Hepatocellular Carcinomas Originate Predominantly from Hepatocytes and Benign Lesions from Hepatic Progenitor Cells

Tummala, Krishna Seshu; Brandt, Marta; Teijeiro, Ana; Graña, Osvaldo; Schwabe, Robert F.; Perna, Cristian; Djouder, Nabil

doi:10.1016/j.celrep.2017.03.059

Cited by 109 publications

(105 citation statements)

References 46 publications

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“…Some of the HPCs were positive for SQSTM1 aggregates although many did not show elevated SQSTM1( Supplementary Figure S1A-B ). The possibility that some of this SQSTM1 positive HPC may be derived from the autophagy-deficient hepatocytes cannot be excluded as such transdifferentiation had been reported previously 11, 14 .…”

Section: Resultsmentioning

confidence: 75%

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The HMGB1-RAGE axis modulates the growth of autophagy-deficient hepatic tumors

Khambu

Hong

Liu

et al. 2019

Preprint

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AbstractAutophagy is an intracellular lysosomal degradative pathway important for tumor surveillance. Autophagy deficiency can lead to tumorigenesis. Autophagy is also known to be important for the aggressive growth of tumors, yet the mechanism that sustains the growth of autophagy-deficient tumors is not known. We previously reported that progression of hepatic tumors developed in autophagy-deficient livers required high mobility group box 1 (HMGB1) that is released from autophagy-deficient hepatocytes. However, the mechanism by which HMGB1 promotes hepatic tumorigenesis is not understood. In this study we examined the pathological features of the hepatic tumors and the mechanism of HMGB1-mediated tumorigenesis using liver-specific autophagy-deficient (Atg7-/-) and Atg7-/-/Hmgb1-/- mice. We found that in Atg7-/- mice the tumors cells were still deficient in autophagy and could also release HMGB1. Histological analysis using cell-specific markers suggested that fibroblast and ductular cells were present only outside the tumor whereas macrophages were present both inside and outside the tumor. Genetic deletion of HMGB1 or one of its receptors, receptor for advanced glycated end product (Rage), retarded liver tumor development. In addition, we found that expression of RAGE was only on ductual cells and Kupffer’s cells but not on hepatoctyes, which suggested that HMGB1 might promote hepatic tumor growth through a paracrine mode that altered the tumor microenvironment. Furthermore, HMGB1 and RAGE enhanced the proliferation capability of the autophagy-deficient hepatocytes and tumors. Finally, RNAseq analysis of the tumors indicated that HMGB1 induced a much broad changes in tumors. In particular, genes related to mitochondrial structures or functions were enriched among those differentially expressed in tumors in the presence or absence of HMGB1, revealing a potential key role of mitochondria in sustaining the growth of autophagy-deficient liver tumors via HMGB1 stimulation.

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Section: Resultsmentioning

confidence: 75%

“…Hepatic progenitor cells(HPC), also known as oval cells or ductular cells, expand during chronic liver injury in patients and in rodents 11, 12 . The expansion of HPCs is significant in the autophagy-deficient livers 2 .…”

Section: Resultsmentioning

confidence: 99%

The HMGB1-RAGE axis modulates the growth of autophagy-deficient hepatic tumors

Khambu

Hong

Liu

et al. 2019

Preprint

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“…Here, tumors arose exclusively from hepatocytes. Using human data as well as mouse models of HCC, HPCs were shown to be activated and expanded by transformed hepatocytes through galectin-3, maintaining HPC stemness, and α-ketoglutarate, preserving an HPC undifferentiated state (54). In the human unconventional prefoldin RPB5 interactor (hURI)-tetOFF hep mouse model, both hepatocytes and HPCs contributed to tumor heterogeneity.…”

Section: Hepatocytes As the Cellular Origin Of Hccmentioning

confidence: 99%

Cellular Origin of Hepatocellular Carcinoma

Schneller

Angel

2019

Hepatocellular Carcinoma

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Molecular features of hepatocellular carcinoma affect patient prognosis and treatment efficiency. This chapter provides an overview of the relevant studies conducted to identify the cell of origin of hepatocellular carcinoma with a special focus on the controversy of hepatocytes versus hepatic progenitors as the main tumor-initiating cell. Furthermore, we introduce the concept of cancer stem cells (CSCs) and highlight recent publications covering this topic in relation to liver cancer. More precisely, we concentrate on the origin of CSCs, discuss accepted markers and the need to define a consistent combination of them that can be utilized to clearly define this heterogeneous cell type, summarize important signaling pathways that govern the stemness, and describe state-of-the-art assays to isolate and evaluate CSCs. We focus on their contributions to oncogenesis and tumor heterogeneity, as well as their feature to resist chemo-and radiotherapy. Finally, the potential of using CSC markers for diagnostic purposes and therapeutic approaches targeting these cells is addressed.

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“…We have demonstrated previously that mutations accumulate linearly with age in liver adult stem cells (ASCs) of healthy individuals, without controlling for lifestyle 24,25 . Stem cells are believed to be an important cell-of-origin for several cancer types, including liver cancer 18,26–28 , although liver cancer can also originate in differentiated cells 29–31 . Here, we studied the accumulation of mutations in ASCs from non-cancerous, cirrhotic livers of patients with a history of chronic alcohol use and compared these to the mutational patterns of healthy liver donors and to mutations that accumulated in the most recent common ancestor (MRCA) cell of an alcohol-related HCC.…”

Section: Introductionmentioning

confidence: 99%

Mutational impact of chronic alcohol use on stem cells in cirrhotic liver

Jager

Kuijk

Lieshout

et al. 2019

Preprint

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27Excessive alcohol consumption increases the risk of developing liver cancer, but the 28 mechanism through which alcohol drives carcinogenesis is as yet unknown. Here, we 29 determined the mutational consequences of chronic alcohol use on the genome of human liver 30 stem cells prior to cancer development. No change in base substitution rate or spectrum could 31 be detected. Analysis of the trunk mutations in an alcohol-related liver tumor by multi-site 32 whole-genome sequencing confirms the absence of specific alcohol-induced mutational 33 signatures driving the development of liver cancer. However, we did identify an enrichment of 34 nonsynonymous base substitutions in cancer genes in stem cells of the cirrhotic livers, such as 35 recurrent nonsense mutations in PTPRK that disturb Epidermal Growth Factor (EGF)-36 signaling. Our results thus suggest that chronic alcohol use does not contribute to 37 carcinogenesis through altered mutagenicity, but instead induces microenvironment changes 38 which provide a 'fertile ground' for selection of cells with oncogenic mutations. 39 40 45hypotheses. The first hypothesis suggests that alcohol consumption may contribute to the 46 development of cancer through an increased mutation accumulation in the genome 4 . 47Consistently, the first metabolite of ethanol, acetaldehyde, is highly carcinogenic 5-7 and can 48 also contribute to the formation of mutagenic reactive oxygen species (ROS) [8][9][10][11] . Analysis of a 49 large number of tumor exomes and genomes showed that alcohol intake is associated with an 50 increased mutation load and different mutational characteristics [12][13][14][15] . The second hypothesis 51 2 suggests that an alcohol-induced change of microenvironment is an essential driver for 52 tumorigenesis by providing a fertile ground for cells with oncogenic mutations [16][17][18] . Indeed, 53 development of HCC is preceded by chronic inflammation and cirrhosis in about 80% of 54 patients and this cell-extrinsic damage appears a prerequisite for the formation of the majority 55 of liver cancers 18-20 . Additionally, Hepatitis C Virus (HCV)-induced cirrhotic livers show an 56 increase in the number and size of clonal patches with mutations in genes that are frequently 57 mutated in HCC 21 . Alcohol use itself has been associated with an increased number of cancer-58 stem-cell-like epithelial cell adhesion molecule (EpCAM)-positive cells in the cirrhotic liver 22 , 59 which may be driven by epithelial to mesenchymal transition through activation of the Wnt 60 pathway 23 , confirming that cellular composition changes can be induced by alcohol use. Yet, 61it is still uncertain whether an altered cellular environment is sufficient to drive the 62 development of cancer, or whether an increase in the mutation load is also required. The here 63 mentioned hypotheses are thus not mutually exclusive. 64 We have demonstrated previously that mutations accumulate linearly with age in liver 65 adult stem cells (ASCs) of healthy individuals, without controlling for...

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Hepatocellular Carcinomas Originate Predominantly from Hepatocytes and Benign Lesions from Hepatic Progenitor Cells

Cited by 109 publications

References 46 publications

The HMGB1-RAGE axis modulates the growth of autophagy-deficient hepatic tumors

The HMGB1-RAGE axis modulates the growth of autophagy-deficient hepatic tumors

Cellular Origin of Hepatocellular Carcinoma

Mutational impact of chronic alcohol use on stem cells in cirrhotic liver

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