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Progressive Enrichment of Stemness Features and Tumor Stromal Alterations in Multistep Hepatocarcinogenesis.

ABSTRACT: Cancer stem cells (CSCs), a subset of tumor cells, contribute to an aggressive biological behavior, which is also affected by the tumor stroma. Despite the role of CSCs and the tumor stroma in hepatocellular carcinoma (HCC), features of stemness have not yet been studied in relation to tumor stromal alterations in multistep hepatocarcinogenesis. We investigated the expression status of stemness markers and tumor stromal changes in B viral carcinogenesis, which is the main etiology of HCC in Asia. Stemness features of tumoral hepatocytes (EpCAM, K19, Oct3/4, c-KIT, c-MET, and CD133), and tumor stromal cells expressing ?-smooth muscle actin (?-SMA), CD68, CD163, and IL-6 were analyzed in 36 low grade dysplastic nodules (DNs), 48 high grade DNs, 30 early HCCs (eHCCs), and 51 progressed HCCs (pHCCs) by immunohistochemistry or real-time PCR. Stemness features (EpCAM and K19 in particular) were progressively acquired during hepatocarcinogenesis in combination with enrichment of stromal cells (CAFs, TAMs, IL-6+ cells). Stemness features were seen sporadically in DNs, more consistent in eHCCs, and peaked in pHCCs. Likewise, stromal cells were discernable in DNs, showed up as consistent cell densities in eHCCs and peaked in pHCCs. The stemness features and tumor stromal alterations also peaked in less differentiated or larger HCCs. In conclusion, progression of B viral multistep hepatocarcinogenesis is characterized by an enrichment of stemness features of neoplastic hepatocytes and a parallel alteration of the tumor stroma. The modulation of neoplastic hepatocytes and stromal cells was at low levels in precancerous lesions (DNs), consistently increased in incipient cancer (eHCCs) and peaked in pHCCs. Thus, in B viral hepatocarcinogenesis, interactions between CSCs and the tumor stroma, although starting early, seem to play a major role in tumor progression.

SUBMITTER: Yoo JE

PROVIDER: S-EPMC5256873 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Progressive Enrichment of Stemness Features and Tumor Stromal Alterations in Multistep Hepatocarcinogenesis.

Yoo Jeong Eun JE Kim Young-Joo YJ Rhee Hyungjin H Kim Haeryoung H Ahn Ei Yong EY Choi Jin Sub JS Roncalli Massimo M Park Young Nyun YN

PloS one 20170123 1

Cancer stem cells (CSCs), a subset of tumor cells, contribute to an aggressive biological behavior, which is also affected by the tumor stroma. Despite the role of CSCs and the tumor stroma in hepatocellular carcinoma (HCC), features of stemness have not yet been studied in relation to tumor stromal alterations in multistep hepatocarcinogenesis. We investigated the expression status of stemness markers and tumor stromal changes in B viral carcinogenesis, which is the main etiology of HCC in Asia ...[more]

PMID: 28114366

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Project description:Hepatocellular carcinoma (HCC) is a complex disease with a multi-step carcinogenic process from preneoplastic lesions, including cirrhosis, low-grade dysplastic nodules (LGDNs), and high-grade dysplastic nodules (HGDNs) to HCC. There is only an elemental understanding of its molecular pathogenesis, for which a key problem is to identify when and how the critical transition happens during the HCC initiation period at a molecular level. In this work, for the first time, we revealed that LGDNs is the tipping point (i.e., pre-HCC state rather than HCC state) of hepatocarcinogenesis based on a series of gene expression profiles by a new mathematical model termed dynamic network biomarkers (DNB)-a group of dominant genes or molecules for the transition. Different from the conventional biomarkers based on the differential expressions of the observed genes (or molecules) for diagnosing a disease state, the DNB model exploits collective fluctuations and correlations of the observed genes, thereby predicting the imminent disease state or diagnosing the critical state. Our results show that DNB composed of 59 genes signals the tipping point of HCC (i.e., LGDNs). On the other hand, there are a large number of differentially expressed genes between cirrhosis and HGDNs, which highlighted the stark differences or drastic changes before and after the tipping point or LGDNs, implying the 59 DNB members serving as the early-warning signals of the upcoming drastic deterioration for HCC. We further identified the biological pathways responsible for this transition, such as the type I interferon signaling pathway, Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway, transforming growth factor (TGF)-β signaling pathway, retinoic acid-inducible gene I (RIG-I)-like receptor signaling pathway, cell adhesion molecules, and cell cycle. In particular, pathways related to immune system reactions and cell adhesion were downregulated, and pathways related to cell growth and death were upregulated. Furthermore, DNB was validated as an effective predictor of prognosis for HCV-induced HCC patients by survival analysis on independent data, suggesting a potential clinical application of DNB. This work provides biological insights into the dynamic regulations of the critical transitions during multistep hepatocarcinogenesis.

Dataset Information

Progressive Enrichment of Stemness Features and Tumor Stromal Alterations in Multistep Hepatocarcinogenesis.

Publications

Progressive Enrichment of Stemness Features and Tumor Stromal Alterations in Multistep Hepatocarcinogenesis.

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