Activated Mammalian Target of Rapamycin Is an Adverse Prognostic Factor in Patients with Biliary Tract Adenocarcinoma

Herberger, Beata; Puhalla, Harald; Lehnert, Martina; Wrba, Fritz; Novak, Sabine; Brandstetter, Anita; Gruenberger, Birgit; Gruenberger, Thomas; Pirker, Robert; Filipits, Martin

doi:10.1158/1078-0432.ccr-07-0738

Cited by 81 publications

(65 citation statements)

References 21 publications

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“…On the other hand, PTEN, p-AKT1, and p-EIF4EBP1 showed weak cytoplasmic staining in normal bile ducts in some cases. p-MTOR showed strong cytoplasmic reactivity in normal bile ducts as previously described, 22 whereas p-RPS6KB2 was not expressed in normal bile ducts. For comparison with the clinical variables and survival, the expression levels of these proteins were semiquantified using an IHC score calculated by multiplication of the staining intensity (0B3) with the percentage of positive tumor cells (0B100%).…”

Section: Interpretation Of Ihc Stainingsupporting

confidence: 80%

The expression of phospho-AKT1 and phospho-MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic cholangiocarcinomas

Lee

Choi

et al. 2012

Modern Pathology

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AKT1 signaling pathway is important for the regulation of protein synthesis and cell survival with implications in carcinogenesis. In this study, we explored the prognostic significance of AKT1 pathway in intrahepatic cholangiocarcinomas. We investigated the status of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), phosphorylated (p) AKT1 (p-AKT1), p-mammalian target of rapamycin (p-MTOR), p-p70 ribosomal protein S6 kinase (p-RPS6KB2) and p-eukaryotic initiation factor 4E-binding protein-1 (p-EIF4EBP1) in 101 intrahepatic cholangiocarcinomas by immunohistochemistry. Western blot analysis was performed to verify the expression levels of p-AKT1 and p-MTOR. The relationship of protein expression with clinicopathological data and the correlations of protein expression levels were explored. The overexpression of p-AKT1, p-MTOR, and PTEN was associated with a better survival in patients with intrahepatic cholangiocarcinoma (P ¼ 0.0137, 0.0194, and 0.0337, respectively). In a multivariate analysis, PTEN was an independent prognostic factor, and p-AKT1 showed tendency (P ¼ 0.032 and 0.051, respectively). The overexpression of p-MTOR was correlated with well-to-moderately differentiated tumors (Po0.001) and tumors without metastasis (P ¼ 0.046). Expression levels of the AKT1 signaling pathway proteins in this study showed positive correlations with each other, except for PTEN. Aberrant expressions of p-AKT1 and p-MTOR in intrahepatic cholangiocarcinoma were associated with a favorable prognosis, possibly in a PTEN-independent manner. Our results indicate that dysregulation of the AKT1 pathway may have an important role in the development of intrahepatic cholangiocarcinoma, but not necessarily in the progression of the disease.

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Section: Interpretation Of Ihc Stainingsupporting

confidence: 80%

The expression of phospho-AKT1 and phospho-MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic cholangiocarcinomas

Lee

Choi

et al. 2012

Modern Pathology

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“…Each sample was examined in a high power field at 200 times magnification. The evaluation of staining was referred to previous report with some modifications (Herberger et al, 2007), as following: Immunostaining was classified based on staining intensity and percentage of positive tumor cells. Staining intensity was determined as 0 (absent), 1 (weak), 2 (moderate), 3 (strong).…”

Section: Evaluation Of Immunohistochemical Staining Resultsmentioning

confidence: 99%

Expression Characteristics of Proteins of the Insulin-like Growth Factor Axis in Non-small Cell Lung Cancer Patients with Preexisting Type 2 Diabetes Mellitus

Jing¹,

Tang²,

Chen³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background: Preexisting type 2 diabetes mellitus (T2DM) affects the prognosis and mortality of patients with some cancers. Insulin like growth factor (IGF) and insulin receptor (IR) signaling axes play important roles in both cancer and diabetes development. We aimed to explore the expression characteristics of proteins in IGF/IR axis in non-small cell lung cancer (NSCLC) cases with preexisting T2DM. Methods: Fifty-five NSCLC patients with preexisting T2DM were retrospectively included and matched by 55 NSCLC without diabetes at a 1:1 ratio. The expression of proteins in IGF/IR axis was detected by immunohistochemical staining. Clinicopathological data were collected to analyze their relationship with the protein expression. Results: Both IGF 1 receptor (IGF-1R) and insulin receptor substrate 2 (IRS-2) showed higher expression in the NSCLC with T2DM group, compared with those without T2DM. The high expression of IGF-1R and IRS-2 were found to be negatively associated with lymph node metastases and T staging in the T2DM group, respectively, and IRS-2 expression was also found more in the subgroup whose T2DM duration was more than 4 years. No difference was detected in the expression of IRS-1, IGF-1, IGF-2, IGFBP3, IR and mTOR between groups with or without T2DM. Conclusion: Our study found higher expression of IGF-1R and IRS-2 proteins in NSCLC patients with preexisting T2DM, and that there was an association with early stage NSCLC, which suggested that IGF signaling may play an important early event in development of NSCLC associated with diabetes.

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“…Some of these patients had been included in previous studies evaluating the clinical role of various molecular biomarkers (7,13,14).…”

Section: Methodsmentioning

confidence: 99%

“…Immunostaining for p-mTOR and EGFR Immunohistochemistry for p-mTOR was done as previously described (7). Briefly, for epitope retrieval, specimens were exposed to 10 mmol/L citrate buffer (pH 6.0) and heated for 10 min in a pressure cooker.…”

Section: Cell Linesmentioning

confidence: 99%

“…EGFR and TGFα expression is frequently increased in BTA and it has been shown that bile acids activate EGFR and cellular proliferation through a TGFα-dependent mechanism in human cholangiocarcinoma cells (4). mTOR, a Ser/Thr protein kinase, is a key factor in cellular growth and homeostasis (5,6) and its overexpression is associated with poor outcome of BTA patients (7). mTOR is activated through the PI3K-AKT signaling pathway by phosphorylation at Ser 2448 and by autophosphorylation at Ser 2481 (8,9).…”

Section: Introductionmentioning

confidence: 99%

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Simultaneous blockade of the epidermal growth factor receptor/mammalian target of rapamycin pathway by epidermal growth factor receptor inhibitors and rapamycin results in reduced cell growth and survival in biliary tract cancer cells

Herberger

Berger²,

Puhalla³

et al. 2009

Molecular Cancer Therapeutics

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The prognosis of patients with biliary tract adenocarcinomas (BTA) is still poor due to lack of effective systemic treatment options. Knowledge of the molecular mechanisms involved in the pathogenesis of this disease is of importance for the development of new treatment strategies. We determined the expression of epidermal growth factor receptor (EGFR) and activated mammalian target of rapamycin (p-mTOR) in paraffin-embedded surgical specimens of BTA (n = 89) by immunohistochemistry. Overall survival was analyzed with Cox models adjusted for clinical and pathologic factors. Combined EGFR/p-mTOR expression was significantly associated with relapse-free survival [adjusted hazard ratio for relapse, 2.20; 95% confidence interval (95% CI), 1.45-3.33; P < 0.001] and overall survival (adjusted hazard ratio for death, 2.32; 95% CI, 1.50-3.58; P < 0.001) of the patients. The effect of the EGFR inhibitors erlotinib or cetuximab and the mTOR inhibitor rapamycin on growth and survival of five BTA cell lines was tested in short-term 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and long-term colony formation assays. Simultaneous blockade of EGFR and mTOR in biliary tract cancer cell lines results in a synergistic inhibition of both phosphatidylinositol-3-kinase and mitogen-activated protein kinase pathways, leading to reduced cell growth and survival. These results suggest that combined targeted therapy with EGFR and mTOR inhibitors may potentially benefit patients with BTAs and should be further evaluated in clinical trials. [Mol Cancer Ther 2009;8(6):1547-56]

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Activated Mammalian Target of Rapamycin Is an Adverse Prognostic Factor in Patients with Biliary Tract Adenocarcinoma

Cited by 81 publications

References 21 publications

The expression of phospho-AKT1 and phospho-MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic cholangiocarcinomas

The expression of phospho-AKT1 and phospho-MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic cholangiocarcinomas

Expression Characteristics of Proteins of the Insulin-like Growth Factor Axis in Non-small Cell Lung Cancer Patients with Preexisting Type 2 Diabetes Mellitus

Simultaneous blockade of the epidermal growth factor receptor/mammalian target of rapamycin pathway by epidermal growth factor receptor inhibitors and rapamycin results in reduced cell growth and survival in biliary tract cancer cells

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