Dataset Information

Heterogeneity of The CD90+ Population in Different Stages of Hepatocarcinogenesis.

ABSTRACT: We have characterized herein the heterogeneity of the CD90+ population at each stage of hepatocarcinogenesis using a computer-assisted immunohistochemical staining evaluation method for quantitative analysis on tissue microarrays. We found that CD90 in Hepatocellular carcinoma (HCC) tissues, which has been shown to be a marker for cancer stem cells, is expressed on tumor cells, in the stroma or on endothelial cells. Sub-classification of the CD90+ population was based on morphology and co-expression with known markers including CD45 and CD31. Multiple linear regression suggested that the percentage of CD90+ cancer cells/hepatocyte (p<0.0001), level of overall CD90 expression (p<0.0014), and level of CD90 expression in tumor islands (p<0.0001) increased significantly in each stage of liver disease progression, while the level of stromal CD90 expression (p=0.1129) did not change significantly. Additionally, only the CD90+ cancer cells were positive for other cancer stem cell (CSC) markers including CD24, CD44 and CD133 whereas the other CD90+ cells were negative for these markers. CD90 expression in cirrhosis was observed in hepatocytes, the portal tract area and fibrous septa while CD90 expression in normal liver was limited only to the portal tract area. This study demonstrates the heterogeneity of the CD90+ population in HCC where a small population of the CD90+ cells that expressed other CSC markers are CSCs and are associated with advanced stages of hepatocarcinogenesis. This heterogeneity should be emphasized in further studies where other methods may not be able to discriminate these distinct types of CD90+ cells.

SUBMITTER: Thakolwiboon S

PROVIDER: S-EPMC4285360 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Heterogeneity of The CD90+ Population in Different Stages of Hepatocarcinogenesis.

Thakolwiboon Smathorn S Zhu Jianhui J Liang Qixing Q Welling Theodore H TH Zhang Min M Lubman David M DM

Journal of proteomics & bioinformatics 20140901 10

We have characterized herein the heterogeneity of the CD90+ population at each stage of hepatocarcinogenesis using a computer-assisted immunohistochemical staining evaluation method for quantitative analysis on tissue microarrays. We found that CD90 in Hepatocellular carcinoma (HCC) tissues, which has been shown to be a marker for cancer stem cells, is expressed on tumor cells, in the stroma or on endothelial cells. Sub-classification of the CD90+ population was based on mo ...[more]

PMID: 25580065

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Project description:TIGIT expression on natural killer (NK) cells is associated with dysfunction during chronic HIV infection, but the phenotype and biological functions of these cells in the context of acute HIV-1 infection remain poorly understood. Here, 19 acutely infected HIV-1 patients traced at first, third and twelfth month, and age-matched patients with chronic HIV-1 infection were enrolled to investigate the phenotype and functions of TIGIT expression on NK cells. We found that TIGIT-expressing NK cells did not increase in frequency in the first, third and twelfth month of infection until chronic HIV-1 infection lasted over 2 years. The number of TIGIT+NK cells in acute infection was positively associated with HIV-1 viral load (r = 0.53, P = 0.0009). CD96 was significantly upregulated on NK cells after acute infection for 1 month and in chronic infection over 2 years, while CD226 was downregulated in chronic infection over 2 years. Further, at different stages of infection, CD96-CD226+ cells diminished among total NK cells, TIGIT+NK and TIGIT-NK cells, while CD96+CD226- cells expanded. Reduced CD96-CD226+ cells and elevated CD96+CD226- cells among NK cells especially TIGIT-NK cells, had opposite associations with viral load in the first month of infection, as well as CD4 T-cell counts in including the twelfth month and more than 2 years of chronic infection. In both HIV-1-infected individuals and healthy donors, TIGIT was predominantly expressed in NKG2A-NKG2C+NK cells, with a significantly higher proportion than in NKG2A+NKG2C-NK cells. Moreover, the frequencies of TIGIT+NK cells were positively associated with the frequencies of NKG2A-NKG2C+NK cells in acute infection (r = 0.62, P < 0.0001), chronic infection (r = 0.37, P = 0.023) and healthy donors (r = 0.36, P = 0.020). Enhanced early activation and coexpression of CD38 and HLA-DR in TIGIT+NK cells were detected compared to TIGIT-NK cells, both of which were inversely associated with the decrease in CD4 T-cell counts in both acute and chronic HIV-1 infection. The ability of TIGIT+NK cells to produce TNF-α, IFN-γ and CD107a degranulation substance were consistently weaker than that of TIGIT-NK cells in both acute and chronic infection. Moreover, the functionalities of TIGIT+NK cells were lower than those of TIGIT-NK cells, except for TNF-α-CD107a+IFN-γ-NK cells. These findings highlight the phenotype and functional characteristics of TIGIT-expressing NK cells which have poor capabilities in inhibiting HIV-1 replication and maintaining CD4 T-cell counts.

Project description:BackgroundHepatocellular carcinoma (HCC) is a highly heterogeneous cancer with major challenges in both prevention and therapy. Metformin, adenosine monophosphate-activated protein kinase (AMPK) activator, has been suggested to reduce the incidence of HCC when used for patients with diabetes in preclinical and clinical studies. However, the possible effects of metformin and their mechanisms of action in non-diabetic HCC have not been adequately investigated.MethodsFah-/- mice were used to construct a liver-injury-induced non-diabetic HCC model for exploring hepatocarcinogenesis and therapeutic potential of metformin. Changes in relevant tumour and biochemical indicators were measured. Bulk and single-cell RNA-sequencing analyses were performed to validate the crucial role of proinflammatory/pro-tumour CD8+ T cells. In vitro and in vivo experiments were performed to confirm Cyp26a1-related antitumour mechanisms of metformin.ResultsRNA-sequencing analysis showed that chronic liver injury led to significant changes in AMPK-, glucose- and retinol metabolism-related pathways in Fah-/- mice. Metformin prevented the formation of non-diabetic HCC in Fah-/- mice with chronic liver injury. Cyp26a1 ddexpression in hepatocytes was significantly suppressed after metformin treatment. Moreover, downregulation of Cyp26a1 occurred in conjunction with increased levels of all-trans-retinoic acid (atRA), which is involved in the activation of metformin-suppressed hepatocarcinogenesis in Fah-/- mice. In contrast, both CD8+ T-cell infiltration and proinflammatory/pro-tumour cytokines in the liver were significantly upregulated in Fah-/- mice during chronic liver injury, which was notably reversed by either metformin or atRA treatment. Regarding mechanisms, metformin regulated the decrease in Cyp26a1 enzyme expression and increased atRA expression via the AMPK/STAT3/Gadd45β/JNK/c-Jun pathway.ConclusionsMetformin inhibits non-diabetic HCC by upregulating atRA levels and downregulating CD8+ T cells. This is the first reporting that the traditional drug metformin regulates the metabolite atRA via the Cyp26a1-involved pathway. The present study provides a potential application of metformin and atRA in non-diabetic HCC.

Dataset Information

Heterogeneity of The CD90+ Population in Different Stages of Hepatocarcinogenesis.

Publications

Heterogeneity of The CD90<sup>+</sup> Population in Different Stages of Hepatocarcinogenesis.

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