Cancer stem cells in the development of liver cancer

Yamashita, Taro; Wang, Xin Wei

doi:10.1172/jci66024

Cited by 474 publications

(450 citation statements)

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“…Some studies have indicated the importance of evaluating ''stemness'' in HCC; it reflects the malignant nature of the tumor and closely correlates with a poor prognosis after surgery [9][10][11][12]. Recent evidence has also suggested that HCC may conform to the cancer stem cell (CSCs) hypothesis, which proposes that a subset of cells with stem cell features play a fundamental role in tumor maintenance and chemo/radiation resistance [13]. CSCs, also called tumor-initiating cells or cancer stem-like cells, possess stem cell features in their self-renewal and differentiation capacity, and contribute to the formation of heterogeneous tumor cell populations.…”

Section: Introductionmentioning

confidence: 99%

“…CSCs, also called tumor-initiating cells or cancer stem-like cells, possess stem cell features in their self-renewal and differentiation capacity, and contribute to the formation of heterogeneous tumor cell populations. In HCC, several stem cell markers, including CD133, CD90, CD13, epithelial cell adhesion molecule (EpCAM), and CD24, have been reported to enrich side populations of CSCs [13][14][15]. We recently reported that the stem cell markers EpCAM and alpha-fetoprotein (AFP) can be used to classify HCC subtypes with distinct gene expression profiles and patient prognoses [11].…”

Section: Introductionmentioning

confidence: 99%

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Defeating EpCAM+ liver cancer stem cells by targeting chromatin remodeling enzyme CHD4 in human hepatocellular carcinoma

Nio

Yamashita

Okada

et al. 2015

Journal of Hepatology

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Background & Aims: Hepatocellular carcinoma is composed of a subset of cells with enhanced tumorigenicity and chemoresistance that are called cancer stem (or stem-like) cells. We explored the role of chromodomain-helicase-DNA-binding protein 4, which is encoded by the CHD4 gene and is known to epigenetically control gene regulation and DNA damage responses in EpCAM + liver cancer stem cells. Methods: Gene and protein expression profiles were determined by microarray and immunohistochemistry in 245 and 144 hepatocellular carcinoma patients, respectively. The relationship between gene/protein expression and prognosis was examined. The functional role of CHD4 was evaluated in primary hepatocellular carcinoma cells and in cell lines in vitro and in vivo. Results: CHD4 was abundantly expressed in EpCAM + hepatocellular carcinoma with expression of hepatic stem cell markers and poor prognosis in two independent cohorts. In cell lines, CHD4 knockdown increased chemosensitivity and CHD4 overexpression induced epirubicin chemoresistance. To inhibit the functions of CHD4 that are mediated through histone deacetylase and poly (ADP-ribose) polymerase, we evaluated the effect of the histone deacetylase inhibitor suberohydroxamic acid and the poly (ADP-ribose) polymerase inhibitor AG-014699. Treatment with either suberohydroxamic acid or AG-014699 reduced the number of EpCAM + liver cancer stem cells in vitro, and suberohydroxamic acid and AG-014699 in combination successfully inhibited tumor growth in a mouse xenograft model.Conclusions: CHD4 plays a pivotal role in chemoresistance and the maintenance of stemness in liver cancer stem cells and is therefore a good target for the eradication of hepatocellular carcinoma. Ó

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Defeating EpCAM+ liver cancer stem cells by targeting chromatin remodeling enzyme CHD4 in human hepatocellular carcinoma

Nio

Yamashita

Okada

et al. 2015

Journal of Hepatology

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“…Chronic inflammation, often associated with liver injury, leads to secretion of cytokines, chemokines, free radicals, and other DNA‐damaging molecules, thereby changing the hepatic microenvironment 78. Persistent inflammation during this long‐term process leads to an expansion of hepatic stem and progenitor cells that accumulate genetic and epigenetic alterations.…”

Section: Tgf‐β In An Invasive Cancer Stem Cell Modelmentioning

confidence: 99%

Transforming growth factor‐β in liver cancer stem cells and regeneration

Rao

Zaidi

Banerjee

et al. 2017

Hepatology Communications

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Cancer stem cells have established mechanisms that contribute to tumor heterogeneity as well as resistance to therapy. Over 40% of hepatocellular carcinomas (HCCs) are considered to be clonal and arise from a stem‐like/cancer stem cell. Moreover, HCC is the second leading cause of cancer death worldwide, and an improved understanding of cancer stem cells and targeting these in this cancer are urgently needed. Multiple studies have revealed etiological patterns and multiple genes/pathways signifying initiation and progression of HCC; however, unlike the transforming growth factor β (TGF‐β) pathway, loss of p53 and/or activation of β‐catenin do not spontaneously drive HCC in animal models. Despite many advances in cancer genetics that include identifying the dominant role of TGF‐β signaling in gastrointestinal cancers, we have not reached an integrated view of genetic mutations, copy number changes, driver pathways, and animal models that support effective targeted therapies for these common and lethal cancers. Moreover, pathways involved in stem cell transformation into gastrointestinal cancers remain largely undefined. Identifying the key mechanisms and developing models that reflect the human disease can lead to effective new treatment strategies. In this review, we dissect the evidence obtained from mouse and human liver regeneration, and mouse genetics, to provide insight into the role of TGF‐β in regulating the cancer stem cell niche. (Hepatology Communications 2017;1:477–493)

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“…Efforts have been made on classifying HCCs according to the status of gene mutations, chromosomal aberrations, gene/protein expression, and epigenetic modification in order to find hidden molecular features that can explain this heterogeneity [1,2]. The recent advances in molecular classification and the re-emergence of a cancer stem cell (CSC) hypothesis have highlighted the central role of stemness in HCC pathogenesis [3]. Moreover, sorafenib increased overall survival in a randomized controlled trial against placebo in advanced HCC, and tumor progression invariably occurred.…”

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confidence: 99%

“…In liver cell lineages, EpCAM is absent in mature hepatocytes but detectable in hepatic stem/progenitor cells and cholangiocytes [8]. Numerous studies have suggested the utility of EpCAM as a marker to identify liver cancer stem cells as well as normal hepatic progenitors [3]. In HCC, EpCAM-positivity correlates with a high frequency of vascular invasion, poor prognosis after surgical resection, and high infection rates with hepatitis B virus (HBV) [9].…”

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confidence: 99%