Immunohistochemical analysis of the mTOR pathway in intrahepatic cholangiocarcinoma

Abstract

The aim of the study was to evaluate the expression of activated mammalian rapamycin (mTOR) and its downstream effectors, phosphorylated p70 ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein 1 (4EBP1), in intrahepatic cholangiocarcinomas (ICC), in order to strengthen the rationale for targeted therapy using mTOR inhibitors in patients with ICC. p-mTOR (Ser 2448), p-4EBP1 (Thr 70) and p-p70S6K (Thr 389) were detected in 77 primary ICC tumors by immunohistochemistry. High levels of p-mTOR, p-4EBP1 and p-p70S6K expression were defined in 48.1% (37/77), 50.6% (39/77) and 51.9% (40/77) of all tumors, respectively. No significant correlation was observed between mTOR pathway proteins overexpression with clinicopathological characteristics and patient's prognosis, except that high p-p70S6K expression correlated with the poorly differentiated subtype, and high expression of p-4EBP1 predicted poor prognosis in ICC patients and retained an independent prognostic factor in multivariate analysis. In conclusion, our results showed high prevalence of activation of mTOR pathway in ICC tumors, suggesting that a high proportion of ICC patients might benefit from mTOR pathway targeted therapies. In addition, p-4EBP1 phosphorylation at Thr 70 could be a useful prognostic biomarker for ICC patients.

Phase II study of everolimus (RAD001) monotherapy as first-line treatment in advanced biliary tract cancer with biomarker exploration: the RADiChol Study

“…In addition, immunohistochemical (IHC) staining of PI3K pathway components phosphorylated (p)-AKT and p-mTOR suggests that up to 50% of BTCs may harbour activation of this pathway, 8,9 which is associated with worse survival outcomes. [10][11][12] Finally, constitutive activation of the PI3K pathway contributes to the development of BTC in genetic mouse models, 13 making mTOR inhibition an attractive therapeutic target in BTC.…”

Fibronectin promotes cell proliferation and invasion through mTOR signaling pathway activation in gallbladder cancer

“…The diagnostic value of FN in human bile fluid for malignant biliary diseases has previously been documented [11,12]; however, FN expression and its biological functions in GBC remain unclear. The mammalian target of the rapamycin (mTOR) signaling pathway is frequently activated in human cancers and plays a prominent role in the regulation of multiple cellular functions in response to tumor microenvironmental stimuli [1,13,14]. As the two most characterized effectors downstream of mTOR, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and p70 ribosomal protein S6 kinase (p70S6K) are critically involved in the translational control of gene expression during cancer progression [15][16][17].…”

AKT/mTOR substrate P70S6K is frequently phosphorylated in gallbladder cancer tissue and cell lines

“…Wang et al49 evaluated the immunohistochemical expression of phosphorylated mTOR and its downstream effectors, phospho-p70S6K and phospho-4E-BP1, in 77 intrahepatic cholangiocarcinomas. They found high levels of the three phosphorylated proteins, demonstrating the high prevalence of mTOR pathway activation in these tumors 49. Similarly, Lee et al explored the prognostic significance of the AKT1 pathway in a large cohort of intrahepatic cholangiocarcinomas (101 cases).…”