Loss of epithelial p53 and αv integrin cooperate through Akt to induce squamous cell carcinoma yet prevent remodeling of the tumor microenvironment.
Loss of epithelial p53 and αv integrin cooperate through Akt to induce squamous cell carcinoma yet prevent remodeling of the tumor microenvironment.
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大多数皮肤和头颈部鳞状细胞癌（SCC）含有p53突变。癌前病变中p53突变的存在表明它们代表肿瘤进展期间的早期事件，并且SCC的发展可能需要额外的改变。在这里，我们表明，共同缺失的p53和αv整合素基因在小鼠复层上皮细胞诱导SCC的100%的小鼠，更频繁和更短的潜伏期比单独删除任何一个基因。在上皮肿瘤细胞中缺乏p53和αv的SCC表现出高Akt活性，缺乏多种类型的浸润性免疫细胞，含有缺陷的脉管系统，并且比表达p53或αv的肿瘤生长缓慢。这些结果表明，缺乏p53的上皮细胞中αv的缺失促进了SCC的发展，但也阻止了肿瘤微环境的重塑并延迟了肿瘤的生长。我们观察到在缺乏p53和αv的SCC细胞中Akt失活促进了失巢凋亡。因此，这些小鼠中的肿瘤可能是由于αv和p53缺失触发的Akt激活诱导的细胞存活增加，以及免疫细胞向这些肿瘤的募集缺陷，这可能允许免疫逃避。然而，有缺陷的血管系统和缺乏支持性基质在这些SCC中产生了限制性微环境，减缓了它们的生长。这些机制可能是缺乏p53和αv的SCC快速发病和缓慢生长的基础。
Most of the squamous cell carcinomas (SCCs) of the skin and head and neck contain p53 mutations. The presence of p53 mutations in premalignant lesions suggests that they represent early events during tumor progression and additional alterations may be required for SCC development. Here we show that co-deletion of the p53 and αv integrin genes in mouse stratified epithelia induced SCCs in 100% of the mice, more frequently and with much shorter latency than deletion of either gene alone. The SCCs that lacked p53 and αv in the epithelial tumor cells exhibited high Akt activity, lacked multiple types of infiltrating immune cells, contained a defective vasculature, and grew slower than tumors that expressed p53 or αv. These results reveal that loss of αv in epithelial cells that lack p53 promotes SCC development, but also prevents remodeling of the tumor microenvironment and delays tumor growth. We observed that Akt inactivation in SCC cells that lack p53 and αv promoted anoikis. Thus, tumors may arise in these mice as a result of the increased cell survival induced by Akt activation triggered by loss of αv and p53, and by the defective recruitment of immune cells to these tumors, which may allow immune evasion. However, the defective vasculature and lack of a supportive stroma create a restrictive microenvironment in these SCCs that slows their growth. These mechanisms may underlie the rapid onset and slow growth of SCCs that lack p53 and αv.
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影响因子：
50.3
作者：
Hanahan, Douglas;Coussens, Lisa M.
通讯作者：
Coussens, Lisa M.
影响因子：
10.3
作者：
Lindelöf, B;Sigurgeirsson, B;Stern, RS
通讯作者：
Stern, RS
DOI：
10.1073/pnas.87.17.6888
发表时间：
1990-09-01
影响因子：
11.1
作者：
DELUCA, M;TAMURA, RN;QUARANTA, V
通讯作者：
QUARANTA, V
影响因子：
11.2
作者：
Martínez-Cruz, Belen Ana;Santos, Mirentxu;Paramio, Jesus M.
通讯作者：
Paramio, Jesus M.
DOI：
10.1073/pnas.0707421104
发表时间：
2007-10-02
影响因子：
11.1
作者：
Lacy-Hulbert, Adam;Smith, Aileen M.;Hynes, Richard O.
通讯作者：
Hynes, Richard O.