Abnormal Protein Glycosylation and Activated PI3K/Akt/mTOR Pathway: Role in Bladder Cancer Prognosis and Targeted Therapeutics.
Abnormal Protein Glycosylation and Activated PI3K/Akt/mTOR Pathway: Role in Bladder Cancer Prognosis and Targeted Therapeutics.
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DOI：
10.1371/journal.pone.0141253
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Santos LL
中科院分区：
文献类型：
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作者：
Costa C;Pereira S;Lima L;Peixoto A;Fernandes E;Neves D;Neves M;Gaiteiro C;Tavares A;Gil da Costa RM;Cruz R;Amaro T;Oliveira PA;Ferreira JA;Santos LL
肌层浸润性膀胱癌（MIBC，分期≥T2）通常与预后不良相关，是泌尿生殖系统肿瘤中第二大常见死亡原因。由于高分子异质性，已观察到自然史和疾病结局的显著变化。这也推迟了个性化治疗的引入，使晚期膀胱癌在治疗方面几乎成为孤儿病。通过唾液酸-Tn抗原（STn）及其前体Tn的表达以及PI 3 K/Akt/mTOR通路的激活翻译的蛋白糖基化改变是癌症相关事件，可能具有患者分层和指导治疗的潜力。因此，采用回顾性设计，筛选了96例不同阶段（Ta，T1-T4）的膀胱肿瘤的STn和Akt（pAkt）、mTOR（pmTOR）、S6（pS 6）和PTEN的磷酸化形式，这些形式与PI 3 K/Akt/mTOR通路的激活有关。在我们的系列研究中，Tn的表达是残留的，与分期或结局无关，而与非肌肉浸润性肿瘤相比，MIBC中STn的表达更高（p = 0.001），相关的癌症特异性生存率降低（对数秩p = 0.024）。相反，PI 3 K/Akt/mTOR通路中间产物在非肌层浸润性膀胱癌（NMIBC）和MIBC之间显示出相等的分布，并且在任何这些组中与癌症特异性存活（CSS）无关。然而，pAKT、pmTOR和/或pS 6的过表达允许区分面临最差CSS的STn阳性晚期膀胱肿瘤（p = 0.027）。此外，多变量考克斯回归分析显示，STn+ MIBC中PI 3 K/Akt/mTOR通路蛋白的过表达与癌症死亡风险的约6倍独立相关（p = 0.039）。携带晚期化学诱导膀胱肿瘤的小鼠模仿人类肿瘤的组织学和分子性质，然后给予mTOR途径抑制剂西罗莫司（雷帕霉素）。这减少了侵袭性病变的数量，同时也减少了STn和pS 6（PI 3 K/Akt/mTOR通路的下游效应物）的表达。总之，STn被发现是膀胱癌预后不良的标志物，结合PI 3 K/Akt/mTOR通路评估，具有改善疾病分期分层的潜力。动物实验表明，mTOR通路抑制可能是这种特定MIBC亚型的潜在治疗方法。
Muscle invasive bladder cancer (MIBC, stage ≥T2) is generally associated with poor prognosis, constituting the second most common cause of death among genitourinary tumours. Due to high molecular heterogeneity significant variations in the natural history and disease outcome have been observed. This has also delayed the introduction of personalized therapeutics, making advanced stage bladder cancer almost an orphan disease in terms of treatment. Altered protein glycosylation translated by the expression of the sialyl-Tn antigen (STn) and its precursor Tn as well as the activation of the PI3K/Akt/mTOR pathway are cancer-associated events that may hold potential for patient stratification and guided therapy. Therefore, a retrospective design, 96 bladder tumours of different stages (Ta, T1-T4) was screened for STn and phosphorylated forms of Akt (pAkt), mTOR (pmTOR), S6 (pS6) and PTEN, related with the activation of the PI3K/Akt/mTOR pathway. In our series the expression of Tn was residual and was not linked to stage or outcome, while STn was statically higher in MIBC when compared to non-muscle invasive tumours (p = 0.001) and associated decreased cancer-specific survival (log rank p = 0.024). Conversely, PI3K/Akt/mTOR pathway intermediates showed an equal distribution between non-muscle invasive bladder cancer (NMIBC) and MIBC and did not associate with cancer-specif survival (CSS) in any of these groups. However, the overexpression of pAKT, pmTOR and/or pS6 allowed discriminating STn-positive advanced stage bladder tumours facing worst CSS (p = 0.027). Furthermore, multivariate Cox regression analysis revealed that overexpression of PI3K/Akt/mTOR pathway proteins in STn+ MIBC was independently associated with approximately 6-fold risk of death by cancer (p = 0.039). Mice bearing advanced stage chemically-induced bladder tumours mimicking the histological and molecular nature of human tumours were then administrated with mTOR-pathway inhibitor sirolimus (rapamycin). This decreased the number of invasive lesions and, concomitantly, the expression of STn and also pS6, the downstream effector of the PI3K/Akt/mTOR pathway. In conclusion, STn was found to be marker of poor prognosis in bladder cancer and, in combination with PI3K/Akt/mTOR pathway evaluation, holds potential to improve the stratification of stage disease. Animal experiments suggest that mTOR pathway inhibition could be a potential therapeutic approach for this specific subtype of MIBC.