Association between high expression of phosphorylated Akt and mammalian target of rapamycin and improved survival in salivary gland adenoid cystic carcinoma

Ouyang, Dai-qiao; Liang, Liyang; Ke, Zunfu; Zheng, Guanghui; Weng, Desheng; Yang, Wei‐En; Su, Yu‐xiong; Liao, Guiqing

doi:10.1002/hed.24732

Cited by 12 publications

(12 citation statements)

References 53 publications

(60 reference statements)

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“…29 This study shows for the first time that high p-mTOR Ser2448 immuno-expression is significantly associated with recurrences and with lower DFS in patients with atypical meningiomas. Interestingly, differing from that reported in other neoplasias, [27][28][29] we did not observe any nuclear staining in the neoplastic cells of atypical meningiomas. Only one previous studies on p-mTOR Ser2448 immuno-expression in meningiomas clearly reported that subcellular localization of the protein could be nuclear and/or cytoplasmic.…”

Section: Discussioncontrasting

confidence: 99%

“…The prognostic role of p-mTOR Ser2448 immunoexpression has been analyzed in several neoplasias, and with contrasting results. Indeed, p-mTOR Ser2448 expression is a favorable prognostic factor in gastric cancer 27 or in salivary gland carcinoma, 28 while it is associated with bad prognosis in tongue squamous cell carcinoma. 29 This study shows for the first time that high p-mTOR Ser2448 immuno-expression is significantly associated with recurrences and with lower DFS in patients with atypical meningiomas.…”

Section: Discussionmentioning

confidence: 99%

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High p‐mTOR expression is associated with recurrence and shorter disease‐free survival in atypical meningiomas

et al. 2018

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Due to their widely variable clinical behavior, the post‐surgical treatment of atypical meningiomas is controversial. Therefore, prognostic factors able to identify high‐risk cases, which may benefit from adjuvant treatments, are warranted. Mammalian target of rapamycin (mTOR) belongs to the PI3K‐AKT pathway. Its phosphorylated form (p‐mTOR Ser2448) is involved in cell growth, differentiation and tumorigenesis. The aim of this study was to evaluate p‐mTOR Ser2448 expression and its eventual correlation with clinicopathological features, recurrence, or disease‐free survival (DFS), in atypical meningiomas. p‐mTOR immunohistochemical expression was analyzed in 48 atypical meningiomas and correlated with clinicopathological parameters and with DFS. Eighty‐one percent of atypical meningiomas expressed p‐mTOR Ser2448. High immuno‐expression was significantly associated with recurrences (P = 0.01) and lower DFS (P = 0.01). The presence of brain invasion, high mitotic index plus sheeting, and Simpson grade were significant and independent prognostic variables at multivariate analysis. p‐mTOR Ser2448 is expressed in atypical meningiomas. High expression predicts development of recurrences and shorter DFS in patients affected by these tumors. Since p‐mTOR Ser2448 is a target of anti‐neoplastic drugs, evaluation of its expression may be used, not only to identify atypical meningiomas at higher risk of recurrence, but also to select those to submit to adjuvant targeted chemotherapy.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

High p‐mTOR expression is associated with recurrence and shorter disease‐free survival in atypical meningiomas

et al. 2018

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“…Also, highly phosphorylated AKT levels in ACC tissue were associated with an increased risk for tumor relapse . In contrast, a recent publication showed that activation of AKT was also associated with better prognosis of salivary gland ACC patients . This discrepancy might arise because of distinct functions of the different AKT isoforms, suggesting the need for AKT isoform‐specific inhibitors in the treatment of salivary gland ACC patients .…”

Section: Discussionmentioning

confidence: 95%

“…Intriguingly, these studies revealed mutations in genes implicated in the PI3K‐AKT‐mTOR signaling cascade, suggesting a prominent role of this pathway in salivary gland tumorigenesis. Indeed, recurrent mutations resulting in activation of the PI3K‐AKT‐mTOR pathway were found in 30% of ACC, and activated (phosphorylated) AKT isoforms and downstream mTOR is enhanced in ACC as compared to healthy adjacent tissue .…”

Section: Introductionmentioning

confidence: 99%

AKT3 drives adenoid cystic carcinoma development in salivary glands

et al. 2017

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Salivary gland cancer is an aggressive and painful cancer, but a rare tumor type accounting for only ~0.5% of cancer cases. Tumors of the salivary gland exhibit heterogeneous histologic and genetic features and they are subdivided into different subtypes, with adenoid cystic carcinomas (ACC) being one of the most abundant. Treatment of ACC patients is afflicted by high recurrence rates, the high potential of the tumors to metastasize, as well as the poor response of ACC to chemotherapy. A prerequisite for the development of targeted therapies is insightful genetic information for driver core cancer pathways. Here, we developed a transgenic mouse model toward establishment of a preclinical model. There is currently no available mouse model for adenoid cystic carcinomas as a rare disease entity to serve as a test system to block salivary gland tumors with targeted therapy. Based on tumor genomic data of ACC patients, a key role for the activation of the PI3K‐AKT‐mTOR pathway was suggested in tumors of secretory glands. Therefore, we investigated the role of Akt3 expression in tumorigenesis and report that Akt3 overexpression results in ACC of salivary glands with 100% penetrance, while abrogation of transgenic Akt3 expression could revert the phenotype. In summary, our findings validate a novel mouse model to study ACC and highlight the druggable potential of AKT3 in the treatment of salivary gland patients.

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“…NGF has been shown to play a role in tumour proliferation in OSCC and salivary adenoid cystic carcinoma (AdCC), which might be a reason for the cancer cells to migrate and invade the nerves. Ex vivo studies show that Akt is phosphorylated in AdCC suggesting that PI3K/Akt signalling pathway has an important role in salivary gland carcinogenesis . In this study, we aimed to investigate the role of NGF‐induced signalling pathway on PNI of oral and salivary gland tumours in vitro and to confirm the involvement of PI3K/Akt pathway in cellular scattering and migration via the use of MK2206 (Akt inhibitor).…”

Section: Introductionmentioning

confidence: 99%

Nerve growth factor‐induced migration in oral and salivary gland tumour cells utilises the PI3K/Akt signalling pathway: Is there a link to perineural invasion?

Alkhadar

Macluskey

White

et al. 2019

J Oral Pathology Medicine

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Objectives The aims of this study were to investigate the role of nerve growth factor on perineural invasion in oral and salivary gland tumour cell lines and whether there is an involvement of PI3K/Akt pathway. Materials and Methods Four cell lines were investigated: HSG and TYS (salivary gland tumours), SAS‐H1 (oral squamous cell carcinoma) and HaCaT (human skin keratinocyte). Initially, Boyden chamber assay was done to examine the effect of different concentration of nerve growth factor on cell migration. Western blot/ immunofluorescence techniques were used to investigate the phosphorylation status of the Akt pathway within the cells in response to nerve growth factor. The effect of this growth factor and the addition of an Akt inhibitor on cell morphology and migration were also examined using scatter/scratch assays. Results Nerve growth factor triggered the PI3K/Akt pathway in oral and salivary tumour cells and induced oral and salivary tumour cell scattering and migration. Inhibitor assays confirmed that oral and salivary gland tumour cell scattering and migration is Akt dependent. Conclusions Nerve growth factor can stimulate scattering and migration in cells derived from oral and salivary gland tumours, thereby potentially enhancing perineural invasion. Phosphorylated Akt controls cancer cell migration and scattering. Blocking the Akt pathway may inhibit cell migration and therefore perineural invasion and metastasis.

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Association between high expression of phosphorylated Akt and mammalian target of rapamycin and improved survival in salivary gland adenoid cystic carcinoma

Abstract: High level of Akt/mTOR activation in ACC is correlated with a significantly improved survival. P-mTOR and nuclear p-Akt are prognostic biomarkers of salivary gland ACC. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1145-1154, 2017.

Cited by 12 publications

References 53 publications

High p‐mTOR expression is associated with recurrence and shorter disease‐free survival in atypical meningiomas

High p‐mTOR expression is associated with recurrence and shorter disease‐free survival in atypical meningiomas

AKT3 drives adenoid cystic carcinoma development in salivary glands

Nerve growth factor‐induced migration in oral and salivary gland tumour cells utilises the PI3K/Akt signalling pathway: Is there a link to perineural invasion?

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