Pathobiological implications of the expression of EGFR, pAkt, NF-κB and MIC-1 in prostate cancer stem cells and their progenies.
Pathobiological implications of the expression of EGFR, pAkt, NF-κB and MIC-1 in prostate cancer stem cells and their progenies.
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DOI：
10.1371/journal.pone.0031919
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Batra SK
中科院分区：
文献类型：
--
作者：
Mimeault M;Johansson SL;Batra SK
前列腺癌（PC）进展为局部侵袭性、雄激素非依赖性和转移性疾病状态通常与治疗抵抗和疾病复发相关。本研究旨在确定联合使用特定致癌产物（包括表皮生长因子受体（EGFR）、pAkt、核因子-κ B（NF-κB）和巨噬细胞抑制性细胞因子-1（MIC-1））作为生物标志物和治疗靶点的可能性，以优化疾病早期局限性PC患者的管理。免疫组化和免疫荧光数据显示，在疾病进展过程中，EGFR、Ser 473-pAkt、NF-κB p65和MIC-1蛋白的表达水平在76例前列腺腺癌标本的同一亚组中显著增强，这些生物标志物在CD 133 + PC细胞的小亚群和CD 133 − PC细胞的肿瘤块中表达。重要的是，所有这些生物标志物也在30个PC转移骨组织标本的80-100%中过表达。此外，结果表明EGF-EGFR信号传导途径可以为来自高侵袭性WPE 1-NB 26细胞的具有干细胞样特征的侧群（SP）细胞的自我更新提供关键功能。在治疗方面，EGFR、pAkt、NF-κB或MIC-1的靶向也有效抑制SP WPE 1-NB 26细胞的基础和EGF促进的前列腺球形成，诱导SP细胞衍生的前列腺球崩解，并降低SP和非SP WPE 1-NB 26细胞部分的活力。此外，这些致癌产物的靶向诱导化疗耐药SP WPE 1-NB 26细胞中的半胱天冬酶依赖性凋亡，并增强其对多西他赛诱导的细胞毒性作用的敏感性。这些结果表明，EGFR、pAkt、NF-κB和/或MIC-1的联合使用可能代表了提高当前诊断和预后方法的准确性以及考虑疾病异质性的PC患者治疗效果的有前景的策略，从而防止PC进展为转移性和致死性疾病状态。
The progression of prostate cancers (PCs) to locally invasive, androgen-independent and metastatic disease states is generally associated with treatment resistance and disease relapse. The present study was undertaken to establish the possibility of using a combination of specific oncogenic products, including epidermal growth factor receptor (EGFR), pAkt, nuclear factor-kappaB (NF-κB) and macrophage inhibitory cytokine-1 (MIC-1) as biomarkers and therapeutic targets for optimizing the management of patients with localized PC at earlier disease stages. The immunohistochemical and immunofluorescence data have revealed that the expression levels of EGFR, Ser473-pAkt, NF-κB p65 and MIC-1 proteins were significantly enhanced in the same subset of 76 cases of prostatic adenocarcinoma specimens during the disease progression and these biomarkers were expressed in a small subpopulation of CD133+ PC cells and the bulk tumor mass of CD133− PC cells. Importantly, all of these biomarkers were also overexpressed in 80–100% of 30 PC metastasis bone tissue specimens. Moreover, the results have indicated that the EGF-EGFR signaling pathway can provide critical functions for the self-renewal of side population (SP) cells endowed with stem cell-like features from highly invasive WPE1-NB26 cells. Of therapeutic interest, the targeting of EGFR, pAkt, NF-κB or MIC-1 was also effective at suppressing the basal and EGF-promoted prostasphere formation by SP WPE1-NB26 cells, inducing disintegration of SP cell-derived prostaspheres and decreasing the viability of SP and non-SP WPE1-NB26 cell fractions. Also, the targeting of these oncogenic products induced the caspase-dependent apoptosis in chemoresistant SP WPE1-NB26 cells and enhanced their sensibility to the cytotoxic effects induced by docetaxel. These findings suggest that the combined use of EGFR, pAkt, NF-κB and/or MIC-1 may represent promising strategies for improving the accuracy of current diagnostic and prognostic methods and efficacy of treatments of PC patients in considering the disease heterogeneity, thereby preventing PC progression to metastatic and lethal disease states.
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DOI：
10.1126/science.1189992
发表时间：
2010-07-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Goldstein AS;Huang J;Guo C;Garraway IP;Witte ON
通讯作者：
Witte ON
影响因子：
11.2
作者：
Gu, Guangyu;Yuan, Jialing;Kasper, Susan
通讯作者：
Kasper, Susan
影响因子：
3.9
作者：
Angelucci, A;Gravina, GL;Bologna, M
通讯作者：
Bologna, M
DOI：
10.1016/j.juro.2009.12.092
发表时间：
2010-05
期刊：
The Journal of urology
影响因子：
--
作者：
Bae KM;Su Z;Frye C;McClellan S;Allan RW;Andrejewski JT;Kelley V;Jorgensen M;Steindler DA;Vieweg J;Siemann DW
通讯作者：
Siemann DW
影响因子：
11.5
作者：
Ayala, G;Thompson, T;Harper, W
通讯作者：
Harper, W