AKT in stromal fibroblasts controls invasion of epithelial cells.
AKT in stromal fibroblasts controls invasion of epithelial cells.
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DOI：
10.18632/oncotarget.1078
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发表时间：
2013-07
期刊：
影响因子：
--
通讯作者：
McCance DJ
中科院分区：
文献类型：
--
作者：
Cichon AC;Pickard A;McDade SS;Sharpe DJ;Moran M;James JA;McCance DJ
肿瘤微环境在癌症进展中具有重要作用，近期的报道提出，基质AKT被激活并调控肿瘤发生和侵袭。通过对口咽癌活检组织进行免疫荧光分析，我们发现与正常基质成纤维细胞相比，肿瘤相关基质成纤维细胞中的AKT活性增加。利用器官型筏式共培养，我们表明基质AKT的激活能够以角质形成细胞生长因子（KGF）依赖的方式诱导表达人乳头瘤病毒16型E6和E7蛋白的角质形成细胞的侵袭。通过分别去除三种AKT异构体中的每一种基质成纤维细胞，或者使用异构体特异性抑制剂，我们确定基质AKT2是侵袭的关键调节因子，并且在口咽癌中表明在基质成纤维细胞中也能识别出AKT2特异性磷酸化事件。基质AKT2的缺失通过激活一种对抗KGF介导的侵袭的保护途径来抑制上皮侵袭。成纤维细胞中AKT2的缺失刺激基质成纤维细胞中IL - 1β的切割和释放，导致上皮中KGF受体（成纤维细胞生长因子受体2B（FGFR2B））表达下调。我们还表明，在一组口咽癌患者中，高IL - 1β与总体生存率提高相关。我们的研究结果证明了基质衍生生长因子和细胞因子在调控肿瘤细胞侵袭过程中的重要性。
The tumour microenvironment has an important role in cancer progression and recent reports have proposed that stromal AKT is activated and regulates tumourigenesis and invasion. We have shown, by immuno-fluorescent analysis of oro-pharyngeal cancer biopsies, an increase in AKT activity in tumour associated stromal fibroblasts compared to normal stromal fibroblasts. Using organotypic raft co-cultures, we show that activation of stromal AKT can induce the invasion of keratinocytes expressing the HPV type 16 E6 and E7 proteins, in a Keratinocyte Growth Factor (KGF) dependent manner. By depleting stromal fibroblasts of each of the three AKT isoforms independently, or through using isoform specific inhibitors, we determined that stromal AKT2 is an essential regulator of invasion and show in oro-pharyngeal cancers that AKT2 specific phosphorylation events are also identified in stromal fibroblasts. Depletion of stromal AKT2 inhibits epithelial invasion through activating a protective pathway counteracting KGF mediated invasions. AKT2 depletion in fibroblasts stimulates the cleavage and release of IL1B from stromal fibroblasts resulting in down-regulation of the KGF receptor (fibroblast growth factor receptor 2B (FGFR2B)) expression in the epithelium. We also show that high IL1B is associated with increased overall survival in a cohort of patients with oro-pharyngeal cancers. Our findings demonstrate the importance of stromal derived growth factors and cytokines in regulating the process of tumour cell invasion.
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DOI：
10.1590/s1678-77572009000500031
发表时间：
2009-09
期刊：
Journal of applied oral science : revista FOB
影响因子：
--
作者：
Silva AC;Faria MR;Fontes A;Campos MS;Cavalcanti BN
通讯作者：
Cavalcanti BN
影响因子：
6.5
作者：
Maas-Szabowski, N;Szabowski, A;Fusenig, NE
通讯作者：
Fusenig, NE
DOI：
10.4161/cc.8.16.9335
发表时间：
2009-08-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Gonzalez E;McGraw TE
通讯作者：
McGraw TE
影响因子：
--
作者：
Hart JR;Vogt PK
通讯作者：
Vogt PK
影响因子：
16
作者：
Brognard, John;Sierecki, Emma;Newton, Alexandra C.
通讯作者：
Newton, Alexandra C.