Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells

Suetsugu, Atsushi; Nagaki, Masahito; Aoki, Hitomi; Motohashi, Tsutomu; Kunisada, Takahiro; Moriwaki, Hisataka

doi:10.1016/j.bbrc.2006.10.128

Cited by 547 publications

(420 citation statements)

References 19 publications

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“…Therefore, to completely eradicate a tumor and prevent recurrence, it is imperative that CSCs be specifically targeted. To date, CSCs have been identified as the driving force behind tumor formation in several tumor types including those of leukemia (2), cancers of the breast (3), brain (4), and prostate (5), and more recently, cancers of the colon (6) and liver (7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Aldehyde Dehydrogenase Discriminates the CD133 Liver Cancer Stem Cell Populations

Ma¹,

Chan²,

Lee³

et al. 2008

Molecular Cancer Research

422

298

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Recent efforts in our study of cancer stem cells (CSC) in hepatocellular carcinoma (HCC) have led to the identification of CD133 as a prominent HCC CSC marker. Findings were based on experiments done on cell lines and xenograft tumors where expression of CD133 was detected at levels as high as 65%. Based on the CSC theory, CSCs are believed to represent only a minority number of the tumor mass. This is indicative that our previously characterized CD133 + HCC CSC population is still heterogeneous, consisting of perhaps subsets of cells with differing tumorigenic potential. We hypothesized that it is possible to further enrich the CSC population by means of additional differentially expressed markers. Using a two-dimensional PAGE approach, we compared protein profiles between CD133 + and CD133 À subpopulations isolated from Huh7 and PLC8024 and identified aldehyde dehydrogenase 1A1 as one of the proteins that are preferentially expressed in the CD133 + subfraction. Analysis of the expression of several different ALDH isoforms and ALDH enzymatic activity in liver cell lines found ALDH to be positively correlated with CD133 expression. Dual-color flow cytometry analysis found the majority of ALDH + to be CD133 + , yet not all CD133 + HCC cells were ALDH + . Subsequent studies on purified subpopulations found CD133 + ALDH + cells to be significantly more tumorigenic than their CD133 À ALDH + or CD133 À ALDH À counterparts, both in vitro and in vivo. These data, combined with those from our previous work, reveal the existence of a hierarchical organization in HCC bearing tumorigenic potential in the order of CD133 + ALDH + > CD133 + ALDH À > CD133 À ALDH À .ALDH, expressed along CD133, can more specifically characterize the tumorigenic liver CSC population.

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Section: Introductionmentioning

confidence: 99%

Aldehyde Dehydrogenase Discriminates the CD133 Liver Cancer Stem Cell Populations

Ma¹,

Chan²,

Lee³

et al. 2008

Molecular Cancer Research

422

298

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“…CD133 þ HCC cells isolated from human HCC cell lines and xenograft tumors not only possess a greater colony-forming efficiency, higher proliferative output and greater ability to form tumor in vivo but are also endowed with characteristics similar to those of stem/progenitor cells including the preferential expression of 'stemness' genes, the ability to selfrenew and the ability to differentiate. Further, CD133 represents only a minority of the tumor cell population in human HCC specimens (Suetsugu et al, 2006;Ma et al, 2007;Yin et al, 2007).…”

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confidence: 99%

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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“…The cell surface marker CD133, a member of the cell membrane protein superfamily, was used to identify TICs as a specific marker in such solid tumors as a brain tumor (Singh et al, 2003;Singh et al, 2004), hepatocellular carcinoma (Suetsugu et al, 2006;Yin et al, 2007), pancreatic cancer (Hermann et al, 2007), prostate cancer (Collins et al, 2005), colon cancer (O'Brien et al, 2007;Ricci-Vitiani et al, 2007), and lung cancer (Eramo et al, 2008). Purified CD133 + TICs from these DOI:http://dx.doi.org/10.7314/APJCP.2014.15.1.161 Molecular Beacon Monitoring of microRNAs in Lung Adenocarcinoma-initiating A549 Cells cancers showed the potential of self-renewal capacity, differentiation, and proliferation and had the capability to form tumors in immunodeficient mice (Collins et al, 2005;Suetsugu et al, 2006;O'Brien et al, 2007). The CD133 + cells from fresh lung tumor samples were also found to have tumor-initiating properties in both small cell and non-small cell lung cancers (Eramo et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Monitoring microRNAs Using a Molecular Beacon in CD133⁺/CD338⁺Human Lung Adenocarcinoma-initiating A549 Cells

Yao

Sun²,

Ma³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells

Cited by 547 publications

References 19 publications

Aldehyde Dehydrogenase Discriminates the CD133 Liver Cancer Stem Cell Populations

Aldehyde Dehydrogenase Discriminates the CD133 Liver Cancer Stem Cell Populations

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

Monitoring microRNAs Using a Molecular Beacon in CD133⁺/CD338⁺Human Lung Adenocarcinoma-initiating A549 Cells

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Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells

Cited by 547 publications

References 19 publications

Aldehyde Dehydrogenase Discriminates the CD133 Liver Cancer Stem Cell Populations

Aldehyde Dehydrogenase Discriminates the CD133 Liver Cancer Stem Cell Populations

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

Monitoring microRNAs Using a Molecular Beacon in CD133+/CD338+Human Lung Adenocarcinoma-initiating A549 Cells

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Monitoring microRNAs Using a Molecular Beacon in CD133⁺/CD338⁺Human Lung Adenocarcinoma-initiating A549 Cells