Combined hepatocellular cholangiocarcinoma originating from hepatic progenitor cells: immunohistochemical and double‐fluorescence immunostaining evidence

Zhang, F; Xp, Chen; Zhang, W; Hh, Dong; Xiang, Shuai; Wg, Zhang; Bx, Zhang

doi:10.1111/j.1365-2559.2007.02929.x

Cited by 152 publications

(115 citation statements)

References 40 publications

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“…28,29 The results obtained here may also be implicated in the histogenesis of combined hepatocellular cholangiocarcinoma; that is, the component of cholangiocarcinoma originates from the transdifferention of the HCC component, forming a combined hepatocellular cholangiocarcinoma that exhibits focal or diffuse immunohistochemical expression of CK19. 30,31 The expression of EGFR has been observed in 40 to 70% of conventional HCC in previous studies. [32][33][34][35] A recent study showed that the expression of EGF was upregulated in advanced HCC compared with that of control liver tissue and early HCC.…”

Section: Discussionmentioning

confidence: 99%

Epidermal growth factor induces cytokeratin 19 expression accompanied by increased growth abilities in human hepatocellular carcinoma

Yoneda

Sato

Kitao

et al. 2011

Laboratory Investigation

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Cytokeratin (CK) 19-positive hepatocellular carcinoma (HCC) has been reported to have a poor prognosis. The mechanism of the development of CK19-positive HCC remains to be studied. To clarify this, in vitro experiments were performed using human HCC cell lines HepG2), and the phenotypic changes after stimulation with several growth factors were examined using quantitative reverse transcriptase PCR, western blotting, and immunofluorescence staining. In vivo experiments using human HCC specimens obtained from a total of 78 patients and clinicopathological analysis were also performed. Among the growth factors tested, epidermal growth factor (EGF) had prominent effects on inducing CK19 expression in PLC-5 and HepG2, which was accompanied by the reduced expression of a-fetoprotein in PLC-5. The induction of CK19 expression after EGF stimulation was accompanied by the phosphorylation of c-Jun-N-terminal kinase (JNK)/stress-activated protein kinase, which was blocked by the addition of JNK inhibitors. EGF also increased proliferative abilities and invasive properties of the HCC cell lines. In vivo, 9 (12%) of 78 HCC cases showed positive immunohistochemical staining of CK19. The extent of positive immunhistochemical signals of EGF, EGF receptor (EGFR), and JNK expression was significantly intense in CK-19-positive HCC than those of CK19-negative HCC. Clinicopathological analysis showed that CK19-positive HCC had a high incidence of portal vein invasion, extrahepatic metastasis and an early relapse, which was associated with the worsened 2-year disease free survival. These results indicate that the activation of the EGF-EGFR signaling pathway is associated with the development of CK19-positive HCC, and the EGF-induced increase in growth abilities of HCC may account for the poor prognosis of the patients.

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Section: Discussionmentioning

confidence: 99%

Epidermal growth factor induces cytokeratin 19 expression accompanied by increased growth abilities in human hepatocellular carcinoma

Yoneda

Sato

Kitao

et al. 2011

Laboratory Investigation

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“…However, the requirement of a transitional differentiation process from the hepatocyte to the cholangiocyte lineage makes it less likely that viral hepatitis-associated ICC arises from the proliferating hepatocytes. More likely is that viral hepatitisassociated HCC and ICC are derived from the same cells of origin that have the potential to develop into both the hepatocyte and cholangiocyte lineages, and have long been exposed to the milieu related to genome injury and consequently, tumour transformation (Alison, 2006;Libbrecht, 2006;Nomoto et al, 2006;Roskams, 2006;Zhang et al, 2008). Indeed, it is now generally believed that cancer can originate from stem cells or progenitor cells rather than from differentiated cells as these are the only cells that persist in the tissue for a sufficient length of time to acquire the requisite number of genetic changes for neoplastic transformation (Alison and Lovell, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it has been suggested that CHCs may arise from hepatic progenitor cells that retain their potential to differentiate into the hepatocytic and biliary lineages (Libbrecht, 2006;Zhang et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Viral hepatitis-associated intrahepatic cholangiocarcinoma shares common disease processes with hepatocellular carcinoma

et al. 2009

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Bile duct cells and hepatocytes differentiate from the same hepatic progenitor cells. To investigate the possible association of viral hepatitis B and C with intrahepatic cholangiocarcinoma (ICC), we conducted a retrospective case -control study using univariate and multivariate logistic analyses to identify risk factors for ICC. Besides hepatic lithiasis (25.6%; Po0.001), seropositivity for hepatitis B surface antigen (37.5% of all ICC patients; odds ratio (OR) ¼ 4.985, Po0.001) and seropositivity for hepatitis C antibodies (13.1%; OR ¼ 2.709; P ¼ 0.021) are the primary independent risk factors for ICC. Cirrhosis exerted synergic effects on the development of ICC. We compared the age distributions of viral-hepatitis associated ICC to that of viral hepatitis-associated hepatocellular carcinoma (HCC). The mean age of ICC patients with viral hepatitis B (56.4 ± 11.1 years) were 9 years younger than that of ICC patients with viral hepatitis C (65.6 ± 9.17 years), similar to that observed in HCC. The incidence ratio of HCC : ICC : CHC (combined hepatocellular cholangiocarcinoma) in our population was 233 : 17 : 1 consistent with the theoretic ratio of hepatocyte number to cholangiocyte number in the liver. Our findings indicated that both viral hepatitis-associated ICC and HCC shared common disease process for carcinogenesis and, possibly, both arose from the hepatic progenitor cells.

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“…In fact, gene expression profiling indicates that cholangiocarcinoma is of hepatic progenitor cell origin because of the expression of specific stem cell markers [15,16]. In addition, a recent study revealed that a specific population of hepatocytes may function as stem cells in the liver [17], indicating that even matured hepatocytes can become cholangiocarcinoma stem cells.…”

Section: Cholangiocarcinoma Stem Cell Hierarchymentioning

confidence: 99%

“…CD117 is used to identify hematopoietic progenitor cells. Although the significance of c-kit expression in hepatic progenitor cells is controversial, combined hepatocellular cholangiocarcinoma (i.e., a more primitive cellular form than typical hepatocellular carcinoma or cholangiocarcinoma) demonstrated high CD117 expression [16].…”

Section: Other Potential Markersmentioning

confidence: 99%

Recent advances in cancer stem cell research for cholangiocarcinoma

Kokuryo

Yokoyama

Nagino

2012

J Hepato Biliary Pancreat

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Cancer stem cells have been identified as cells with the capacity to self‐renew and differentiate into multiple lineages of human malignancies. Cholangiocarcinoma is one of the most difficult intra‐abdominal malignancies that can be treated using a surgical approach. Chemotherapy in addition to surgery is necessary to improve patient survival. However, its clinical benefit is limited, and, to date, no other effective anticancer drug is available for this disease. Several reports have shown the existence of cholangiocarcinoma stem cells. Cell surface antigens such as CD133, CD24, EpCAM, CD44, and others have been used to isolate cholangiocarcinoma stem cells. In general, enhanced expression of these markers in resected specimens of cholangiocarcinoma was associated with malignant potential. Distinct and specific pathways are expected to be present in cancer stem cells compared to other cancer cells that have no stem cell properties. To date, reports showing possible signaling pathways in cholangiocarcinoma stem cells are limited. More research is anticipated. Targeting therapies for surface molecular markers or specific signaling pathways of cholangiocarcinoma stem cells may be important in order to change the clinical outcome of patients with this disease. However, no clinical trial has been performed so far. This review will focus on the markers and signaling pathways used to define cholangiocarcinoma stem cells. A novel therapeutic approach of targeting cholangiocarcinoma stem cells will also be discussed.

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Combined hepatocellular cholangiocarcinoma originating from hepatic progenitor cells: immunohistochemical and double‐fluorescence immunostaining evidence

Cited by 152 publications

References 40 publications

Epidermal growth factor induces cytokeratin 19 expression accompanied by increased growth abilities in human hepatocellular carcinoma

Epidermal growth factor induces cytokeratin 19 expression accompanied by increased growth abilities in human hepatocellular carcinoma

Viral hepatitis-associated intrahepatic cholangiocarcinoma shares common disease processes with hepatocellular carcinoma

Recent advances in cancer stem cell research for cholangiocarcinoma

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