Characterization of a Side Population of Cancer Cells from Human Gastrointestinal System

Haraguchi, Naotsugu; Utsunomiya, Tohru; Inoue, Hiroshi; Tanaka, Fumiaki; Mimori, Koshi; Barnard, Graham F.; Mori, Masaki

doi:10.1634/stemcells.2005-0282

Cited by 533 publications

(463 citation statements)

References 30 publications

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“…CD133 þ HCC cells confer chemoresistance to conventional chemotherapeutic agents We hypothesized that CD133 þ HCC cells, which we have recently shown to represent the exclusive population of CSCs in HCC, would demonstrate resistance to traditional chemotherapeutic agents (Dean et al, 2005;Haraguchi et al, 2006). Both cell proliferation and apoptosis binding assays were used to examine the sensitivity of sorted CD133 þ and CD133 À cells from both human HCC cell line PLC8024 (Figure 1, expressed CD133 in 60% of the cells) and short-term culture of cells derived from CD133 þ (Huh7 human cell line)-induced xenograft tumor (Ma et al, 2007) (data not shown, expressed CD133 in 65% of the cells).…”

Section: Resultsmentioning

confidence: 99%

“…To date, the existence of CSCs has been proven in the context of many cancers, including those of leukemia, breast cancer, glioblastoma, prostate cancer, pancreatic cancer and colon cancer (Lapidot et al, 1994;Bonnet and Dick, 1997;Al-Hajj et al, 2003;Hemmati et al, 2003;Singh et al, 2003Singh et al, , 2004Collins et al, 2005;Ponti et al, 2005;Haraguchi et al, 2006;Patrawala et al, 2006;Li et al, 2007;O'Brien et al, 2007;Ricci-Vitiani et al, 2007). Recently, we have determined that HCC is hierarchically organized and originates from a primitive stem/progenitor group of cells for which CD133 þ precursors constitute one of the most immature stage (Ma et al, 2007).…”

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confidence: 99%

“…Preliminary studies have attributed the high expression levels of specific ABC drug transporters to the increased resistance of CD133 CSCs to chemotherapeutic agents (Dean et al, 2005;Haraguchi et al, 2006). Yet despite extensive research efforts, the specific signaling pathway and mechanism of action to how CD133 CSCs are able to evade conventional therapies, in HCC or other cancer types, remains largely unknown.…”

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confidence: 99%

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CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway

et al. 2007

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The recent discovery of cancer stem cells (CSCs) has played a pivotal role in changing our view of carcinogenesis and chemotherapy. Based on this concept, CSCs are responsible for the formation and growth of neoplastic tissue and are naturally resistant to chemotherapy, explaining why traditional chemotherapies can initially shrink a tumor but fails to eradicate it in full, allowing eventual recurrence. Recently, we identified a CSC population in hepatocellular carcinoma (HCC) characterized by their CD133 phenotype. However, the molecular mechanism by which it escapes conventional therapies remains unknown. Here, we examined the sensitivity of these cells to chemotherapeutic agents (doxorubicin and fluorouracil) and the possible mechanistic pathway by which resistance may be regulated. Purified CD133 þ HCC cells isolated from human HCC cell line and xenograft mouse models survived chemotherapy in increased proportions relative to most tumor cells which lack the CD133 phenotype; the underlying mechanism of which required the preferential expression of survival proteins involved in the Akt/PKB and Bcl-2 pathway. Treatment of CD133 þ HCC cells with an AKT1 inhibitor, specific to the Akt/PKB pathway, significantly reduced the expression of the survival proteins that was normally expressed endogenously. In addition, treatment of unsorted HCC cells with both anticancer drugs in vitro significantly enriched the CD133 þ subpopulation.In conclusion, our results show that CD133 þ HCC cells contribute to chemoresistance through preferential activation of Akt/PKB and Bcl-2 cell survival response. Targeting of this specific survival signaling pathway in CD133 þ HCC CSCs may provide a novel therapeutic model for the disease.

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Section: Resultsmentioning

confidence: 99%

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CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway

et al. 2007

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“…Blocking the N and A1B1 domains of CEACAM5/CEACAM6 can impede the metastatic process (Blumenthal et al, 2005). Interestingly, another study showed that the CEACAM6 gene was one of the most overexpressed genes in a side population of cells of hepatocellular carcinoma (Haraguchi et al, 2006). Most of the side population of cells are considered to be equal to stem cells that show strong chemoresistance to anticancer drugs.…”

Section: Discussionmentioning

confidence: 99%

CEACAM6 gene expression in intrahepatic cholangiocarcinoma

et al. 2006

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The purpose of this study was to investigate the clinicopathological and biological significance of human carcinoembryonic antigenrelated cell adhesion molecule 6 (CEACAM6) gene expression in human intrahepatic cholangiocarcinoma. CEACAM6 is reported to be involved in human malignancies. However, in cholangiocarcinoma expression of CEACAM6 and its clinicopathological significance have not been investigated. CEACAM6 expression status was determined and analysed with respect to various clinicopathological parameters in 23 intrahepatic cholangiocarcinomas. Additionally, we investigated effects of CEACAM6 gene in the cholangiocarcinoma cell lines. CEACAM6 gene expression in cancer tissues was higher than in noncancerous tissues in 16 of the 23 cases; however, it was not statistically significant. The tumours with elevated CEACAM6 expression showed a tendency to be associated with lymphatic invasion and stage of the disease. Interestingly, patients with high CEACAM6 expression showed a significantly poorer disease-free survival rate than those with low CEACAM6 expression. We demonstrated that CEACAM6-transfected cells were more proliferative, more invasive and more chemoresistant to gemcitabine compared to mock-transfected cells. Furthermore, CEACAM6 gene silencing by CEACAM6-specific siRNA resulted in higher chemosensitivity to gemcitabine. CEACAM6 is a potential prognostic indicator and potential chemoresistant marker to gemcitabine for patients with intrahepatic cholangiocarcinoma.

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“…Also in Bcrp1/Mdr1a/1b triple knockout mice, it was shown that Bcrp1, but not Mdr1a/1b, is responsible for the SP phenotype in the bone marrow, while both transporters are required for the SP phenotype in the mammary gland (Jonker et al, 2005). It has now been demonstrated that SP cells are present in several tumour samples, possess stem cell-like properties, overexpress BCRP and possess inherent drug resistance (Haraguchi et al, 2006). Consistently, BCRP overexpression was reported on primary CML CD34 þ cells (Jordanides et al, 2006).…”

Section: Bcrp In Stem Cellsmentioning

confidence: 99%

Drug transporters: recent advances concerning BCRP and tyrosine kinase inhibitors

2008

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Characterization of a Side Population of Cancer Cells from Human Gastrointestinal System

Abstract: STEM CELLS 2006;24:506 -513

Cited by 533 publications

References 30 publications

CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway

CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway

CEACAM6 gene expression in intrahepatic cholangiocarcinoma

Drug transporters: recent advances concerning BCRP and tyrosine kinase inhibitors

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