The impact of osteoblastic differentiation on osteosarcomagenesis in the mouse.
The impact of osteoblastic differentiation on osteosarcomagenesis in the mouse.
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骨肉瘤仍然是一个谜组的恶性肿瘤，共同存在的转化细胞产生骨样基质，即使这些细胞构成的肿瘤体积的少数。因此，骨肉瘤的分化状态已成为研究这一疾病的人感兴趣和挑战的话题。为了测试原始细胞如何促进转化细胞的最终分化状态，我们比较了使用Prx 1-Cre、胶原蛋白-1 α1-Cre和骨钙素-Cre分别转化未分化间充质、前成骨细胞和成熟成骨细胞的Cre-LoxP条件性破坏细胞周期检查点肿瘤抑制基因Trp 53和Rb 1的相对致瘤性。Prx 1和Col 1 α1谱系发生肿瘤，几乎完全转移，如预期。44%的Oc-Cre; Rb 1fl/fl; Trp 53 fl/fl小鼠也发生了骨肉瘤。我们使用EdU点击化学证实，Oc-Cre谱系包括非常少的活跃循环细胞。通过评估放射学矿化和组织学类骨质生成，肿瘤的分化状态与起源谱系的分化状态无关。一些骨钙素谱系来源的骨肉瘤是成骨细胞最少的。骨钙素在肿瘤中的免疫组化与DNA甲基转移酶的表达相关，这表明这些表观遗传调节因子的沉默可能会影响骨肉瘤的最终分化状态。分化的、增殖性最低的成骨细胞的转化是可能的，但可能需要这样的表观遗传重编程，使得肿瘤不再类似于它们的分化起源。
Osteosarcomas remain an enigmatic group of malignancies that share in common the presence of transformed cells producing osteoid matrix, even if these cells comprise a minority of the tumor volume. The differentiation state of osteosarcomas has therefore become a topic of interest and challenge to those who study this disease. In order to test how the cell of origin contributes to the final state of differentiation in the transformed cells, we compared the relative tumorigenicity of Cre-LoxP conditional disruption of the cell cycle checkpoint tumor suppressor genes Trp53 and Rb1 using Prx1-Cre, Collagen-1α1-Cre, and Osteocalcin-Cre to transform undifferentiated mesenchyme, pre-osteoblasts, and mature osteoblasts, respectively. The Prx1 and Col1α1 lineages developed tumors with nearly complete penetrance, as anticipated. Osteosarcomas also developed in 44 percent of Oc-Cre;Rb1fl/fl;Trp53fl/fl mice. We confirmed using EdU click chemistry that the Oc-Cre lineage includes very few actively cycling cells. By assessing radiographic mineralization and histologic osteoid production, the differentiation state of tumors did not correlate with the differentiation state of the lineage of origin. Some of the osteocalcin-lineage-derived osteosarcomas were among the least osteoblastic. Osteocalcin immunohistochemistry in tumors correlated well with expression of DNA methyl transferases, suggesting that silencing of these epigenetic regulators may influence the final differentiation state of an osteosarcoma. Transformation of differentiated, minimally proliferative osteoblasts is possible, but may require such an epigenetic reprogramming that the tumors no longer resemble their differentiated origins.
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影响因子：
5.6
作者：
San Martin, Inga A.;Varela, Nelson;Gaete, Marcia;Villegas, Karina;Osorio, Mariana;Tapia, Julio C.;Antonelli, Marcelo;Mancilla, Edna E.;Pereira, Barry P.;Nathan, Saminathan S.;Lian, Jane B.;Stein, Janet L.;Stein, Gary S.;Van Wijnen, Andre J.;Galindo, Mario
通讯作者：
Galindo, Mario
影响因子：
2.7
作者：
LIU, F;MALAVAL, L;AUBIN, JE
通讯作者：
AUBIN, JE
DOI：
10.1073/pnas.0805462105
发表时间：
2008-08-19
影响因子：
11.1
作者：
Berman, Seth D.;Calo, Eliezer;Lees, Jacqueline A.
通讯作者：
Lees, Jacqueline A.
影响因子：
0.7
作者：
Liu, F;Woitge, HW;Kream, BE
通讯作者：
Kream, BE
DOI：
10.1083/jcb.129.5.1421
发表时间：
1995-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Rossert J;Eberspaecher H;de Crombrugghe B
通讯作者：
de Crombrugghe B