Local Mesenchymal Stem/Progenitor Cells Are a Preferential Target for Initiation of Adult Soft Tissue Sarcomas Associated with p53 and Rb Deficiency
Local Mesenchymal Stem/Progenitor Cells Are a Preferential Target for Initiation of Adult Soft Tissue Sarcomas Associated with p53 and Rb Deficiency
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DOI：
10.2353/ajpath.2010.100306
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发表时间：
2010-11-01
影响因子：
6
通讯作者：
Nikitin, Alexander Yu.
中科院分区：
文献类型：
--
作者：
Choi, Jinhyang;Curtis, Stephen J.;Nikitin, Alexander Yu.
大多数成人软组织肉瘤（STS）的起源细胞和发病机制仍然知之甚少。由于P53和RB肿瘤抑制基因的突变在人类STS中是常见的，我们通过Cre-loxP介导的重组在p53和Rb突变的小鼠中灭活了这些基因。在单次皮下注射携带Cre重组酶的腺病毒后，93%的小鼠发展为梭形细胞/多形性肉瘤。与人类STS相似，这些肉瘤过度表达Cxcr 4，这有助于其侵袭性。使用通过将骨髓细胞移植到携带Roso 26 Stop（loXP）Lacz或Z/EG报告基因以及floxed p53和Rb基因的小鼠体内而产生的辐射嵌合体，将经过辐射的p53（loXP/loXP）Rb（loXP/loXP）小鼠体内，可以确定肉瘤不是起源于骨髓来源的细胞，例如巨噬细胞，而是起源于局部驻留细胞。与此同时，根据软琼脂、侵袭和致瘤性试验，通过严格塑料粘附和低水平Sca-1表达（Sca-1（低）、CD 31（阴性）、CD 45（阴性））分离的真皮间充质干细胞显示出恶性转化的可能性增强。p53和Rb条件性失活后的致瘤性试验。这些细胞移植后形成的肉瘤具有未分化的高度多形性肉瘤的典型特征。总之，我们的研究表明，局部Sca-1（低）真皮间充质干/祖细胞是与p53和Rb缺陷相关的恶性转化的优先靶点。(Am J Pathol 2010，177：2645-2658; DOI：10.2353/ajpath.2010.100306）
The cell of origin and pathogenesis of the majority of adult soft tissue sarcomas (STS) remains poorly understood. Because mutations in both the P53 and RB tumor suppressor genes are frequent in STS in humans, we inactivated these genes by Cre-loxP-mediated recombination in mice with foxed p53 and Rb. Ninety-three percent of mice developed spindle cell/pleomorphic sarcomas after a single subcutaneous injection of adenovirus carrying Cre-recombinase. Similar to human STS, these sarcomas overexpress Cxcr4, which contributes to their invasive properties. Using irradiation chimeras generated by transplanting bone marrow cells front mice carrying either the Roso26Stop(loxP)Lacz or the Z/EG reporter, as well as the floxed p53 and Rb genes, into irradiated p53(loxP/loxP)Rb(loxP/loxP) mice, it was determined that sarcomas do not originate from bone marrow derived cells, such as macrophages, but arise from the local resident cells. At the same time, dermal mesenchymal stem cells isolated by strict plastic adherence and low levels of Sca-1 expression (Sca-1(low), CD31(neg)CD45(neg)) have shown enhanced potential for malignant transformation according to soft agar, invasion, and tumorigenicity assays, after the conditional inactivation of both p53 and Rb. Sarcomas formed after transplantation of these cells have features typical for undifferentiated high-grade pleomorphic sarcomas. Taken together, our studies indicate that local Sca-1(low) dermal mesenchymal stem/progenitor cells are preferential targets for malignant transformation associated with deficiencies in both p53 and Rb. (Am J Pathol 2010, 177:2645-2658; DOI: 10.2353/ajpath.2010.100306)