Differential responses of epithelial cells from urinary and biliary tract to eggs of Schistosoma haematobium and S. mansoni

Rafael Nacif-Pimenta,Shannon E Karinshak,Gabriel Rinaldi,Paulo Marcos Zech Coelho,Kenji Ishida,José M Correia Da Costa,Alessandra Da Silva Orfanó,Victoria H Mann,Paul J Brindley,Michael H Hsieh,Ilana A Mosley

doi:10.1038/s41598-019-46917-y

Abstract

Chronic urogenital schistosomiasis can lead to squamous cell carcinoma of the bladder. The International Agency for Research on Cancer classifies the infection with S. haematobium as a group 1 carcinogen, a definitive cause of cancer. By contrast, hepatointestinal schistosomiasis due to the chronic infection with S. mansoni or S. japonicum associated with liver periportal fibrosis, does not apparently lead to malignancy. The effects of culturing human epithelial cells, HCV29, established from normal urothelium, and H69, established from cholangiocytes, in the presence of S. haematobium or S. mansoni eggs were investigated. Cell growth of cells co-cultured with schistosome eggs was monitored in real time, and gene expression analysis of oncogenesis, epithelial to mesenchymal transition and apoptosis pathways was undertaken. Schistosome eggs promoted proliferation of the urothelial cells but inhibited growth of cholangiocytes. In addition, the tumor suppressor P53 pathway was significantly downregulated when exposed to schistosome eggs, and downregulation of estrogen receptor was predicted in urothelial cells exposed only to S. haematobium eggs. Overall, cell proliferative responses were influenced by both the tissue origin of the epithelial cells and the schistosome species.

Highlights

The blood flukes Schistosoma japonicum and S. mansoni are agents of hepatointestinal schistosomiasis in East Asia, Africa, northeastern South America and the Caribbean, whereas S. haematobium causing urogenital schistosomiasis (UGS) is present through Africa and the Middle East
We have previously studied human cholangiocyte cells H69 employing the xCELLigence Real Time Cell Assay[17], we had not quantified the proliferation of the human urothelial cell line HCV29 using this approach
It is critical to set up a priori the conditions for cell proliferation analysis for every new cell line in the laboratory mediated xCELLigence, even though the same cell line has been already analyzed by others[18]

Summary

Introduction

The blood flukes Schistosoma japonicum and S. mansoni are agents of hepatointestinal schistosomiasis in East Asia, Africa, northeastern South America and the Caribbean, whereas S. haematobium causing urogenital schistosomiasis (UGS) is present through Africa and the Middle East. Many of the eggs of S. haematobium become trapped in host tissues, in particular urogenital organs, leading to inflammation and eventually squamous cell carcinoma of the bladder (SCC)[4]. Research of UGS-induced bladder cancer is challenging due to the absence of laboratory animal models that mirror the human disease; in rodent models the vast majority of S. haematobium adult worms reside in the mesenteric veins. Eggs of both schistosome species induced cell death of cholangiocytes. These phenotypic effects were associated with dysregulation of genes involved in oncogenesis, epithelial-mesenchymal transition and apoptosis pathways. Future studies to decipher cellular and/or molecular mechanisms underlying the association between UGS and bladder cancer will contribute to the discovery of new interventions for this neglected tropical disease-related cancer

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Conclusion