Keratin 19 Epithelial Patterns in Cirrhotic Stroma Parallel Hepatocarcinogenesis

Lennerz, Jochen K.; Chapman, William C.; Brunt, Elizabeth M.

doi:10.1016/j.ajpath.2011.04.040

Cited by 16 publications

(6 citation statements)

References 98 publications

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“…Consistent with our findings, Cai et al [ 21 ] have found that proliferative ductular reaction is related to HPC activation in patients with combined hepatocellular-cholangiocarcinoma. Lennerz and colleagues [ 22 ] suggested marked alterations in cellular identity as an underlying mechanism for the reproducible perinodular DR that parallels progressive stages of intranodular hepatocarcinogenesis. Several studies have also shown that high levels of proliferation rate within DRs has been demonstrated in both oval cell-mediated liver regeneration in an animal model and human liver disease [ 23 , 24 ].…”

Section: Discussionmentioning

confidence: 99%

Proliferative ductular reactions correlate with hepatic progenitor cell and predict recurrence in HCC patients after curative resection

Jing

Guo

et al. 2014

Cell Biosci

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BackgroundDuctular reactions (DRs) are well documented in many acute and chronic liver disease.The DRs are thought to be the transit amplifying cells deriving from activation of the stem/progenitor cell compartments of the liver. The aim of this study was to examine the presence of proliferative index of DR (PI-DR) and HPC markers’ expression in HCCs after curative hepatectomy, as well as their relationship with clinicopathological features and prognosis.ResultsTissue microarray with peritumoral and intratumoral tissue samples of 120 HCCs after hepatectomy was analysed for peritumoral expression of proliferating cell nuclear antigen for PI-DR. Peritumoral and intratumoral expression status of HPC markers including EpCAM, OV6, CD133 and c-kit were also examined by immunohistochemistry. TMA analysis of HCCs revealed that peritumoral PI-DR strongly correlated with the degree of inflammation and fibrosis. The peritumoral PI-DR positively correlated with peritumoral HPC markers EpCAM, OV6, CD133 and c-kit expression. Moreover, there were highly significant correlations between peritumoral PI-DR and intratumoral HPC markers EpCAM, OV6, CD133 and c-kit expression. Further, multivariate analysis showed that peritumoral PI-DR was the independent prognostic factor for overall survival (HR; 3.316, P < 0.001), and peritumoral PI-DR had a better power to predict disease-free survival (HR; 2.618, P < 0.001).ConclusionsPeritumoral PI-DR, as a valid surrogate for peritumoral and intratumoral expression of HPC markers, could be served as a potential prognostic marker for recurrence and survival in HCC after hepatectomy.

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Section: Discussionmentioning

confidence: 99%

Proliferative ductular reactions correlate with hepatic progenitor cell and predict recurrence in HCC patients after curative resection

Jing

Guo

et al. 2014

Cell Biosci

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“…Recently, an increased risk of hepatocarcinogenesis in HCV-infected patients whose biopsies showed foci of IHBCs may have common mechanisms with our proposed progenitor dominant regeneration with highest recurrence risk. 36 Alternatively, Lennerz et al 41 found a vanishing of DR with stepwise hepatocarcinogenesis in cirrhotic liver that may suggest the involvement of DR in HCC development, a novel hypothetical mechanism that DR may contribute to the generation of cancer-associated fibroblasts cross-talking with the microenvironment. These studies and our findings cumulatively suggest HPC activation may contribute to liver cancer recurrence by driving ''field cancerization.''…”

Section: Discussionmentioning

confidence: 99%

Background progenitor activation is associated with recurrence after hepatectomy of combined hepatocellular-cholangiocarcinoma

et al. 2012

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Hepatic progenitor cells (HPC) play important roles in both liver regeneration and carcinogenesis. Combined hepatocellular‐cholangiocarcinoma (CHC), a malignant primary liver tumor with poor prognosis, is thought to be of HPC origin. However, the prognostic significance of this etiology is not well defined. Therefore, we retrospectively investigated the relationship of HPC‐related pathological features and long‐term outcome in patients with CHC in our department. In a cohort of 80 patients identified between 1997 and 2003, including 70 patients who underwent resection with curative intent, overall survival (OS) and disease‐free survival (DFS) were correlated with the proliferative activity of nontumor ductular reaction (DR) and the expression levels of HPC and biliary markers including α‐fetoprotein (AFP), keratin 7 (K7), keratin 19 (K19), oval cell (OV)‐6, epithelial cell adhesion molecule (EpCAM), and c‐Kit in both tumor and nontumor liver. We found that nontumor ductular reactions (DRs), specifically the proliferating cell nuclear antigen (PCNA) labeling index of the ductular reaction (PI‐DR), a surrogate for transit‐amplifying compartments, was an independent prognostic factor for both OS and DFS. By contrast, intratumoral expression of only one marker, absence of AFP, was associated with OS. PI‐DR was also independently associated with synchronous “multicentric occurrence” in hepatocellular carcinoma components, a feature of CHC that may predispose to metachronous multifocal tumorigenesis. Conclusion: Proliferative ductular reaction related to HPC activation is associated with recurrence of CHC. Background HPC activation is strongly associated with multifocal occurrence and related tumor recurrence, highlighting the critical role of background liver disease, a “field effect,” in the recurrence of CHC. (Hepatology 2012;56:1804–1816)

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“…Markers of stemness have been associated with increased telomere length and chromosomal instability [11], microvascular invasion [12], high metastatic potential [13] and poor survival [14][15][16]. There is also increasing evidence suggesting that K19 immunohistochemical expression may be used as a prognostic marker in human HCC [10,14,[17][18][19][20][21][22]. However, the majority of these studies are based on HCC of Asian origin.…”

Section: Introductionmentioning

confidence: 99%

Keratin 19 protein expression is an independent predictor of survival in human hepatocellular carcinoma

Fatourou

Koskinas²,

Karandrea

et al. 2015

European Journal of Gastroenterology & Hepatology

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Keratin 19 Epithelial Patterns in Cirrhotic Stroma Parallel Hepatocarcinogenesis

Abstract: Cirrhotic septa harbor vessels and inflammatory, fibrogenic, and ductular epithelial cells, collectively referred to as the ductular reaction (DR).

Cited by 16 publications

References 98 publications

Proliferative ductular reactions correlate with hepatic progenitor cell and predict recurrence in HCC patients after curative resection

Proliferative ductular reactions correlate with hepatic progenitor cell and predict recurrence in HCC patients after curative resection

Background progenitor activation is associated with recurrence after hepatectomy of combined hepatocellular-cholangiocarcinoma

Keratin 19 protein expression is an independent predictor of survival in human hepatocellular carcinoma

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