Forfeited hepatogenesis program and increased embryonic stem cell traits in young hepatocellular carcinoma (HCC) comparing to elderly HCC (original) (raw)
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Cancers, 2012
Hepatocellular carcinoma (HCC) remains a difficult disease to study even after a decade of genomic analysis. Patient and disease heterogeneity, differences in statistical methods and multiple testing issues have resulted in a fragmented understanding of the molecular basis of tumor biology. Some researchers have suggested that HCC appears to share pathways with embryonic development. Therefore we generated targeted hypotheses regarding changes in developmental genes specific to the liver in HCV-cirrhosis and HCV-HCC. We obtained microarray studies from 30 patients with HCV-cirrhosis and 49 patients with HCV-HCC and compared to 12 normal livers. Genes specific to non-liver development have known associations with other cancer types but none were expressed in either adult liver or tumor tissue, while 98 of 179 (55%) genes specific to liver development had differential expression between normal and cirrhotic or HCC samples. We found genes from each developmental stage dysregulated in t...
A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells
Nature Medicine, 2006
The variability in the prognosis of individuals with hepatocellular carcinoma (HCC) suggests that HCC may comprise several distinct biological phenotypes. These phenotypes may result from activation of different oncogenic pathways during tumorigenesis and/or from a different cell of origin. Here we address whether the transcriptional characteristics of HCC can provide insight into the cellular origin of the tumor. We integrated gene expression data from rat fetal hepatoblasts and adult hepatocytes with HCC from human and mouse models. Individuals with HCC who shared a gene expression pattern with fetal hepatoblasts had a poor prognosis. The gene expression program that distinguished this subtype from other types of HCC included markers of hepatic oval cells, suggesting that HCC of this subtype may arise from hepatic progenitor cells. Analyses of gene networks showed that activation of AP-1 transcription factors in this newly identified HCC subtype might have key roles in tumor development.
Stem cell expression profile in hepatocellular carcinoma, small cell dysplasia, and cirrhosis
Stem Cell and Translational Investigation, 2015
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with various etiologies and its incidence still continues to increase. Tumors with progenitor/stem cell (P/SC) immunophenotype are currently the main focus of interest. Human hepatic P/SCs are located in ductal plates in fetal and neonatal livers and they remain relatively constant throughout life. Enhanced self-renewal level of normal hepatic P/SCs serves as an early event in hepatocarcinogenesis. Approximately 40% of HCCs arise from P/SCs and these cells have a critical role in development and progression of HCC. Thus, CD133 expression was found to be upregulated during early liver restoration. In spite of the increasing evidence of the impact of cancer stem cells (CSCs) in hepatocarcinogenesis, the role of CSCs in the sequence of cirrhosis (Crh)-dysplastic nodules (DN)-HCC is still not clear. In our recent research, we investigated the expression rate and staining patterns of CD133 and CD90 in Crh, small cell dysplasia, and HCC. We also evaluated the relationship between the expression rates of CSC markers and the etiology of liver diseases. Among the P/SC markers, we like to attract more attention to CD133 and CD90. Both CD133 and CD90 expressions were higher in poorly differentiated HCC cases than well differentiated ones. According to the etiology, we found that the highest staining rate for CD133 in HCC cases developed in a cirrhotic background with chronic hepatitis B and D co-infection. The highest rate for CD90 was determined in HCC cases with chronic hepatitis C. Since Crh is the end-stage of chronic injury with continuing regeneration, detection of accompanying P/SC activation by CSC markers in suspicious nodules may suggest the initiation of early phases of hepatocarcinogenesis. Some other immunophenotypical features such as Glypican 3, heat shock protein-70, and glutamine synthetase stainings are also being used to diagnose precursor lesions. Facing the emerging concept of personalized treatment strategy, it is obvious that the studies in hepatocarcinogenesis related to the theory of CSCs will provide new ideas on genesis, development, and metastasis of HCC and will bring new insights for the diagnosis and treatment of these tumors.
Molecular characteristics of hepatocellular carcinomas from different age groups
Oncotarget, 2017
While most patients in Western countries who are diagnosed with HCC are in their 50s and 60s, HCCs diagnosed at extremes of the age spectrum (i.e., < 40 years and ≥ 75 years) are less common and have been linked with distinct geographic locations and etiologies. Using multiplatform profiling, we identified differences in genetic alterations and protein expression in different age groups within a large cohort of HCC patients (N = 421). Young adult HCC patients (18-39 years' old) were more likely to be female, living in the West and Midwestern United States, and showed decreased androgen receptor, drug resistance and pro-angiogenic protein expression compared to older patients. TP53 mutations were the most frequent alteration in young adults (19%), whereas CTNNB1 mutations occurred in 30-33% of patients ≥ 40 years' old. The overall frequency of pathogenic and presumed pathogenic mutations was observed to increase significantly with advancing age. To our knowledge, these dat...
Annals of hepatology
BACKGROUND. The liver possesses two distinct mechanisms for healing. Wound healing via hepatic stem cells recapitulates early development (hepatoblast proliferation), while liver regeneration resembles late embryonic growth (hepatocyte proliferation). Loss of control over both of these processes have been proposed as mechanisms that may contribute to poor outcomes in HCC. MATERIAL AND METHODS. We used microarray gene expression profiles to examine the involvement of hepatic stem cell and hepatocyte proliferation markers and regulators in HCV-induced cirrhosis and HCC. We compared 30 cirrhosis and 49 HCC samples to 12 disease-free control livers. RESULTS. Cirrhosis and HCC expressed markers of stem cell. Inhibitors of hepatocyte proliferation (HP) were highly expressed in cirrhosis. Loss of these HP inhibitors in HCC patients was associated poor prognosis (94 vs. 38% 2-year recurrence- free survival, p = 0.0003). Principal Components Analysis discriminated cirrhotic and HCC tissues, ...
Molecular medicine (Cambridge, Mass.)
The role of chronic hepatitis C virus (HCV) in the pathogenesis of HCV-associated hepatocellular carcinoma (HCC) remains controversial. To understand the transition from benign to malignant, we studied the gene expression patterns in liver tissues at different stages, including normal, cirrhosis, and different HCC stages. We studied 108 liver tissue samples obtained from 88 distinct patients (41 HCV-cirrhotic tissues, 17 HCV-cirrhotic tissues from patients with HCC, and 47 HCV-HCC tissues). Differentially expressed genes (DEG) were studied by use of high-density oligonucleotide arrays. Among probe sets identified as differentially expressed via the F test, all pairwise comparisons were performed. Cirrhotic tissues with and without concomitant HCC were further evaluated, and a classifier was used to predict whether the tissue type was associated with HCC. Differential expression profiles were analyzed using Interaction Networks and Functional Analysis. Characteristic gene signatures ...
World journal of gastroenterology : WJG, 2007
To evaluate the predictive value of hepatocyte proliferation and hepatic angiogenesis for the occurrence of Hepatocellular carcinoma (HCC) in hepatitis C virus (HCV) cirrhotic patients. One hundred-five patients (69 males, 36 females; age range, 51-90 year; median 66 year) with biopsy proven HCV cirrhosis were prospectively monitored for HCC occurrence for a median time of 64 mo. Angiogenesis was assessed by using microvessel density (MVD), hepatocyte turnover by MIB1 and PCNA indexes at inclusion in liver biopsies. Forty six patients (43.8%) developed HCC after a median time of 55 (6-120) mo while 59 (56.2%) did not. Patients were divided into two groups according to the median value of each index. The difference between patients with low (median MVD = 3; range 0-20) and high (median MVD = 7; range 1-24) MVD was statistically significant (chi(2) = 22.06; P < 0.0001) which was not the case for MIB1 or PCNA (MIB-1: chi(2) = 1.41; P = 0.2351; PCNA: chi(2) = 1.27; P = 0.2589). The m...
Hepatitis C virus-induced hepatocellular carcinoma
Clinical and Molecular Hepatology, 2015
Hepatitis C virus (HCV) is a leading etiology of hepatocellular carcinoma (HCC). The interaction of HCV with its human host is complex and multilayered; stemming in part from the fact that HCV is a RNA virus with no ability to integrate in the host's genome. Direct and indirect mechanisms of HCV-induced HCC include activation of multiple host pathways such as liver fibrogenic pathways, cellular and survival pathways, interaction with the immune and metabolic systems. Host factors also play a major role in HCV-induced HCC as evidenced by genomic studies identifying polymorphisms in immune, metabolic, and growth signaling systems associated with increased risk of HCC. Despite highly effective direct-acting antiviral agents, the morbidity and incidence of liver-related complications of HCV, including HCC, is likely to persist in the near future. Clinical markers to selectively identify HCV subjects at higher risk of developing HCC have been reported however they require further validation, especially in subjects who have experienced sustained virological response. Molecular biomarkers allowing further refinement of HCC risk are starting to be implemented in clinical platforms, allowing objective stratification of risk and leading to individualized therapy and surveillance for HCV individuals. Another role for molecular biomarker-based stratification could be enrichment of HCC chemoprevention clinical trials leading to smaller sample size, shorter trial duration, and reduced costs. (Clin Mol Hepatol 2015;21:105-114)
Progenitor-derived hepatocellular carcinoma model in the rat
Hepatology, 2010
Human hepatocellular carcinoma (HCC) is a heterogeneous disease of distinct clinical subgroups. A principal source of tumor heterogeneity may be cell type of origin which in liver includes hepatocyte and/or adult stem/progenitor cells. To address this issue, we investigated the molecular mechanisms underlying the fate of the enzyme-altered preneoplastic lesions in the resistant hepatocyte (RH) model. Sixty samples classified as focal lesions, adenoma, early and advanced HCCs were micro-dissected after morphological and immunohistochemical evaluation and subjected to global gene expression profiling. The analysis of progression of the persistent GSTP + focal lesions to fully developed HCC showed that about 50% of persistent nodules and all HCCs expressed CK19 whereas 14% of remodeling nodules were CK19 + . Unsupervised hierarchical clustering of the expression profiles also grouped the samples according to CK19 expression. Further, supervised analysis using the differentially expressed genes in each cluster combined with the gene connectivity tools identified 1308 unique genes and a predominance of the AP-1/JUN network in the CK19 + lesions. In contrast, the CK19-negative cluster exhibited only limited molecular changes (156 differentially expressed genes vs. normal liver) consistent with remodeling towards differentiated phenotype. Finally, comparative functional genomics revealed a stringent clustering of CK19 + early lesions and advanced HCCs with human HCCs characterized by poor prognosis. Furthermore, the CK19 associated gene expression signature accurately predicted the patient survival (P<0.009) and tumor recurrence (P<0.006).