Insight into the molecular basis of Schistosoma haematobium-induced bladder cancer through urine proteomics
Infection due to Schistosoma haematobium is carcinogenic. However, the cellular and molecular mechanisms underlying urogenital schistosomiasis (UGS)-induced carcinogenesis have not been well defined. Conceptually, early molecular detection of this phenomenon, through non-invasive procedures, seems feasible and is desirable. Previous analysis of urine collected during UGS suggests that estrogen metabolites, including depurinating adducts, may be useful for this purpose. Here, a new direction was pursued: the identification of molecular pathways and potential biomarkers in S. haematobium-induced bladder cancer by analyzing the proteome profiling of urine samples from UGS patients. GeLC-MS/MS followed by protein-protein interaction analysis indicated oxidative stress and immune defense systems responsible for microbicide activity are the most representative clusters in UGS patients. Proteins involved in immunity, negative regulation of endopeptidase activity, and inflammation were more prevalent in UGS patients with bladder cancer, whereas proteins with roles in renal system process, sensory perception, and gas and oxygen transport were more abundant in subjects with urothelial carcinoma not associated with UGS. These findings highlighted a Th2-type immune response induced by S. haematobium, which seems to be further modulated by tumorigenesis, resulting in high-grade bladder cancer characterized by an inflammatory response and complement activation alternative pathway. These findings established a starting point for the development of multimarker strategies for the early detection of UGS-induced bladder cancer.
KeywordsUrogenital schistosomiasis Immune response Squamous cell carcinoma GeLC-MS/MS Urine proteomics
This work was supported by the Portuguese Foundation for Science and Technology (FCT), European Union, QREN, FEDER, and COMPETE for funding the QOPNA; by iBiMED research unit (project PEst-C/QUI/UI0062/2013, UID/BIM/04501/2013, UID/IC/00051/2013, and COST action BM1305) and PhD fellowship SFRH/BD/80855/2011 (CB); and by the Portuguese Mass Spectrometry Network (RNEM). The authors also acknowledge Clínica Sagrada Esperança and Serviço de Urologia do Hospital Américo Boavida from Luanda, Angola.
Compliance with ethical standards
Urine samples were obtained according to a collaborative program between Clínica da Sagrada Esperança, Américo Boavida University Hospital and IPO-Porto after obtaining informed consent from all participants. This study was approved by the local ethics committee and followed the Declaration of Helsinki.
Conflicts of interest
- 2.IARC A review of human carcinogens. Part B: biological agents. In: IARC Work. Gr. Eval. Carcinog. Risks to humans. Lyon, France; 2012. p. 371–384.Google Scholar
- 9.Correia da Costa JM, Vale N, Gouveia MJ, et al. Schistosome and liver fluke derived catechol-estrogens and helminth associated cancers. Front Genet. 2014;5:444. doi: 10.3389/fgene.2014.00444.
- 29.Thivierge K, Cotton S, Schaefer DA, et al. Cathelicidin-like helminth defence molecules (HDMs): absence of cytotoxic, anti-microbial and anti-protozoan activities imply a specific adaptation to immune modulation. PLoS Negl Trop Dis. 2013;7:e2307. doi: 10.1371/journal.pntd.0002307.CrossRefPubMedPubMedCentralGoogle Scholar
- 42.Warren W, Biggs PJ, El-Baz M, et al. Mutations in the p53 gene in schistosomal bladder cancer: a study of 92 tumours from Egyptian patients and a comparison between mutational spectra from schistosomal and non-schistosomal urothelial tumours. Carcinogenesis. 1995;16:1181–9.CrossRefPubMedGoogle Scholar