Uncommitted precursor cells might contribute to increased incidence of embryonal rhabdomyosarcoma in heterozygous Patched1-mutant mice
Uncommitted precursor cells might contribute to increased incidence of embryonal rhabdomyosarcoma in heterozygous Patched1-mutant mice
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DOI：
10.1038/onc.2011.157
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发表时间：
2011-10-01
期刊：
影响因子：
8
通讯作者：
Hahn, H.
中科院分区：
文献类型：
--
作者：
Nitzki, F.;Zibat, A.;Hahn, H.
胚胎横纹肌肉瘤(ERMS)是一种儿童骨骼肌肿瘤，常由Hedgehog(HH)受体Patched1(PTCH)杂合性胚系突变引起，在人类和小鼠中都是如此。在PTCH(FLOX/+)小鼠中使用条件性基因敲除策略，我们证明了早期胚胎阶段比后期更容易发生ERMS，并且在这个阶段通常不致力于进行肌肉发生的细胞是ERMS的主要来源。我们发现，使用普遍活跃的Rosa26CreERT2在E9.5处缺失Ptch等位基因的单个拷贝导致88%的肿瘤发生率，但当Ptch等位基因在E11.5和E13.5处失活时，肿瘤发生率仅为44%和12%。与在E11.5和E13.5诱导肿瘤相比，在E9.5诱导PTCH突变也显著缩短了无ERMS生存期并增加了肿瘤的多样性。有趣的是，我们观察到，当在表达Myf5的细胞中特异性地引入Ptch突变时，ERMS的发生率降低了10倍以上，Myf5是在E9.5的所有肌肉细胞中表达的肌源性因子。我们得出结论，Myf5阴性的细胞比Myf5阳性的胚胎前体细胞更容易发生ERMS。随着年龄的增长，发生肿瘤转化的倾向下降，伴随着稳定连接的肌肉细胞的增加，PTCH突变似乎有利于尚未获得肌肉细胞命运的前体细胞中的肿瘤形成。Oncogene(2011年)30,4428-4436；doi：10.1038/onc.2011.157；2011年5月23日在线发布
Embryonal rhabdomyosarcoma (ERMS) is a tumor of the skeletal muscle in children and is frequently initiated by heterozygous germline mutations in the Hedgehog (Hh) receptor Patched1 (Ptch), both in humans and mice. Using a conditional knock-out strategy in Ptch(flox/+) mice, we demonstrate that early embryonic stages are more susceptible to ERMS development than later stages and that cells normally not committed to undergo myogenesis at this stage represent the major source of ERMS. We found that deletion of a single copy of the Ptch allele at E9.5 using the ubiquitously active Rosa26CreERT2 resulted in a tumor incidence of 88% but reached only 44% and 12% when the Ptch allele was inactivated at E11.5 and E13.5, respectively. Induction of the Ptch mutation at E9.5 did also significantly shorten ERMS-free survival and increased tumor multiplicity compared with tumor induction at E11.5 and E13.5. Interestingly, we observed a more that 10-fold reduction of ERMS incidence when the Ptch mutation was specifically introduced in Myf5-expressing cells, which is the myogenic factor expressed in all muscle cells at E9.5. We conclude that Myf5-negative cells are more susceptible to ERMS development than Myf5-positive embryonic precursors. As the propensity to undergo tumorigenic transformation declined with age, concomitant with the increase of stably committed muscle cells, it seems likely that the Ptch mutation favors tumor formation in progenitor cells, which have not yet acquired a muscle cell fate. Oncogene (2011) 30, 4428-4436; doi:10.1038/onc.2011.157; published online 23 May 2011