Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal.
Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal.
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抑制启动的癌基因通常会导致广泛的肿瘤细胞死亡，这一现象被称为癌基因成瘾。这导致了对特定靶向和抑制癌基因的化合物作为抗癌剂的寻找。有丝分裂检查点通路是实体肿瘤的常见特征，染色体不稳定(CIN)的产生是否会对癌基因成瘾产生影响，目前还没有系统的研究。我们在这里表明，通过过度表达有丝分裂检查点基因MAD2而诱导的染色体不稳定性并不影响Kras驱动的肺癌在Kras抑制后的消退。然而，经历一过性MAD2过度表达和随之而来的染色体不稳定的肿瘤的复发率显著升高。复发的肿瘤是高度非整倍体的，并具有不同的促增殖途径的激活。因此，在看似有效的抗癌治疗后，早期的CIN可能是肿瘤复发的原因。
Inhibition of an initiating oncogene often leads to extensive tumor cell death, a phenomenon known as oncogene addiction. This has led to the search for compounds that specifically target and inhibit oncogenes as anti-cancer agents. Whether chromosomal instability (CIN) generated as a result of deregulation of the mitotic checkpoint pathway, a frequent characteristic of solid tumors, has any effect on oncogene addiction, however, has not been explored systematically. We show here that induction of chromosome instability by overexpression of the mitotic checkpoint gene Mad2 does not affect the regression of Kras driven lung tumors upon Kras inhibition. However, tumors that experience transient Mad2 overexpression and consequent chromosome instability recur at dramatically elevated rates. The recurrent tumors are highly aneuploid and have varied activation of pro-proliferative pathways. Thus, early CIN may be responsible for tumor relapse after seemingly effective anti-cancer treatments.
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DOI：
10.1083/jcb.200706015
发表时间：
2007-10-22
期刊：
The Journal of cell biology
影响因子：
--
作者：
Jeganathan K;Malureanu L;Baker DJ;Abraham SC;van Deursen JM
通讯作者：
van Deursen JM
影响因子：
158.5
作者：
Kobayashi, S;Boggon, TJ;Halmos, B
通讯作者：
Halmos, B
影响因子：
64.5
作者：
Dobles, M;Liberal, V;Sorger, PK
通讯作者：
Sorger, PK
DOI：
10.1038/nrc2781
发表时间：
2010-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Schvartzman JM;Sotillo R;Benezra R
通讯作者：
Benezra R
影响因子：
4.8
作者：
Tichelaar, JW;Lu, W;Whitsett, JK
通讯作者：
Whitsett, JK