Aberrant activation of Notch signaling in extrahepatic cholangiocarcinoma: clinicopathological features and therapeutic potential for cancer stem cell-like propertiesReportar como inadecuado

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BMC Cancer

, 16:854

Experimental therapeutics and drug development


BackgroundLittle is known about the roles of Notch signaling in cholangiocarcinoma CC. The expression of hairy and enhancer of split 1 Hes-1 has not been investigated yet in resected specimens of CC. Notch signaling has been reported to be related to cancer stem cell CSC like properties in some malignancies. Our aim is to investigate the participation of Notch signaling in resected specimens of extrahepatic CC EHCC and to evaluate the efficacy of CC cells with CSC-like properties by Notch signaling blockade.

MethodsFirst, the expression of Notch1, 2, 3, 4 and Hes-1 was examined by immunohistochemistry in 132 resected EHCC specimens. The clinicopathological characteristics in the expression of Notch receptors and Hes-1 were investigated. Second, GSI IX, which is a γ-secretase-inhibitor, was used for Notch signaling blockade in the following experiment. Alterations of the subpopulation of CD24CD44 cells, which are surface markers of CSCs in EHCC, after exposure with GSI IX, gemcitabine GEM, and the combination of GSI IX plus GEM were assessed by flow cytometry using the human CC cell lines, RBE, HuCCT1 and TFK-1. Also, anchorage-independent growth and mice tumorigenicity in the cells recovered by regular culture media after GSI IX exposure were assessed.

ResultsNotch1, 2, 3, 4 and Hes-1 in the resected EHCC specimens were expressed in 50.0, 56.1, 42.4, 6.1, and 81.8 % of the total cohort, respectively. Notch1 and 3 expressions were associated with poorer histological differentiation P = 0.008 and 0.053. The patients with the expression of at least any one of Notch1-3 receptors, who were in 80.3 % of the total, exhibited poorer survival P = 0.050. Similarly, the expression of Hes-1 tended to show poor survival P = 0.093. In all of the examined CC cell lines, GSI IX treatment significantly diminished the subpopulation of CD24CD44 cells. Although GEM monotherapy relatively increased the subpopulation of CD24CD44 cells in all lines, GSI IX plus GEM attenuated it. Anchorage-independent growth and mice tumorigenicity were inhibited in GSI IX-pretreated cells in RBE and TFK-1 P < 0.05.

ConclusionAberrant Notch signaling is involved with EHCC. Inhibition of Notch signaling is a novel therapeutic strategy for targeting cells with CSC-like properties.

KeywordsNotch signaling Cholangiocarcinoma Hes-1 Cancer stem cell AbbreviationsBSABovine serum albumin



CSCsCancer stem cells

DMSODimethyl sulfoxide

ECOGEastern Cooperative Oncology Group

EDTAEthylenedinitrilotetraacetic acid

EGFREpidermal growth factor receptor

EHCCExtrahepatic CC

FBSFetal bovine serum


GSIγ-secretase inhibitor

Hes-1Hairy and enhancer of split 1


IHCCIntrahepatic CC

NICDNotch intracellular domain

NOD-SCIDNonobese diabetic-severe combined immunodeficiency

OSOverall survival

PBSPhosphate buffered saline

PMSFPhenylmethanesulfonyl Fluioride

pNETPancreatic neuroendocrine tumors


qPCRQuantitative real-time reverse transcription polymerase chain reaction


SDSSodium dodecyl sulfate

UICCUnion for the International Cancer Control

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Autor: Shuichi Aoki - Masamichi Mizuma - Yayoi Takahashi - Yoichi Haji - Ryo Okada - Tomoya Abe - Hideaki Karasawa - Keiichi Tama

Fuente: https://link.springer.com/

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