Heterogeneous tumor evolution initiated by loss of pRb function in a preclinical prostate cancer model
Heterogeneous tumor evolution initiated by loss of pRb function in a preclinical prostate cancer model
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DOI：
10.1158/0008-5472.can-05-1579
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发表时间：
2005-11-15
期刊：
影响因子：
11.2
通讯作者：
Van Dyke, T
中科院分区：
文献类型：
--
作者：
Hill, R;Song, YR;Van Dyke, T
因为癌症进化中的每一个变化都是基于先前事件的影响，所以只有在适当的起始事件的背景下，才能充分理解选择性变化及其对肿瘤进展的影响。在这里，我们定义了前列腺上皮中pRb功能失活对前列腺癌起始和导致Pten功能减弱和肿瘤进化的选择压力的影响。通过基因工程小鼠，我们发现pRb家族蛋白（Rb/p107/p130）的失活可诱导上皮细胞增殖和凋亡，并足以产生前列腺上皮内瘤变（PIN）病变。随着时间的推移，腺癌在所有小鼠中发展，没有神经内分泌肿瘤的证据。与之前测试的其他上皮细胞类型不同，凋亡依赖于Pten功能而不是p53。因此，Pten半合子性减少了50%的细胞凋亡，加速了向异质性组成的腺癌的进展。异质性与Pten单倍不全和局灶性选择性进展到完全Pten丢失有关，这产生了不同的肿瘤特性。鉴于该分析模拟了人类前列腺癌中高渗透事件的明显时间，观察到的影响可能概括了前列腺癌发展的自然演变。
Because each change in the evolution of a cancer is predicated on the effects of previous events, a full understanding of selective changes and their effect on tumor progression can only be understood in the context of appropriate initiating events. Here, we define the effect of pRb function inactivation in prostate epithelium on both the initiation of prostate cancer and the establishment of selective pressures that lead to diminished Pten function and tumor evolution. Using genetically engineered mice, we show that inactivation of the pRb family proteins (Rb/p107/p130) induces epithelial proliferation and apoptosis and is sufficient to produce prostatic intraepithelial neoplasia (PIN) lesions. Over time, adenocarcinomas develop in all mice with no evidence of neuroendocrine tumors. Apoptosis is dependent on Pten function and not p53, unlike other epithelial cell types tested previously. Consequently, Pten hemizygosity reduces apoptosis by 50%, accelerating progression to adenocarcinomas with heterogeneous composition. Heterogeneity is associated with concurrent Pten haploinsufficiency and focal selective progression to complete Pten loss, which yields distinct tumor properties. Given that this analysis models the apparent timing of highly penetrant events in human prostate cancer, observed effects may recapitulate the natural evolution of prostate cancer development.