occurs, we characterized cerebellar abnormalities that precede tumor appearance in Ptc1(neo67/+) mice. We show that inactivation of only one copy of Ptc1 is sufficient to give rise to abnormal cerebellar proliferations with different degree of altered cell morphology, but lacking potential to progress to neoplasia. Furthermore, we identify biallelic Ptc1 loss as the event causally related to the transition from the preneoplastic stage to full blown medulloblastoma. These results underscore the utility of the Ptc1(neo67/+) mouse model for studies on the mechanisms of medulloblastoma and for development of new therapeutic strategies.
一个Ptc1等位基因的失活使人类和小鼠易患自发性髓母细胞瘤，对新生的Ptc1杂合小鼠进行辐射会导致髓母细胞瘤发病率显著增加。虽然野生型（wt）Ptc1缺失（LOH）在Ptc1(neo67/+)小鼠辐射诱导的髓母细胞瘤中的作用已得到充分证实，但该事件在自发性髓母细胞瘤中的重要性仍不清楚。在这里，我们证明双等位基因Ptc1缺失在自发性髓母细胞瘤中起关键作用，这在自发性肿瘤中wt Ptc1的高缺失率中得到体现。此外，自发性和辐射诱导的髓母细胞瘤中涉及Ptc1基因座的染色体事件存在显著差异，这表明Ptc1缺失的机制不同。为了评估在肿瘤发生过程中Ptc1何时发生缺失，我们对Ptc1(neo67/+)小鼠肿瘤出现之前的小脑异常进行了特征描述。我们发现仅一个Ptc1拷贝失活就足以导致小脑异常增殖，细胞形态有不同程度的改变，但没有发展为肿瘤的潜力。此外，我们确定双等位基因Ptc1缺失是与从肿瘤前阶段转变为成熟髓母细胞瘤因果相关的事件。这些结果强调了Ptc1(neo67/+)小鼠模型在研究髓母细胞瘤发生机制和开发新治疗策略方面的实用性。
