Efficacy of Using Cancer Stem Cell Markers in Isolating and Characterizing Liver Cancer Stem Cells

Wilson, George S.; Hu, Zenan; Duan, Wei; Tian, Anmin; Wang, Xin M.; McLeod, Duncan; Lam, Vincent; George, Jacob; Qiao, Liang

doi:10.1089/scd.2012.0703

Cited by 45 publications

(30 citation statements)

References 43 publications

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“…1C). Altogether, these results indicated that CD133 and EpCAM markers were convenient for identifying cells that have cancer stem cell like features in epithelial-like HCC cell lines and were compatible with the literature (11,12).…”

Section: Isolated Cd133+/epcam+ Cells Display Cancer Stem Cell Characsupporting

confidence: 86%

Differential alteration of IL-8 in liver cancer stem cell enrichment in response to PI3K/Akt/mTOR inhibitors and sorafenib

Kahraman¹,

Kahraman

Cetin-Atalay³

2018

Preprint

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Liver cancer stem cells (LCSCs) indicating that IL-8 signaling is crucial for the conservation of stemness features of cancer cells.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/306910 doi: bioRxiv preprint first posted online Apr. 25, 2018; 3 Conclusion: PI3K/Akt/mTOR pathway inhibitors alter hepatic CSC composition and gene expression in favor or to the detriment of cancer stem cell survival. Blockade of IL-8 signaling provides a promising therapeutic approach for prevention of LCSC enrichment.Keywords: Hepatocellular carcinoma, Liver cancer stem cells, Sorafenib, PI3K/AKT pathway, interleukin 8All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/306910 doi: bioRxiv preprint first posted online Apr. 25, 2018; 4 Introductory StatementHepatocellular carcinoma (HCC) is the second common cause of cancer mortality and the fifth most common malignancy in human cancers (1) .Chronic liver injury is caused by viral diseases, exposure to chemicals, and other environmental or autoimmune conditions which constitute the risk factors for HCC (2, 3). Liver cancer is known to originate from hepatic progenitor cells (HPC) during cirrhosis and has a very heterogeneous histological structure. In this process, HPCs are damaged and transformed to liver cancer stem cells (LCSCs) which are responsible for chemoresistance, tumor relapse and metastasis (4). Sorafenib and Regorafenib are multikinase inhibitors, which are the only clinical treatment options for advanced HCC patients approved by Markers validated for the identification of LCSCs include CD133, EpCAM, CD90, CD44, CD24, CD13, and OV6 as well as Hoechst dye efflux or aldehyde dehydrogenase (ALDH) activity (7). In our previous study, it was well defined that CD133 and EpCAM were convenient to detect LCSCs of epithelial like (well-differentiated) cells, whereas CD90 was efficient to detect LCSCs of mesenchymal like (poorly differentiated) cells (8, 9).We report here that the small molecule inhibitor Rapamycin inhibits the enrichment of LCSCs and regulates pathways related with stemness. Additionally, gene expression analysis along with pathway scoring results have revealed several potential targets such as IL-8 against cancer stem cell enrichment, where blockade of IL-8 pathway was shown to prevent enrichment of LCSC population significantly.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/306910 doi: bioRxiv preprint first posted online Apr. 25, 2018; 5 Experimental Pro...

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Section: Isolated Cd133+/epcam+ Cells Display Cancer Stem Cell Characsupporting

confidence: 86%

Differential alteration of IL-8 in liver cancer stem cell enrichment in response to PI3K/Akt/mTOR inhibitors and sorafenib

Kahraman¹,

Kahraman

Cetin-Atalay³

2018

Preprint

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“…42 With regard to the controversial outcome of using signal biomarkers to identify and isolate CSCs, a growing pool of data suggested that combinations of multiple biomarkers might be the more effectual means of identifying CSCs and prognostic assessment in HCC. [41][42][43] Considering PTEN is a vital upstream initiator and key activation manager of the PTEN/AKT/mTOR pathway, we opted for the combination of PTEN and LCSC markers to evaluate prognosis. We found that HCC patients with PTEN À /CD133 + or PTEN À /EpCAM + expression had a high risk of recurrence and poor prognosis, compared to the other combinations.…”

Section: Discussionmentioning

confidence: 99%

Associations of components of PTEN/AKT/mTOR pathway with cancer stem cell markers and prognostic value of these biomarkers in hepatocellular carcinoma

Nan

Guo

et al. 2016

Hepatology Research

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“…T‐ICs have been implicated in recurrence and therapeutic resistance. Several recent studies support this hypothesis and have revealed that epithelial cell adhesion molecule (EpCAM) + and label‐retaining HCC cells are more resistant to sorafenib treatment . Recently, we have identified CD47 as a novel therapeutic target for elimination of liver T‐ICs .…”

mentioning

confidence: 81%

Nuclear factor kappa B–mediated CD47 up‐regulation promotes sorafenib resistance and its blockade synergizes the effect of sorafenib in hepatocellular carcinoma in mice

et al. 2015

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Sorafenib is a new standard treatment for patients with advanced hepatocellular carcinoma (HCC). However, the survival benefit of this treatment is modest, partly owing to drug resistance. Recent evidence has demonstrated the existence of tumor-initiating cells (T-ICs) as the culprit for treatment resistance. To examine whether sorafenib resistance was a result of the presence of liver T-ICs, we developed sorafenib-resistant HCC cells both in vitro and in vivo through continuous exposure to sorafenib. Using these models, we found that sorafenibresistant clones demonstrated enhanced T-IC properties, including tumorigenicity, selfrenewal, and invasiveness. In addition, several T-IC markers were found to be up-regulated, among which CD47 was found to be most significant. Using chromatin immunoprecipitation assays and expression analyses, CD47 expression was found to be regulated by nuclear factor kappa B (NF-jB) through a specific response element in the promoter of CD47, and the site occupancy and expression were increased and decreased upon stimulation and inhibition of NF-jB, respectively. Consistently, NF-jB was activated in sorafenib-resistant HCC cells, and this finding was confirmed in clinical HCC samples, which showed a positive correlation between NF-jB and CD47 expression. Functional characterization of CD47 in sorafenib-resistant HCC cells was evaluated using a lentivirus-based knockdown approach and showed increased sensitization to sorafenib upon CD47 knockdown. Furthermore, blockade of CD47 using anti-CD47 antibody (Ab) showed a similar effect. Using a patientderived HCC xenograft mouse model, we found that anti-CD47 Ab (500 lg/mouse) in combination with sorafenib (100 mg/kg, orally) exerted synergistic effects on tumor suppression, as compared with sorafenib and anti-CD47 Ab alone. Conclusions: NF-jB-mediated CD47 up-regulation promotes sorafenib resistance, and targeting CD47 in combination with sorafenib is an attractive therapeutic regimen for the treatment of HCC patients. (HEPATOLOGY 2015;62:534-545) L iver cancer (hepatocellular carcinoma; HCC) is a major malignancy worldwide, 1 and the front-line treatment for this disease is liver transplantation and surgical resection. However, most HCCs are inoperable, given that patients typically present at advanced stages, and even after surgical resection, the long-term prognosis of HCC remains unsatisfactory owing to its high recurrence rate. For advanced-staged HCC

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Efficacy of Using Cancer Stem Cell Markers in Isolating and Characterizing Liver Cancer Stem Cells

Cited by 45 publications

References 43 publications

Differential alteration of IL-8 in liver cancer stem cell enrichment in response to PI3K/Akt/mTOR inhibitors and sorafenib

Differential alteration of IL-8 in liver cancer stem cell enrichment in response to PI3K/Akt/mTOR inhibitors and sorafenib

Associations of components of PTEN/AKT/mTOR pathway with cancer stem cell markers and prognostic value of these biomarkers in hepatocellular carcinoma

Nuclear factor kappa B–mediated CD47 up‐regulation promotes sorafenib resistance and its blockade synergizes the effect of sorafenib in hepatocellular carcinoma in mice

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