Development of A New Mouse Model for Intrahepatic Cholangiocellular Carcinoma: Accelerating Functions of Pecam-1.

Ihtzaz Malik,Philipp Ströbel,Gesa Malik,Jörg Wilting

doi:10.3390/cancers11081045

Ihtzaz Malik, Philipp Ströbel + Show 2 more

Open Access

https://doi.org/10.3390/cancers11081045

Copy DOI

Journal: Cancers	Publication Date: Jul 24, 2019
Citations: 3	License type: CC BY 4.0

Affiliation: University of Göttingen

Abstract

Due to the lack of suitable in-vivo models, the etiology of intrahepatic cholangiocellular carcinoma (ICC) is poorly understood. We previously showed the involvement of platelet endothelial cell adhesion molecule-1 (Pecam-1/CD31) in acute liver damage. Here, we developed a model of ICC using thioacetamide (TAA) in drinking water of wild-type (WT)-mice and Pecam-1-knock-out (KO)-mice. Gross inspection and microscopy revealed liver-cirrhosis and ICC in both groups after 22 weeks of TAA. The severity of cirrhosis and ICC (Ck-19-positive) was reduced in Pecam-1 KO mice (stage-4 cirrhosis in WT vs. stage-3 in KO mice). Tumor networks (accompanied by neutrophils) were predominantly located in portal areas, with signs of epithelial-to-mesenchymal transition (EMT). In serum, TAA induced an increase in hepatic damage markers, with lower levels in Pecam-1 null mice. With qPCR of liver, elevated expression of Pecam-1 mRNA was noted in WT mice, in addition to Icam-1, EpCam, cytokines, cMyc, and Mmp2. Thereby, levels of EpCAM, cytokines, cMyc, and Mmp2 were significantly lower in Pecam-1 null mice. Lipocalin-2 and Ccl5 were elevated significantly in both WT and Pecam-1 null mice after TAA administration. Also, EMT marker Wnt5a (not Twist-1) was increased in both groups after TAA. We present a highly reproducible mouse model for ICC and show protective effects of Pecam-1 deficiency.

Highlights

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocellular carcinoma (ICC) are the most common primary hepatic malignancies, accounting for roughly 70% and 15% of cases, respectively [1,2].Despite the large number of ICC in primary liver cancer, studies on the disease are very scarce.Treatment depends on the site and extent of the lesion, and only surgical resection can improve the outcome significantly
We present the first mouse model for ICC and we show that the loss of Pecam-1 has protective effects
Whereas WT-mice generally presented with stage 4 liver cirrhosis, all Pecam-1 KO mice had stage 3 cirrhosis

Summary

Introduction

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocellular carcinoma (ICC) are the most common primary hepatic malignancies, accounting for roughly 70% and 15% of cases, respectively [1,2].Despite the large number of ICC in primary liver cancer, studies on the disease are very scarce.Treatment depends on the site and extent of the lesion, and only surgical resection can improve the outcome significantly. Hepatocellular carcinoma (HCC) and intrahepatic cholangiocellular carcinoma (ICC) are the most common primary hepatic malignancies, accounting for roughly 70% and 15% of cases, respectively [1,2]. Despite the large number of ICC in primary liver cancer, studies on the disease are very scarce. Treatment depends on the site and extent of the lesion, and only surgical resection can improve the outcome significantly. Even with modern disease management, there has still not been any significant improvement in the patients’ prognosis; for example, in the United States of America, the 5-year survival rate for patients with ICC has remained at a low 8% (American Cancer Society, 2018, [3]). The lesions are usually diagnosed only at advanced stages, and there are no drugs approved for the treatment of ICC so far

Methods

Results

Discussion

Conclusion