Cyclin D1 and cdk4 mediate development of neurologically destructive oligodendroglioma.
Cyclin D1 and cdk4 mediate development of neurologically destructive oligodendroglioma.
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DOI：
10.1158/0008-5472.can-11-1031
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发表时间：
2011-10-01
期刊：
影响因子：
11.2
通讯作者：
Koff A
中科院分区：
文献类型：
--
作者：
Ciznadija D;Liu Y;Pyonteck SM;Holland EC;Koff A
虽然已经研究了表征胶质瘤的分子变化，但是肿瘤发展的发病机制仍然不清楚。p21通过稳定细胞周期蛋白D1-cdk 4激酶复合物而促进胶质瘤的发生，这表明细胞周期蛋白D1和cdk 4也可能是胶质瘤发生所必需的。在这项研究中，我们使用小鼠模型试图证实这一假设，发现细胞周期蛋白D1和cdk 4不仅在肿瘤中，而且在肿瘤微环境中发挥积极作用。cdk 4的缺失阻断了肿瘤的发展，但细胞周期蛋白D1的缺失并不能阻止胶质瘤的发展。相反，细胞周期蛋白D1的丢失阻碍了恶性肿瘤向更高阶段的进展。细胞周期蛋白D1的强制表达不足以纠正在细胞周期蛋白D1缺陷动物中观察到的进展缺陷。相反，在cdk 4缺陷动物中cdk 4的恢复恢复了细胞增殖和肿瘤形成，尽管是在较低的肿瘤等级。值得注意的是，细胞周期蛋白D1和cdk 4缺陷动物中肿瘤进展到更高级别的失败与肿瘤微环境中小胶质细胞的完全激活失败相关。此外，当PDGF转化的神经胶质细胞原位移植到小鼠中时，形成的肿瘤在野生型小鼠中进展到高级别，而在细胞周期蛋白D1缺陷的动物中则没有。总之，我们的研究结果表明，cyclinD 1-cdk 4轴不仅在神经胶质肿瘤细胞中至关重要，而且在周围肿瘤微环境中的基质源性细胞中也至关重要，这些细胞对维持肿瘤生长至关重要。
Although the molecular changes that characterize gliomas have been studied, the pathogenesis of tumor development remains unclear. p21 contributes to gliomagenesis by stabilizing cyclin D1-cdk4 kinase complexes, suggesting that cyclin D1 and cdk4 may also be required for glial tumor development. In this study, we used a mouse model to attempt to confirm this hypothesis, finding that cyclin D1 and cdk4 played active roles in not only the tumor but also the tumor microenvironment. Loss of cdk4 blocked tumor development, but loss of cyclin D1 did not prevent gliomas from developing. Instead, loss of cyclin D1 impeded progression to higher stages of malignancy. Enforcing expression of cyclin D1 was insufficient to correct the progression defect observed in cyclin D1 deficient animals. In contrast, restoration of cdk4 in the cdk4 deficient animals restored cell proliferation and tumor formation, although at lower tumor grades. Notably, the failure of tumors in the cyclin D1 and cdk4 deficient animals to progress to higher grades was correlated with a failure to fully activate microglia in the tumor microenvironment. Moreover, when PDGF-transformed glial cells were engrafted orthotopically into the mice, the tumors that formed progressed to high grades in wild type mice but not cyclin D1 deficient animals. Together, our findings establish that the cyclinD1-cdk4 axis is not only critical in glial tumor cells, but also in stromal-derived cells in the surrounding tumor microenvironment that are vital to sustain tumor outgrowth.