Overexpression of the mammalian target of rapamycin (mTOR) and angioinvasion are poor prognostic factors in early stage NSCLC: A verification study

Gately, Kathy; Al-Alao, Bassel; Dhillon, Tony; Mauri, Francesco; Cuffe, Sinéad; Seckl, Michael J.; O’Byrne, Kenneth J.

doi:10.1016/j.lungcan.2011.06.012

Cited by 33 publications

(37 citation statements)

References 46 publications

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“…For example, rapamycin has been shown to induce the phosphorylation of AKT and eIF4E, which was suppressed by a PI3K inhibitor (50). To the best of our knowledge, although there are a few studies investigating the prognostic significance of the PI3K/p-AKT/ mTOR pathway in NSCLC (18)(19)(20)(21)(22)(23)(26)(27)(28)(29)(30)(31)(32), the prognostic utility of p-4E-BP1 expression in this regard has not been documented thus far.…”

Section: Discussionmentioning

confidence: 99%

“…The prognostic role of the remaining components of the PI3K/AKT/mTOR pathway remains a controversial issue, with the majority of studies proposing p-AKT and/or (p-) mTOR as adverse (18,20,21,(28)(29)(30)(31)(32) and others as favourable (19,26) prognosticators. The overexpression of p-p70S6K (or pS6) (21,23), p85 or p110 subunits of PI3K (27), as well as PTEN loss (20) reportedly confer shorter survival.…”

Section: Discussionmentioning

confidence: 99%

“…On the basis of this experimental evidence, it is not surprising that much effort has been devoted to the investigation of the expression profiles of various components of the PI3K/AKT/ mTOR pathway in NSCLC (16,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32), sometimes yielding inconsistent results. In particular, a comprehensive analysis of all components of this pathway, along with the PIK3CA, K-RAS, AKT1 and PTEN mutational status has not been performed thus far.…”

Section: Introductionmentioning

confidence: 99%

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A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: Correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features

et al. 2013

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Abstract. The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT)/mammalian target of rapamycin (mTOR) pathway is upregulated in a number of human cancers, including non-small cell lung cancer (NSCLC). Its potential role in NSCLC progression provides an attractive target for anticancer therapy. The expression of phosphorylated mTOR (p-mTOR), phosphorylated AKT (p-AKT), p85α and p110γ subunits of PI3K, phosphorylated p70S6K (p-p70S6K), phosphatase and tensin homolog (PTEN) and phosphorylated 4E-BP1 (p-4E-BP1) was examined by immunohistochemistry in 102 NSCLC specimens. The results were correlated with clinicopathological features. We also examined 61 of our cases for the presence of PIK3CA, AKT1, PTEN and K-RAS mutations. A common PIK3CA mutation was detected at exon 9 in 2 samples (p.E545K), whereas another sample displayed a rare mutation (p.D1018N). Furthermore, 10 out of 54 cases (18.5%) had a K-RAS mutation at codon 12, 5 had a PTEN mutation (exons 7 and 8) and 1 case had an AKT1 mutation (p.E17K). PTEN mutations were associated with nodal metastases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: Correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features

et al. 2013

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“…Immunohistochemical scores were calculated as percent positive cells (0 to 100) Â staining intensity (0 to 3) with a cutoff score of 30 (range, 0-300) distinguishing positive from negative tumors. This immunohistochemical scoring system is in routine use in the Departments of Medicine and Surgery and Cancer at Imperial College London (13).…”

Section: Immunohistochemical Analysismentioning

confidence: 99%

Survival Outcome and EMT Suppression Mediated by a Lectin Domain Interaction of Endo180 and CD147

Rodriguez-Teja

Gronau

Minamidate

et al. 2015

Molecular Cancer Research

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Epithelial cell-cell contacts maintain normal glandular tissue homeostasis, and their breakage can trigger epithelialto-mesenchymal transition (EMT), a fundamental step in the development of metastatic cancer. Despite the ability of C-type lectin domains (CTLD) to modulate cell-cell adhesion, it is not known if they modulate epithelial adhesion in EMT and tumor progression. Here, the multi-CTLD mannose receptor, Endo180 (MRC2/uPARAP), was shown using the Kaplan-Meier analysis to be predictive of survival outcome in men with early prostate cancer. A proteomic screen of novel interaction partners with the fourth CTLD (CTLD4) in Endo180 revealed that its complex with CD147 is indispensable for the stability of three-dimensional acini formed by nontransformed prostate epithelial cells (PEC). Mechanistic study using knockdown of Endo180 or CD147, and treatment with an Endo180 mAb targeting CTLD4 (clone 39.10), or a dominant-negative GST-CTLD4 chimeric protein, induced scattering of PECs associated with internalization of Endo180 into endosomes, loss of E-cadherin (CDH1/ECAD), and unzipping of cell-cell junctions. These findings are the first to demonstrate that a CTLD acts as a suppressor and regulatory switch for EMT; thus, positing that stabilization of Endo180-CD147 complex is a viable therapeutic strategy to improve rates of prostate cancer survival.Implications: This study identifies the interaction between CTLD4 in Endo180 and CD147 as an EMT suppressor and indicates that stabilization of this molecular complex improves prostate cancer survival rates.

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“…Dysregulation of the mTOR pathway has been reported in lung cancers (6,7). A member of the small G protein family, RagD, which encodes a recently discovered activator of the mTOR pathway (8), was significantly upregulated in cells expressing mutant NRF2 (9).…”

Section: Introductionmentioning

confidence: 99%

RagD gene expression and NRF2 mutations in lung squamous cell carcinomas

et al. 2012

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Abstract. RagD is a member of the small G protein family, which encodes a recently discovered activator of the mTOR pathway. In vitro, RagD plays an important role in the proliferation of NRF2 gene (NFE2L2) mutated cancer cells. We hypothesized that tumor RagD expression may be correlated with the mutation status of NRF2 in lung cancers. RagD mRNA levels were analyzed by quantitative real-time polymerase chain reaction (qPCR) in 90 surgically-treated lung squamous cell cancer cases, including 14 NRF2 mutation cases, and normalized by β-actin mRNA levels. Mean RagD/β-actin mRNA levels of lung squamous cell carcinoma patients did not differ with age (≤65 vs. >65), Brinkman index (<400 vs. ≥400) or gender. RagD/β-actin mRNA levels were significantly higher in stage III samples (3.204±3.623) compared to stage I samples (1.357±1.560) (P= 0.0039). In addition, higher RagD/β-actin mRNA levels were identified in NRF2 mutant samples (3.107±3.633) compared to wild-type samples (1.774±2.301) (P= 0.074). These results suggest that RagD induction by NRF2 activation plays a role in the proliferation of lung squamous cell cancers. IntroductionDespite recent improvements in diagnosis, lung cancer is a major cause of mortality from malignant diseases due to its high incidence, malignant behavior and lack of major advancements in treatment strategy (1). Although there have been advances in understanding the biology of lung cancer and introduction of new chemotherapeutic agents for treatment, the 5-year survival rate remains less than 15% (2). Recently, progression in understanding oncogenic kinase signaling pathways has provided more successful targets for developing effective therapeutic strategies (3), which may improve the outcome of lung cancer.A potential therapeutic target is the mammalian target of rapamysin (mTOR) pathway, which plays a central role in regulating cell functions, including proliferation, growth, survival, mobility and angiogenesis (4,5). Dysregulation of the mTOR pathway has been reported in lung cancers (6,7). A member of the small G protein family, RagD, which encodes a recently discovered activator of the mTOR pathway (8), was significantly upregulated in cells expressing mutant NRF2 (9). It has been demonstrated that mutations of the NRF2 gene (NFE2L2) are associated with primary lung cancer (10-13). It has also been revealed that patients with lung tumors containing the NRF2 gene mutation display a poorer prognosis compared to patients with non-mutant tumors (11,12). Additionally, NRF2 gene somatic mutation is more common in lung squamous cell carcinomas (11).Although we have revealed the NRF2 gene mutation status in lung cancer (11), the correlation between NRF2 gene mutation and RagD expression status in lung cancer has not been reported. To determine the RagD mRNA expression status, we performed quantitative real-time polymerase chain reaction (qPCR) using a LightCycler (Roche Diagnostics GmbH, Mannheim, Germany). The findings were compared to the clinicopathological features of lung squamous cell ...

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Overexpression of the mammalian target of rapamycin (mTOR) and angioinvasion are poor prognostic factors in early stage NSCLC: A verification study

Cited by 33 publications

References 46 publications

A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: Correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features

A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: Correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features

Survival Outcome and EMT Suppression Mediated by a Lectin Domain Interaction of Endo180 and CD147

RagD gene expression and NRF2 mutations in lung squamous cell carcinomas

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