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Stimulation of hepatocarcinogenesis by neutrophils upon induction of oncogenic kras expression in transgenic zebrafish.

Yan C, Huo X, Wang S, Feng Y, Gong Z - J. Hepatol. (2015)

Bottom Line: Both oncogenic hepatocytes and tumor-associated neutrophils (TANs) were isolated via fluorescence-activated cell sorting.Molecular analyses indicated a pro-inflammatory microenvironment, as marked by increased tgfβ1a expression in kras(V12)-expressing hepatocytes and a loss of anti-tumor activities in TANs.Depletion of Tgf-β significantly reduced the number of TANs and the size of oncogenic liver.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, National University of Singapore, Singapore; National University of Singapore Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.

No MeSH data available.


Related in: MedlinePlus

Histological analyses of effects of neutrophils on hepatocarcinogenesis. (A) H&E staining of liver sections. 8 dpf kras−/lyz+ and kras+/lyz+ larvae after exposure to FPR A14 or PR-39 with or without doxycycline, as indicated in the pictures, and were subject to H&E staining. Abbreviations: eHCC, early HCC; N, normal liver region. Dashed arrow: pseudo glandular pattern; white arrows: enlarged nuclei. (B) Quantification of phenotype observed in liver histology sections (n = 10, *p <0.05).
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f0030: Histological analyses of effects of neutrophils on hepatocarcinogenesis. (A) H&E staining of liver sections. 8 dpf kras−/lyz+ and kras+/lyz+ larvae after exposure to FPR A14 or PR-39 with or without doxycycline, as indicated in the pictures, and were subject to H&E staining. Abbreviations: eHCC, early HCC; N, normal liver region. Dashed arrow: pseudo glandular pattern; white arrows: enlarged nuclei. (B) Quantification of phenotype observed in liver histology sections (n = 10, *p <0.05).

Mentions: Histologically, as shown in Fig. 6A, all H&E staining of 8 dpf kras+ larvae exposed to doxycycline showed histological features of early carcinoma, e.g. disorganized cell plate, large nucleus-to-cytoplasm ratio and pseudo glandular patterns. All kras+ larvae exposed to FPR-A14 and doxycycline showed similar early carcinoma histology, but with significantly less proportion of normal tissue, suggesting that the additional exposure to FPR-A14 had further stimulated HCC progression. In contrast, most kras+ larvae exposed to PR-39 and doxycycline did not display the early carcinoma phenotype and instead resembles closely to the liver phenotype of control kras− larvae, implying exposure to PR-39 deters progression into HCC. Fig. 6B summarizes the quantitative distribution of histological phenotypes in each treatment group, further indicating that inhibition of neutrophils led to moderated tumor phenotype while activation of neutrophils deteriorated the phenotype. The liver phenotype was also examined by immunostaining using two fibrosis markers, Laminin and Collagen 1a [30] (Supplementary Fig. 2) and we observed increases of both biomarkers in induced kras+ oncogenic livers, which were further increased by FPR-A14 but attenuated by PR-39, consistent with the general trends of liver tumor severity based on H&E staining.


Stimulation of hepatocarcinogenesis by neutrophils upon induction of oncogenic kras expression in transgenic zebrafish.

Yan C, Huo X, Wang S, Feng Y, Gong Z - J. Hepatol. (2015)

Histological analyses of effects of neutrophils on hepatocarcinogenesis. (A) H&E staining of liver sections. 8 dpf kras−/lyz+ and kras+/lyz+ larvae after exposure to FPR A14 or PR-39 with or without doxycycline, as indicated in the pictures, and were subject to H&E staining. Abbreviations: eHCC, early HCC; N, normal liver region. Dashed arrow: pseudo glandular pattern; white arrows: enlarged nuclei. (B) Quantification of phenotype observed in liver histology sections (n = 10, *p <0.05).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4508360&req=5

f0030: Histological analyses of effects of neutrophils on hepatocarcinogenesis. (A) H&E staining of liver sections. 8 dpf kras−/lyz+ and kras+/lyz+ larvae after exposure to FPR A14 or PR-39 with or without doxycycline, as indicated in the pictures, and were subject to H&E staining. Abbreviations: eHCC, early HCC; N, normal liver region. Dashed arrow: pseudo glandular pattern; white arrows: enlarged nuclei. (B) Quantification of phenotype observed in liver histology sections (n = 10, *p <0.05).
Mentions: Histologically, as shown in Fig. 6A, all H&E staining of 8 dpf kras+ larvae exposed to doxycycline showed histological features of early carcinoma, e.g. disorganized cell plate, large nucleus-to-cytoplasm ratio and pseudo glandular patterns. All kras+ larvae exposed to FPR-A14 and doxycycline showed similar early carcinoma histology, but with significantly less proportion of normal tissue, suggesting that the additional exposure to FPR-A14 had further stimulated HCC progression. In contrast, most kras+ larvae exposed to PR-39 and doxycycline did not display the early carcinoma phenotype and instead resembles closely to the liver phenotype of control kras− larvae, implying exposure to PR-39 deters progression into HCC. Fig. 6B summarizes the quantitative distribution of histological phenotypes in each treatment group, further indicating that inhibition of neutrophils led to moderated tumor phenotype while activation of neutrophils deteriorated the phenotype. The liver phenotype was also examined by immunostaining using two fibrosis markers, Laminin and Collagen 1a [30] (Supplementary Fig. 2) and we observed increases of both biomarkers in induced kras+ oncogenic livers, which were further increased by FPR-A14 but attenuated by PR-39, consistent with the general trends of liver tumor severity based on H&E staining.

Bottom Line: Both oncogenic hepatocytes and tumor-associated neutrophils (TANs) were isolated via fluorescence-activated cell sorting.Molecular analyses indicated a pro-inflammatory microenvironment, as marked by increased tgfβ1a expression in kras(V12)-expressing hepatocytes and a loss of anti-tumor activities in TANs.Depletion of Tgf-β significantly reduced the number of TANs and the size of oncogenic liver.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, National University of Singapore, Singapore; National University of Singapore Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.

No MeSH data available.


Related in: MedlinePlus