Characterisation of the main PSA glycoforms in aggressive prostate cancer

Abstract

Serum levels of prostate specific antigen (PSA) are commonly used for prostate cancer (PCa) detection. However, their lack of specificity to distinguish benign prostate pathologies from PCa, or indolent from aggressive PCa have prompted the study of new non-invasive PCa biomarkers. Aberrant glycosylation is involved in neoplastic progression and specific changes in PSA glycosylation pattern, as the reduction in the percentage of α2,6-sialic acid (SA) are associated with PCa aggressiveness. In this study, we have characterised the main sialylated PSA glycoforms from blood serum of aggressive PCa patients and have compared with those of standard PSA from healthy individuals’ seminal plasma. PSA was immunoprecipitated and α2,6-SA were separated from α2,3-SA glycoforms using SNA affinity chromatography. PSA N-glycans were released, labelled and analysed by hydrophilic interaction liquid chromatography combined with exoglycosidase digestions. The results showed that blood serum PSA sialylated glycoforms containing GalNAc residues were largely increased in aggressive PCa patients, whereas the disialylated core fucosylated biantennary structures with α2,6-SA, which are the major PSA glycoforms in standard PSA from healthy individuals, were markedly reduced in aggressive PCa. The identification of these main PSA glycoforms altered in aggressive PCa opens the way to design specific strategies to target them, which will be useful to improve PCa risk stratification.

Glycosylation: Rising Potential for Prostate Cancer Evaluation

“…The results indicated that levels of serum PSA sialylated glycoforms bearing GalNAc moieties (LacdiNAc) were raised in aggressive PCa patients. Concomitantly, levels of disialylated core fucosylated biantennary structures with α2,6-linked sialic acid, which were previously indicated as major PSA glycoforms characteristic for standard PSA from healthy men, were significantly lowered in aggressive PCa (Table 1) [79].…”

“…This approach may lead to the establishment of new biomarkers with higher specificity for early cancer detection or for diagnosis in precancerous lesions [134,135]. Such research has become possible to carry out using newly developed, high-throughput platform technologies, which additionally enable the effective analysis of large sample cohorts [79,134]. Numerous studies have investigated whether a cancer-specific glycosylation pattern on PSA can be used to differentiate between BPH and PCa [75,133].…”

Serum core‐type fucosylated prostate‐specific antigen index for the detection of high‐risk prostate cancer

“…Kekki et al reported a significant increase in PSA fucosylation in PCa tissue compared to benign tissue and in urine from PCa patients compared to BPH patients using a nanoparticle‐based AAL‐immunoassay for analyzing the fucosylation of PSA 34 . Gratacos‐Mulleras et al characterized serum PSA glycoforms with hydrophilic interaction liquid chromatography and showed an important decrease of the disialylated core fucosylated biantennary structures with α2,6‐sialic acid and an increase of the α2,3‐disialylated core fucosylated biantennary and α2,3‐monosialylated noncore fucosylated structures in patients with aggressive PCa compare to PSA from healthy individuals' seminal plasma 35 . Since high levels of PSA exist in urine, analysis of glycosylations in urinary PSA could be a promising approach for biomarker discovery 36 .…”

“…-monosialylated noncore fucosylated structures in patients with aggressive PCa compare to PSA from healthy individuals' seminal plasma 35. Since high levels of PSA exist in urine, analysis of glycosylations in urinary PSA could be a promising approach for biomarker discovery 36.…”

Glycoproteogenomics: Setting the Course for Next-Generation Cancer Neoantigen Discovery for Cancer Vaccines

“…Previous studies have shown the significance of glycosylation for patient stratification and identification of novel biomarkers and therapeutic targets [41] , [42] . As example, altered sialylation and fucosylation have been used to improve the predictive value of PSA [86] , [87] , [88] . Targeting sialyl-Tn (STn) glycoforms of plasminogen in the serum of patients holds potential for non-invasive clinical diagnosis of individuals with gastric precancerous lesions [89] .…”