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

2区 · 医学

ArticleOA

作者: Morikawa, Takanori ; Motoi, Fuyuhiko ; Abe, Tomoya ; Takahashi, Yayoi ; Aoki, Shuichi ; Tamai, Keiichi ; Katayose, Yu ; Nakagawa, Kei ; Haji, Yoichi ; Hayashi, Hiroki ; Naitoh, Takeshi ; Unno, Michiaki ; Okada, Ryo ; Karasawa, Hideaki ; Okada, Takaho ; Mizuma, Masamichi

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 CD24⁺CD44⁺ 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 CD24⁺CD44⁺ cells. Although GEM monotherapy relatively increased the subpopulation of CD24⁺CD44⁺ 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.

2016-10-25·Proceedings of the National Academy of Sciences1区 · 综合性期刊

Notch3 drives development and progression of cholangiocarcinoma

1区 · 综合性期刊

Article

作者: Morton, Jennifer P ; Robson, Andrew J ; Komuta, Mina ; Boulter, Luke ; Roskams, Tania ; Gonzalez, Sofia Ferreira ; Lu, Wei-Yu ; Forbes, Stuart J ; Wojtacha, Davina ; Sansom, Owen J ; Dwyer, Benjamin J ; Raven, Alexander ; Kendall, Timothy J ; Minnis-Lyons, Sarah E ; Man, Tak-Yung ; Wigmore, Stephen J ; Guest, Rachel V

SignificanceClinical outcomes in cholangiocarcinoma (CC) are poor; few patients are candidates for curative resection, and palliative chemotherapy produces only modest effects on survival. With an increasing incidence, new targets are urgently needed. Notch has been identified as having potential to induce CC when transgenically overexpressed, and this study aimed to characterize how endogenous Notch might drive tumorigenesis. We identify the atypical receptor Notch3 as differentially overactivated in CCs in humans, rats, and mice, with genetic deletion significantly reducing CC growth. Notch3 sustains tumor cell survival through PI3k/Akt activation via a noncanonical mechanism independent of Recombinant Signal Binding Protein for Immunoglobulin Kappa J Region (RBPJ), presenting an opportunity to target the pathway without disrupting classical Notch and bypassing toxicities associated with γ-secretase inhibitors.

Cells

A Non-Canonical p75HER2 Signaling Pathway Underlying Trastuzumab Action and Resistance in Breast Cancer

Article

作者: Nami, Babak ; Wang, Zhixiang

Overexpression of HER2 occurs in 25% of breast cancer. Targeting HER2 has proven to be an effective therapeutic strategy for HER2-positive breast cancer. While trastuzumab is the most commonly used HER2 targeting agent, which has significantly improved outcomes, the overall response rate is low. To develop novel therapies to boost trastuzumab efficacy, it is critical to identify the mechanisms underlying trastuzumab action and resistance. We recently showed that the inhibition of breast cancer cell growth by trastuzumab is not through the inhibition of HER2 canonical signaling. Here we report the identification of a novel non-canonical HER2 signaling pathway and its interference by trastuzumab. We showed that HER2 signaled through a non-canonical pathway, regulated intramembrane proteolysis (RIP). In this pathway, HER2 is first cleaved by metalloprotease ADAM10 to produce an extracellular domain (ECD) that is released and the p95HER2 that contains the transmembrane domain (TM) and intracellular domain (ICD). p95HER2, if further cleaved by an intramembrane protease, γ-secretase, produced a soluble ICD p75HER2 with nuclear localization signal (NLS). p75HER2 is phosphorylated and translocated to the nucleus. Nuclear p75HER2 promotes cell proliferation. Trastuzumab targets this non-canonical HER2 pathway via inhibition of the proteolytic cleavage of HER2 by both ADAM10 and γ-secretase. However, p75HER2 pathway also confers resistance to trastuzumab once aberrantly activated. Combination of trastuzumab with ADAM10 and γ-secretase inhibitors completely blocks p75HER2 production in both BT474 and SKBR3 cells. We concluded that HER2 signals through the RIP signaling pathway that promotes cell proliferation and is targeted by trastuzumab. The aberrant HER2 RIP signaling confers resistance to trastuzumab that could be overcome by the application of inhibitors to ADAM10 and γ-secretase.

100 项与 γ-secretase modulators( Technische Universität Darmstadt) 相关的药物交易

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