title: P53 and cancer-associated sialylated glycans are surrogate markers of cancerization of the bladder associated with Schistosoma haematobium infection.
abstract: BACKGROUND
  Bladder cancer is a significant health problem in rural areas of Africa and the Middle East where Schistosoma haematobium is prevalent, supporting an association between malignant transformation and infection by this blood fluke. Nevertheless, the molecular mechanisms linking these events are poorly understood. Bladder cancers in infected populations are generally diagnosed at a late stage since there is a lack of non-invasive diagnostic tools, hence enforcing the need for early carcinogenesis markers.
  
  
  RESULTS
  Forty-three formalin-fixed paraffin-embedded bladder biopsies of S. haematobium-infected patients, consisting of bladder tumours, tumour adjacent mucosa and pre-malignant/malignant urothelial lesions, were screened for bladder cancer biomarkers. These included the oncoprotein p53, the tumour proliferation rate (Ki-67>17%), cell-surface cancer-associated glycan sialyl-Tn (sTn) and sialyl-Lewisa/x (sLea/sLex), involved in immune escape and metastasis. Bladder tumours of non-S. haematobium etiology and normal urothelium were used as controls. S. haematobium-associated benign/pre-malignant lesions present alterations in p53 and sLex that were also found in bladder tumors. Similar results were observed in non-S. haematobium associated tumours, irrespectively of their histological nature, denoting some common molecular pathways. In addition, most benign/pre-malignant lesions also expressed sLea. However, proliferative phenotypes were more prevalent in lesions adjacent to bladder tumors while sLea was characteristic of sole benign/pre-malignant lesions, suggesting it may be a biomarker of early carcionogenesis associated with the parasite. A correlation was observed between the frequency of the biomarkers in the tumor and adjacent mucosa, with the exception of Ki-67. Most S. haematobium eggs embedded in the urothelium were also positive for sLea and sLex. Reinforcing the pathologic nature of the studied biomarkers, none was observed in the healthy urothelium.
  
  
  CONCLUSIONS
  This preliminary study suggests that p53 and sialylated glycans are surrogate biomarkers of bladder cancerization associated with S. haematobium, highlighting a missing link between infection and cancer development. Eggs of S. haematobium express sLea and sLex antigens in mimicry of human leukocytes glycosylation, which may play a role in the colonization and disease dissemination. These observations may help the early identification of infected patients at a higher risk of developing bladder cancer and guide the future development of non-invasive diagnostic tests.
authors.affiliation: Experimental Pathology and Therapeutics group, Portuguese Institute for Oncology of Porto, Porto, Portugal; Clínica Sagrada Esperança, Luanda, Angola.
authors.forename: Júlio
authors.initials: J
authors.lastname: Santos
authors.affiliation: Experimental Pathology and Therapeutics group, Portuguese Institute for Oncology of Porto, Porto, Portugal; Grupo de Investigação em Cancro Digestivo (GICD), Porto, Portugal.
authors.forename: Elisabete
authors.initials: E
authors.lastname: Fernandes
authors.affiliation: Experimental Pathology and Therapeutics group, Portuguese Institute for Oncology of Porto, Porto, Portugal; Department of Chemistry of the University of Aveiro, Aveiro, Portugal.
authors.forename: José Alexandre
authors.initials: JA
authors.lastname: Ferreira
authors.affiliation: Experimental Pathology and Therapeutics group, Portuguese Institute for Oncology of Porto, Porto, Portugal; Research Department, LPCC-Portuguese League Against Cancer (NRNorte), Porto, Portugal; Núcleo de Investigação em Farmácia - Centro de Investigação em Saúde e Ambiente (CISA), School of Allied Health Sciences - Polytechnic Institute of Porto, Porto, Portugal.
authors.forename: Luís
authors.initials: L
authors.lastname: Lima
authors.affiliation: Experimental Pathology and Therapeutics group, Portuguese Institute for Oncology of Porto, Porto, Portugal; Department of Pathology, Portuguese Institute for Oncology of Porto, Porto, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Tavares
authors.affiliation: Experimental Pathology and Therapeutics group, Portuguese Institute for Oncology of Porto, Porto, Portugal.
authors.forename: Andreia
authors.initials: A
authors.lastname: Peixoto
authors.affiliation: Experimental Pathology and Therapeutics group, Portuguese Institute for Oncology of Porto, Porto, Portugal.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Parreira
authors.affiliation: Center for the Study of Animal Science (ICETA), University of Porto, Porto, Portugal; INSA, National Institute of Health, Porto, Portugal.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Correia da Costa
authors.affiliation: Research Center for Neglected Diseases of Poverty- Department of Microbiology, Immunology & Tropical Medicine, School of Medicine & Health Sciences, George Washington University, Washington, D.C., United States of America.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Brindley
authors.affiliation: Experimental Pathology and Therapeutics group, Portuguese Institute for Oncology of Porto, Porto, Portugal; Abel Salazar Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopes
authors.affiliation: Experimental Pathology and Therapeutics group, Portuguese Institute for Oncology of Porto, Porto, Portugal; Health School of University of Fernando Pessoa, Porto, Portugal; Department of Surgical Oncology, Portuguese Institute for Oncology, Porto, Portugal; National Cancer Center, Luanda, Angol.
authors.forename: Lúcio L
authors.initials: LL
authors.lastname: Santos
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D011134:Polysaccharides / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D012548:Schistosoma haematobium / Q000302:isolation & purification*; D012553:Schistosomiasis haematobia / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D001745:Urinary Bladder Diseases / Q000469:parasitology* / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000469:parasitology* / Q000473:pathology; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D011134:Polysaccharides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019158:N-Acetylneuraminic Acid