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IPSE, an abundant egg-secreted protein of the carcinogenic helminth Schistosoma haematobium, promotes proliferation of bladder cancer cells and angiogenesis

Authors :
Evaristus Chibunna Mbanefo
Franco H. Falcone
Mohammad Afzal Khan
Theodore S. Jardetzky
Justin I. Odegaard
Alex Loukas
Kim H. Thai
Paul J. Brindley
Irina V. Saltikova
Chi Ling Fu
Michael J. Smout
Olivia K. Lamanna
Chinwike Terry Agbo
Yuanlong Zhao
Shannon E. Karinshak
Michael H. Hsieh
Mark R. Nicolls
Luke F. Pennington
Source :
Infectious Agents and Cancer, Vol 15, Iss 1, Pp 1-10 (2020), BASE-Bielefeld Academic Search Engine
Publication Year :
2020
Publisher :
Springer Science and Business Media LLC, 2020.

Abstract

Background Schistosoma haematobium, the helminth causing urogenital schistosomiasis, is a known bladder carcinogen. Despite the causal link between S. haematobium and bladder cancer, the underlying mechanisms are poorly understood. S. haematobium oviposition in the bladder is associated with angiogenesis and urothelial hyperplasia. These changes may be pre-carcinogenic events in the bladder. We hypothesized that the Interleukin-4-inducing principle of Schistosoma mansoni eggs (IPSE), an S. haematobium egg-secreted “infiltrin” protein that enters host cell nuclei to alter cellular activity, is sufficient to induce angiogenesis and urothelial hyperplasia. Methods: Mouse bladders injected with S. haematobium eggs were analyzed via microscopy for angiogenesis and urothelial hyperplasia. Endothelial and urothelial cell lines were incubated with recombinant IPSE protein or an IPSE mutant protein that lacks the native nuclear localization sequence (NLS-) and proliferation measured using CFSE staining and real-time monitoring of cell growth. IPSE’s effects on urothelial cell cycle status was assayed through propidium iodide staining. Endothelial and urothelial cell uptake of fluorophore-labeled IPSE was measured. Findings: Injection of S. haematobium eggs into the bladder triggers angiogenesis, enhances leakiness of bladder blood vessels, and drives urothelial hyperplasia. Wild type IPSE, but not NLS-, increases proliferation of endothelial and urothelial cells and skews urothelial cells towards S phase. Finally, IPSE is internalized by both endothelial and urothelial cells. Interpretation: IPSE drives endothelial and urothelial proliferation, which may depend on internalization of the molecule. The urothelial effects of IPSE depend upon its NLS. Thus, IPSE is a candidate pro-carcinogenic molecule of S. haematobium. Summary Schistosoma haematobium acts as a bladder carcinogen through unclear mechanisms. The S. haematobium homolog of IPSE, a secreted schistosome egg immunomodulatory molecule, enhances angiogenesis and urothelial proliferation, hallmarks of pre-carcinogenesis, suggesting IPSE is a key pro-oncogenic molecule of S. haematobium.

Details

ISSN :
17509378
Volume :
15
Database :
OpenAIRE
Journal :
Infectious Agents and Cancer
Accession number :
edsair.doi.dedup.....7c653018cac05de3f18295778613d4da
Full Text :
https://doi.org/10.1186/s13027-020-00331-6