CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity

Yin, Shengyong; Li, Jinjun; Hu, Chen; Chen, Xinhua; Yao, Ming; Yan, Mingxia; Jiang, Guoping; Ge, Chao; Xie, Haiyang; Wan, Dafang; Yang, Shengli; Zheng, Shusen; Gu, Jianren

doi:10.1002/ijc.22476

Cited by 504 publications

(406 citation statements)

References 27 publications

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“…Furthermore, it is worthwhile to mention that our group previously demonstrated that when these cells were injected into nude or SCID animals, CD133 þ cells were only maintained at a very low frequency in contrast to their in vitro culture environment (Ma et al, 2007). And in addition to our recent findings, there is also another research group that provided evidence in support of the existence of CD133 þ cells in cancer patient specimens (Yin et al, 2007). Results show that CD133 þ fraction in human HCC specimens and xenografts ranged from 1 to 3%.…”

Section: Discussionsupporting

confidence: 70%

“…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%

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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: Discussionsupporting

confidence: 70%

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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 pentaspan transmembrane glycoprotein CD133, also known as Prominin-1, was originally described as a hematopoietic stem cell marker (Yin et al, 1997) and was subsequently shown to be expressed by a number of progenitor cells including those of the epithelium, where it is expressed on the apical surface (Corbeil et al, 2000). CD133 expression distinguishes a number of cancer-initiating cells, including those associated with brain (Singh et al, 2004;Liu et al, 2006), pancreatic (Olempska et al, 2007), liver (Ma et al, 2002;Yin et al, 2007), skin (Monzani et al, 2007), prostate (Collins et al, 2005;Miki et al, 2007) and colon cancers (O'Brien et al, 2007;Ricci-Vitiani et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells

et al. 2008

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The cancer stem cell hypothesis posits that malignant growth arises from a rare population of progenitor cells within a tumor that provide it with unlimited regenerative capacity. Such cells also possess increased resistance to chemotherapeutic agents. Resurgence of chemoresistant disease after primary therapy typifies epithelial ovarian cancer and may be attributable to residual cancer stem cells, or cancer-initiating cells, that survive initial treatment. As the cell surface marker CD133 identifies cancerinitiating cells in a number of other malignancies, we sought to determine the potential role of CD133 þ cells in epithelial ovarian cancer. We detected CD133 on ovarian cancer cell lines, in primary cancers and on purified epithelial cells from ascitic fluid of ovarian cancer patients. We found CD133 þ ovarian cancer cells generate both CD133 þ and CD133À daughter cells, whereas CD133À cells divide symmetrically. CD133 þ cells exhibit enhanced resistance to platinum-based therapy, drugs commonly used as first-line agents for the treatment of ovarian cancer. Sorted CD133 þ ovarian cancer cells also form more aggressive tumor xenografts at a lower inoculum than their CD133À progeny. Epigenetic changes may be integral to the behavior of cancer progenitor cells and their progeny. In this regard, we found that CD133 transcription is controlled by both histone modifications and promoter methylation. Sorted CD133À ovarian cancer cells treated with DNA methyltransferase and histone deacetylase inhibitors show a synergistic increase in cell surface CD133 expression. Moreover, DNA methylation at the ovarian tissue active P2 promoter is inversely correlated with CD133 transcription. We also found that promoter methylation increases in CD133À progeny of CD133 þ cells, with CD133 þ cells retaining a less methylated or unmethylated state. Taken together, our results show that CD133 expression in ovarian cancer is directly regulated by epigenetic modifications and support the idea that CD133demarcates an ovarian cancer-initiating cell population. The activity of these cells may be epigenetically detected and such cells might serve as pertinent chemotherapeutic targets for reducing disease recurrence.

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“…CD133 expression has been detected in several normal tissues including neuroepithelium, embryonic and adult immature epithelia (Weigmann et al, 1997;Corbeil et al, 2000;Richardson et al, 2004;Shmelkov et al, 2005). The association between CD133 and CSCs has been documented in haematological malignancies (Horn et al, 1999) and since then, CD133 expression has been identified in various types of solid tumours, including brain tumours (Singh et al, 2003(Singh et al, , 2004Beier et al, 2007), prostate cancer (Collins et al, 2005), kidney cancer (Florek et al, 2005), melanoma (Klein et al, 2007;Monzani et al, 2007), ovarian cancer (Ferrandina et al, 2007), hepatocellular carcinoma (Suetsugu et al, 2006;Ma et al, 2007;Yin et al, 2007), and colon cancer (Ieta et al, 2007;O'Brien et al, 2007;Ricci-Vitiani et al, 2007).…”

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confidence: 99%

“…CD133 þ cells in colon cancer cell lines have a high degree of tumorigenic ability in vivo, and their levels of proliferation, colony formation, and invasive ability were found to be higher than those of CD133 À cells in vitro (Ieta et al, 2007). There are also small populations of CD133 þ cells in human hepatocellular carcinoma (HCC) cell lines and primary HCC tissues (Yin et al, 2007). In contrast with these findings, it was reported that as many as half of Huh-7 cells, a human liver cancer cell line, are CD133 þ (Suetsugu et al, 2006).…”

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confidence: 99%

CD133 expression is correlated with lymph node metastasis and vascular endothelial growth factor-C expression in pancreatic cancer

et al. 2008

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Although CD133 has been shown to be a marker for cancer stem cells in various tumours, its expression in pancreatic cancer has not yet been clinically reported. In this study, we investigated the relationship between CD133 expression and clinicopathological factors in pancreatic cancer. Pancreatic head carcinoma specimens from 80 patients who underwent surgical resection were immunohistochemically assessed for CD133, vascular endothelial growth factor (VEGF)-C, CXCR4, CD34, Ki-67, and cytokeratin (CK) expressions. Sixty percentage (48/80) of specimens were CD133-positive, with less than 15% cells per specimen expressing the marker. CD133-positive cells were found at the peripheral site of adenocarcinoma glandular structures and were negative for CK. There was a significant correlation between CD133 expression and clinicopathological factors, including histological type, lymphatic invasion, and lymph node metastasis (P ¼ 0.0215, 0.0023, and 0.0024, respectively). Vascular endothelial growth factor-C expression was also significantly correlated with CD133 expression (P ¼ 0.0002). Consequently, the 5-year survival rate of CD133-positive patients was significantly lower than that of CD133-negative patients (P ¼ 0.0002) and multivariate analysis revealed that CD133 expression was an independent prognostic factor (P ¼ 0.0103). These results suggest that CD133 expression in pancreatic cancer was significantly associated with lymphatic metastasis, VEGF-C expression, and prognosis.

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CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity

Cited by 504 publications

References 27 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

Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells

CD133 expression is correlated with lymph node metastasis and vascular endothelial growth factor-C expression in pancreatic cancer

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