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P53 and cancer-associated sialylated glycans are surrogate markers of cancerization of the bladder associated with Schistosoma haematobium infection.

Santos J, Fernandes E, Ferreira JA, Lima L, Tavares A, Peixoto A, Parreira B, Correia da Costa JM, Brindley PJ, Lopes C, Santos LL - PLoS Negl Trop Dis (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Experimental Pathology and Therapeutics group, Portuguese Institute for Oncology of Porto, Porto, Portugal; Clínica Sagrada Esperança, Luanda, Angola.

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.

Methodology/principal findings: 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.

Conclusion/significance: 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.

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Related in: MedlinePlus

Expression of cancer-associated glycans antigens A) sTn, B)sLea and C-D) sLex in Schistosoma haematobium eggs.The white arrows point to positive eggs. The treatment of the tissue sections with a α-neuraminidase led to the loss of immunoreactivity, confirming the validating the structural assignment.
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pntd-0003329-g002: Expression of cancer-associated glycans antigens A) sTn, B)sLea and C-D) sLex in Schistosoma haematobium eggs.The white arrows point to positive eggs. The treatment of the tissue sections with a α-neuraminidase led to the loss of immunoreactivity, confirming the validating the structural assignment.

Mentions: Moreover, it was observed that 60% of the cases presented S. haematobium eggs embedded in the bladder urothelium, predominantly in benign/pre-malignant lesions without the presence of tumour (75% vs 45%). However, no associations were found between the expression of the studied markers and the presence and absence of the eggs in the bladder at the time of diagnosis. Altogether, these findings suggest that the presence of eggs in the bladder may be an early event leading to carcinogenesis. Whether the disorganization of the tissue associated with malignant transformation may favor their release into the environment, therefore explaining is lower presence in malignant tissues and consequently the lack of correlation with the studied biomarkers, warrants further investigation. It was further observed that the majority of the cases (>75%) presented sLea and sLea positive eggs and approximately half displayed eggs expressing the sTn antigen, suggesting some degree of mimicry of host glycosylation patterns (Fig. 2). The expression of sialylated glycans was validated by observing the loss of reactivity against anti-glycans monoclonal antibodies after treatment of the tissue with a neuraminidase. It was noteworthy that both positive and negative eggs for these antigens could be found within the same biopsy, denoting some degree of heterogeneity at this level.


P53 and cancer-associated sialylated glycans are surrogate markers of cancerization of the bladder associated with Schistosoma haematobium infection.

Santos J, Fernandes E, Ferreira JA, Lima L, Tavares A, Peixoto A, Parreira B, Correia da Costa JM, Brindley PJ, Lopes C, Santos LL - PLoS Negl Trop Dis (2014)

Expression of cancer-associated glycans antigens A) sTn, B)sLea and C-D) sLex in Schistosoma haematobium eggs.The white arrows point to positive eggs. The treatment of the tissue sections with a α-neuraminidase led to the loss of immunoreactivity, confirming the validating the structural assignment.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263606&req=5

pntd-0003329-g002: Expression of cancer-associated glycans antigens A) sTn, B)sLea and C-D) sLex in Schistosoma haematobium eggs.The white arrows point to positive eggs. The treatment of the tissue sections with a α-neuraminidase led to the loss of immunoreactivity, confirming the validating the structural assignment.
Mentions: Moreover, it was observed that 60% of the cases presented S. haematobium eggs embedded in the bladder urothelium, predominantly in benign/pre-malignant lesions without the presence of tumour (75% vs 45%). However, no associations were found between the expression of the studied markers and the presence and absence of the eggs in the bladder at the time of diagnosis. Altogether, these findings suggest that the presence of eggs in the bladder may be an early event leading to carcinogenesis. Whether the disorganization of the tissue associated with malignant transformation may favor their release into the environment, therefore explaining is lower presence in malignant tissues and consequently the lack of correlation with the studied biomarkers, warrants further investigation. It was further observed that the majority of the cases (>75%) presented sLea and sLea positive eggs and approximately half displayed eggs expressing the sTn antigen, suggesting some degree of mimicry of host glycosylation patterns (Fig. 2). The expression of sialylated glycans was validated by observing the loss of reactivity against anti-glycans monoclonal antibodies after treatment of the tissue with a neuraminidase. It was noteworthy that both positive and negative eggs for these antigens could be found within the same biopsy, denoting some degree of heterogeneity at this level.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Experimental Pathology and Therapeutics group, Portuguese Institute for Oncology of Porto, Porto, Portugal; Clínica Sagrada Esperança, Luanda, Angola.

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.

Methodology/principal findings: 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.

Conclusion/significance: 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.

Show MeSH
Related in: MedlinePlus