Research Article: P53 and Cancer-Associated Sialylated Glycans Are Surrogate Markers of Cancerization of the Bladder Associated with Schistosoma haematobium Infection

Date Published: December 11, 2014

Publisher: Public Library of Science

Author(s): Júlio Santos, Elisabete Fernandes, José Alexandre Ferreira, Luís Lima, Ana Tavares, Andreia Peixoto, Beatriz Parreira, José Manuel Correia da Costa, Paul J. Brindley, Carlos Lopes, Lúcio L. Santos, Jason Mulvenna.

Abstract: BackgroundBladder 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.Methodology/Principal FindingsForty-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.Conclusion/SignificanceThis 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.

Partial Text: Schistosoma haematobium, a parasitic flatworm infecting millions of people in Angola and other countries of Africa and Middle East, is responsible for the development of urinary schistosomiasis, a neglected tropical disease [1], [2]. The World Health Organization estimates that 500 to 600 million people residing in rural agricultural and periurban areas are at risk of infection and over 200 million people are currently infected, 10% of which will experience sever health complications; [3], [4].

Bladder tumours associated with S. haematobium infection were screened for the accumulation of p53, proliferation rate (Ki-67>17%) and cancer-associated sialylated glycans sTn, sLea and sLex (Fig. 1). We could observe that all the biomarkers were expressed throughout the different layers of the urothelium in benign/pre-malignant lesions and also homogeneously expressed in the tumours, irrespectively of their histological classification. As presented in Table 2, the majority of the bladder tumors exhibited p53 alterations (84%) and sLex overexpression (74%). Similar percentages of p53 and sLex could also be observed in bladder tumour sections from patients non-infected with Schistosoma haematobium, irrespectively of their histological natures. Conversely, non-proliferative phenotypes predominated among low malignant lesions (papilloma and PUNLMP; 100% of the cases) when compared to the other groups comprehending more aggressive lesions presenting either invasion and/or high potential to invade the bladder wall (UCC, SCC, SCC+UC; approximately 50% of the cases) (Table 2). Contrasting with these findings, the percentage of proliferative phenotypes in the less aggressive non-schistosome associated lesions (low grade papillary tumours) was 30%. The percentage of proliferative phenotypes in more aggressive high grade lesions, including high grade urothelial cell and squamous cell carcinomas, was similar to described for S. haematobium infection related lesions. The sLea antigen was detected in approximately 50% of the S. haematobium-associated malignant lesions, irrespectively of their histology. These observations contrasted with the significantly higher expression of sLea observed in lesions not associated with the parasite (80% of the cases). Regarding the sTn antigen, its frequency varies among the histological groups of tumours, papilloma and UCC did not express the antigen, PUNLMP and SCC showed an equal distribution of negative and positive cases. However, the antigen was expressed by 75% of the cases presenting both an UCC and SCC phenotype, which is in accordance with our previous results for non-schistosome associated bladder tumors, where sTn antigen was present in approximately 75% of aggressive bladder tumors (high grade papillary tumors and muscle invasive bladder cancer) [31]. Altogether, the studied biomarkers, with the exception of sLea presented similar expressions in both schistosome and non-schistosome associated bladder tumors.

In contrast to the extensive cytogenetic and molecular signatures existing for urothelial cell carcinoma, mainly found in western populations, little is known about the molecular alterations underlying the development of S. haematobium-associated bladder cancer. Nevertheless, such information is pivotal to support a definitive association between schistosomiasis and bladder cancer development that, until now, has been mostly supported by epidemiological studies. Furthermore, it may provide means for an early identification of infected populations at a risk of developing bladder cancer, which is a particular critical matter since the majority of the cases are detected at a late stage due the absence of appropriate medical facilities.



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