Colorectal cancer stem cell and chemoresistant colorectal cancer cell phenotypes and increased sensitivity to Notch pathway inhibitor

Huang, Rui; Wang, Guiyu; Song, Yanni; Tang, Qingchao; You, Qi Sheng; Liu, Zheng; Chen, Yinggang; Zhang, Qian; Li, Jiaying; Muhammand, Shan; Wang, Xishan

doi:10.3892/mmr.2015.3694

Cited by 53 publications

(40 citation statements)

References 35 publications

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“…Here, we demonstrate that acquired endocrine resistance potentiates sensitivity of the CSC-like compartment to TRAIL in primary-derived breast cancer samples, and that this significantly correlates with a reduction in c-FLIP levels. These observations are particularly significant given that CSCs have been demonstrated to evade conventional chemotherapy agents and potentially endocrine agents, either due to cell quiescence, through the prevention of drug uptake or modulation of intracellular signaling (18,21,(61)(62)(63). Targeted therapies that initiate cell death through cell surface receptors circumvent these resistance mechanisms and therefore may prove to be a more effective strategy for targeting CSCs (64)(65)(66).…”

Section: Discussionmentioning

confidence: 99%

Acquired Resistance of ER-Positive Breast Cancer to Endocrine Treatment Confers an Adaptive Sensitivity to TRAIL through Posttranslational Downregulation of c-FLIP

Piggott

Silva

Robinson

et al. 2018

Clinical Cancer Research

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Purpose: One third of ER-positive breast cancer patients who initially respond to endocrine therapy become resistant to treatment. Such treatment failure is associated with poor prognosis and remains an area of unmet clinical need. Here, we identify a specific posttranslational modification that occurs during endocrine resistance and which results in tumor susceptibility to the apoptosis-inducer TRAIL. This potentially offers a novel stratified approach to targeting endocrine-resistant breast cancer.Experimental Design: Cell line and primary-derived xenograft models of endocrine resistance were investigated for susceptibility to TRAIL. Tumor viability, cancer stem cell (CSC) viability (tumorspheres), tumor growth kinetics, and metastatic burden were assessed. Western blots for the TRAIL-pathway inhibitor, c-FLIP, and upstream regulators were performed. Results were confirmed in primary culture of 26 endocrineresistant and endocrine-na€ ve breast tumors.Results: Breast cancer cell lines with acquired resistance to tamoxifen (TAMR) or faslodex were more sensitive to TRAIL than their endocrine-sensitive controls. Moreover, TRAIL eliminated CSC-like activity in TAMR cells, resulting in prolonged remission of xenografts in vivo. In primary culture, TRAIL significantly depleted CSCs in 85% endocrineresistant, compared with 8% endocrine-na€ ve, tumors, whereas systemic administration of TRAIL in endocrine-resistant patient-derived xenografts reduced tumor growth, CSC-like activity, and metastases. Acquired TRAIL sensitivity correlated with a reduction in intracellular levels of c-FLIP, and an increase in Jnk-mediated phosphorylation of E3-ligase, ITCH, which degrades c-FLIP.Conclusions: These results identify a novel mechanism of acquired vulnerability to an extrinsic cell death stimulus, in endocrine-resistant breast cancers, which has both therapeutic and prognostic potential.

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Section: Discussionmentioning

confidence: 99%

Acquired Resistance of ER-Positive Breast Cancer to Endocrine Treatment Confers an Adaptive Sensitivity to TRAIL through Posttranslational Downregulation of c-FLIP

Piggott

Silva

Robinson

et al. 2018

Clinical Cancer Research

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“…Many studies have shown that ovarian CSC contribute to apoptosis inhibition and EMT phenotypes from the activation of the PI3K/Akt signaling pathway, [31] MAPK signaling pathway, and Wnt signaling pathway, [43] eventually leading to drug resistance. Signaling pathway is complex, and its targeting drug efficacy still remains controversial.…”

Section: Discussionmentioning

confidence: 99%

STROBE-compliant integrin through focal adhesion involve in cancer stem cell and multidrug resistance of ovarian cancer

et al. 2017

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Cancer stem cells (CSCs) are considered to be the root of carcinoma relapse and drug resistance in ovarian cancer. Hunting for the potential CSC genes and explain their functions would be a feasible strategy to meet the challenge of the drug resistance in ovarian cancer. In this study, we performed bioinformatic approaches such as biochip data extraction and pathway enrichment analyses to elucidate the mechanism of the CSC genes in regulation of drug resistance. Potential key genes, integrins, were identified to be related to CSC in addition to their associations with drug resistance and prognosis in ovarian cancer. A total of 36 ovarian CSC genes involved in regulation of drug resistance were summarized, and potential drug resistance-related CSC genes were identified based on 3 independent microarrays retrieved from the Gene Expression Omnibus (GEO) Profiles. Pathway enrichment of CSC genes associated with drug resistance in ovarian cancer indicated that focal adhesion signaling might play important roles in CSC genes-mediated drug resistance. Integrins are members of the adhesion molecules family, and integrin subunit alpha 1, integrin subunit alpha 5, and integrin subunit alpha 6 (ITGA6) were identified as central CSC genes and their expression in side population cells, cisplatin-resistant SKOV3 (SKOV3/DDP2) cells, and cisplatin-resistant A2780 (A2780/DDP) cells were dysregulated as measured by real-time quantitative polymerase chain reaction. The high expression of ITGA6 in 287 ovarian cancer patients of TCGA cohort was significantly associated with poorer progression-free survival. This study provide the basis for further understanding of CSC genes in regulation of drug resistance in ovarian cancer, and integrins could be a potential biomarker for prognosis of ovarian cancer.

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“…Enhanced therapeutic resistance has been attributed to CSCs [80,82–87], which subsequently leads to increased tumor growth, invasion, and relapse. A common contributor to therapeutic resistance is enhanced DNA damage response.…”

Section: Therapy-resistant Cscs In Disease Relapsementioning

confidence: 99%

Cancer Stem Cells: Cellular Plasticity, Niche, and its Clinical Relevance

Lee

Hall

Ahmed

2016

J Stem Cell Res Ther

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Cancer handles an estimated 7.6 million deaths worldwide per annum. A recent theory focuses on the role Cancer Stem Cells (CSCs) in driving tumorigenesis and disease progression. This theory hypothesizes that a population of the tumor cell with similar functional and phenotypic characteristics as normal tissue stem cells are responsible for formation and advancement of many human cancers. The CSCs subpopulation can differentiate into non-CSC tumor cells and promote phenotypic and functional heterogeneity within the tumor. The presence of CSCs has been reported in a number of human cancers including blood, breast, brain, colon, lung, pancreas prostate and liver. Although the origin of CSCs remains a mystery, recent reports suggest that the phenotypic characteristics of CSCs may be plastic and are influenced by the microenvironment specific for the individual tumor. Such factors unique to each tumor preserve the dynamic balance between CSCs to non-CSCs cell fate, as well as maintain the proper equilibrium. Alternating such equilibrium via dedifferentiation can result in aggressiveness, as CSCs are considered to be more resistant to the conventional cancer treatments of chemotherapy and radiation. Understanding how the tumoral microenvironment affects the plasticity driven CSC niche will be critical for developing a more effective treatment for cancer by eliminating its aggressive and recurring nature that now is believed to be perpetuated by CSCs.

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Colorectal cancer stem cell and chemoresistant colorectal cancer cell phenotypes and increased sensitivity to Notch pathway inhibitor

Cited by 53 publications

References 35 publications

Acquired Resistance of ER-Positive Breast Cancer to Endocrine Treatment Confers an Adaptive Sensitivity to TRAIL through Posttranslational Downregulation of c-FLIP

Acquired Resistance of ER-Positive Breast Cancer to Endocrine Treatment Confers an Adaptive Sensitivity to TRAIL through Posttranslational Downregulation of c-FLIP

STROBE-compliant integrin through focal adhesion involve in cancer stem cell and multidrug resistance of ovarian cancer

Cancer Stem Cells: Cellular Plasticity, Niche, and its Clinical Relevance

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