Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways

Takebe, Naoko; Harris, Pamela Jo; Warren, Ronald Q.; Ivy, S. Percy

doi:10.1038/nrclinonc.2010.196

Cited by 877 publications

(723 citation statements)

References 130 publications

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“…3 The origin of CSCs is not fully understood; however, data suggest that they originate from normal stem or progenitor cells or, possibly, from other cancer cells. 18 Tumors composed of small populations of CSCs and large numbers of differentiated tumor cells may be particularly susceptible to combination drug regimens that target each cell population. Therapeutic targeting of both CSCs and bulk tumor populations may provide a strategy to suppress tumor regrowth.…”

Section: Notch1 Expression Can Predict the Prognosis Of Patients Withmentioning

confidence: 99%

“…Therapeutic targeting of both CSCs and bulk tumor populations may provide a strategy to suppress tumor regrowth. 18 Tumor relapse and metastasis remain major obstacles to improving overall cancer survival, and CSCs are considered a major cause of tumor relapse after conventional therapy because of their resistance to chemotherapy and radiotherapy modalities. 19,20 The slow growth rate and chemoresistant characteristics suggest that CSCs may survive routine chemotherapy, only to reinitiate tumor growth at a later point in time.…”

Section: Notch1 Expression Can Predict the Prognosis Of Patients Withmentioning

confidence: 99%

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Notch1 signaling contributes to stemness in head and neck squamous cell carcinoma

Lee

et al. 2016

Laboratory Investigation

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Section: Notch1 Expression Can Predict the Prognosis Of Patients Withmentioning

confidence: 99%

Section: Notch1 Expression Can Predict the Prognosis Of Patients Withmentioning

confidence: 99%

Notch1 signaling contributes to stemness in head and neck squamous cell carcinoma

Lee

et al. 2016

Laboratory Investigation

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“…metastasis | mammary tumor E merging data suggest that tumor recurrence and poor clinical outcome of cancer patients may be due to the fact that a small subset of stem-like cells, called cancer stem cells (CSCs) (1), identified on the basis of a combination of CD44 + /CD24 − , and/or aldehyde dehydrogenase 1 (ALDH1) activity (2,3), evade effects of systemic therapies. Alterations in critical signaling pathways such as Notch, Hedgehog, and Wnt allow stem cells to undergo uncontrolled proliferation and form tumors (4,5).…”

mentioning

confidence: 99%

Nicastrin regulates breast cancer stem cell properties and tumor growth in vitro and in vivo

Lombardo

Filipović

Molyneux

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Nicastrin (NCT) is a crucial component of the γ-secretase (GS) enzyme, which prompted investigations into its biological role in cancer. We have previously shown that nicastrin is overexpressed in breast cancer (BC), conferring worse overall survival in invasive, ERα negative patients. Here, we used 2D and 3D Matrigel, anchorage-independent growth conditions and a breast cancer xenograft mouse model to assess the impact of nicastrin on breast cancer stem cell (BCSC) propagation and invasion in vitro and tumor growth in vivo. Stable knockdown of nicastrin in HCC1806 breast cancer cells reduced cell invasion by 51.4 ± 1.7%, accompanied by a morphological change to a rounded cell phenotype and downregulation of vimentin, Snail, Twist, MMP2, and MMP9. We observed a reduction of the pool of CD44 + /CD24 − and ALDH1 high breast cancer stem cells by threefold and twofold, respectively, and a reduction by 2.6-fold of the mammospheres formation. Nicastrin overexpression in nontransformed MCF10A cells caused an induction of epithelial to mesenchymal regulators, as well as a fivefold increased ALDH1 activity, a threefold enrichment for CD44 + /CD24 − stem cells, and a 3.2-fold enhanced mammosphere-forming capacity. Using the γ-sescretase inhibiton, Notch1/4 siRNA, and Akt inhibition, we show that nicastrin regulates breast cancer stem cells partly through Notch1 and the Akt pathway. Exploiting serial dilution transplantation of the HCC1806 cells expressing nicastrin and HCC1806 stably depleted of nicastrin, in vivo, we demonstrate that nicastrin inhibition may be relevant for the reduced tumorigenicity of breast cancer cells. These data could serve as a benchmark for development of nicastrin-targeted therapies in breast cancer. metastasis | mammary tumor

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“…Cyclopamine was the first Hh inhibitor to be identified (20) and its mechanism of action is well established (21). A number of preclinical and clinical studies have been performed using cyclopamine and synthetic SMO antagonists (23,39). Studies using disease animal models have reinforced the potential of cyclopamine as an anticancer drug (19,(40)(41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

Selective Release of a Cyclopamine Glucuronide Prodrug toward Stem-like Cancer Cell Inhibition in Glioblastoma

Balbous

Renoux

Cortes

et al. 2014

Molecular Cancer Therapeutics

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Recent data suggest that inhibition of the Hedgehog pathway could be a therapeutic target for glioblastoma. Alkaloid cyclopamine inhibits Hedgehog signaling, depleting stem-like cancer cells derived from glioblastoma. However, this compound is toxic for somatic stem cells, preventing its use for clinical applications. In this study, we tested a derivatization product of cyclopamine in the form of cyclopamine glucuronide prodrug (CGP-2). This compound was used in vitro and in vivo toward glioblastoma-initiating cells (GIC). Results obtained in vitro indicate that CGP-2 is active only in the presence of b-glucuronidase, an enzyme detected in high levels in necrotic areas of glioblastomas. CGP-2 decreased proliferation and inhibited the self-renewal of all GIC lines tested. Hedgehog pathway blockade by 10 mmol/L of CGP-2 induced a 99% inhibition of clonogenicity on GICs, similar to cyclopamine treatment. Combination of CGP-2 with radiation decreased clonogenic survival in all GIC lines compared with CGP-2 alone. In a subcutaneous glioblastoma xenograft model, a two-week CGP-2 treatment prevented tumor growth with 75% inhibition at 8 weeks, and this inhibition was still significant after 14 weeks. Unlike cyclopamine, CGP-2 had no detectable toxic effects in intestinal crypts. Our study suggests that inhibition of the Hedgehog pathway with CGP-2 is more effective than conventional temozolomide adjuvant, with much lower concentrations, and seems to be an effective therapeutic strategy for targeting GICs. Mol Cancer Ther; 13(9); 2159-69. Ó2014 AACR.

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Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways

Cited by 877 publications

References 130 publications

Notch1 signaling contributes to stemness in head and neck squamous cell carcinoma

Notch1 signaling contributes to stemness in head and neck squamous cell carcinoma

Nicastrin regulates breast cancer stem cell properties and tumor growth in vitro and in vivo

Selective Release of a Cyclopamine Glucuronide Prodrug toward Stem-like Cancer Cell Inhibition in Glioblastoma

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