Uhrbom Lene, Dai Chengkai, Celestino Joseph C, Rosenblum Marc K, Fuller Gregory N, Holland Eric C
Department of Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Cancer Res. 2002 Oct 1;62(19):5551-8.
Deletion of the INK4a-ARF locus is found in the majority of human malignant gliomas. However, the role of INK4a-ARF loss in gliomagenesis is unclear. Animal modeling has shown that mice with targeted deletions in the Ink4a-Arf gene do not develop spontaneous gliomas. We have previously reported that combined KRas and Akt signaling could induce glioblastoma (GBM) formation from neural progenitor cells but had no effect in differentiated astrocytes. In this investigation, we have studied the effects of Ink4a-Arf loss on the formation of GBM induced by KRas and Akt gene transfer into neural progenitor cells and astrocytes. We show here that Ink4a-Arf deficiency allows for GBM formation from astrocytes and that it enhances tumor incidence in neural progenitor cells. Furthermore, KRas alone can cooperate with deletion of the Ink4a-Arf locus in tumor formation from both neural progenitor cells and astrocytes. The resulting tumors were nestin positive and resembled a spectrum of glioma morphologies ranging in astrocytic character depending on cell-of-origin and presence of activated Akt. Our data strongly supports the view that one role of loss of Ink4a-Arf in gliomagenesis could be to sensitize astrocytes to transformation through dedifferentiation in response to the appropriate oncogenic stimuli.
在大多数人类恶性胶质瘤中都发现了INK4a - ARF基因座的缺失。然而，INK4a - ARF缺失在胶质瘤发生中的作用尚不清楚。动物模型研究表明，Ink4a - Arf基因发生靶向缺失的小鼠不会自发形成胶质瘤。我们之前曾报道，KRas和Akt信号通路共同作用可诱导神经祖细胞形成胶质母细胞瘤（GBM），但对分化的星形胶质细胞没有影响。在本研究中，我们研究了Ink4a - Arf缺失对KRas和Akt基因导入神经祖细胞和星形胶质细胞后诱导形成GBM的影响。我们在此表明，Ink4a - Arf缺陷会使星形胶质细胞形成GBM，并增加神经祖细胞中的肿瘤发生率。此外，单独的KRas可与Ink4a - Arf基因座缺失协同作用，促使神经祖细胞和星形胶质细胞形成肿瘤。所形成的肿瘤巢蛋白呈阳性，根据起源细胞和激活的Akt的存在情况，呈现出一系列具有不同星形细胞特征的胶质瘤形态。我们的数据有力地支持了这样一种观点，即Ink4a - Arf缺失在胶质瘤发生中的一个作用可能是使星形胶质细胞在受到适当的致癌刺激时通过去分化而对转化敏感。
