Prostate cancer (PCa) is the most common malignancy in males and largely incurable after metastatic spread. As aberrant glycosylation patterns have been associated with metastasis formation in several malignancies, RNA expression of 84 glycosylation genes was profiled in four common PCa cell lines and compared to that of normal prostate epithelium. By this analysis, an over-expression of ß(1,6)-N-acetylglucosaminyltransferase-Vb (GnT-Vb, Mgat-5b) was identified in all tested PCa cell lines [1], whereas polypeptide N-acetylgalactosaminyltransferases (GALNT3, 6, 8, and 14), ß(1,3)-N-acetylglucosaminyltransferases (B3GNT2 and 3) and O-glycan core structure glycosyltransferases (C1GALT1, C2GNT1, 2, and 3) were mainly down-regulated. The corresponding glycoconjugates were determined by lectin histochemistry using Phaseolus vulgaris leukoagglutinin (PHA-L, for GlcNAcß1-6 branched N-glycans) [1] and Helix pomatia agglutinin (HPA, for carbohydrates terminating in GalNAc and GlcNAc). Lectin histochemistry was performed on xenograft tumors and spontaneous lung metastases of the respective PCa cell lines after subcutaneous engraftment into immunodeficient mice.
PHA-L binding was detectable in primary xenograft tumors and their corresponding spontaneous lung metastases, while non-metastatic primary tumors did not bind PHA-L. In accordance, PHA-L binding intensity in clinical samples correlated with increased prostate specific antigen (PSA-) values of PCa patients (n=1,950) [1]. In contrast, HPA-binding was almost completely absent in metastatic xenografts and metastases, but weakly detectable in non-metastatic xenografts. These findings were corroborated by a clinical study demonstrating a decreased relapse-free survival of HPA-negative patients (n=1,285) and a higher percentage of biochemical recurrences in this cohort. HPA-negativity was also correlated with increasing tumor stages, tumor grades and rising PSA-values. Summarized, increased ß(1,6)-branched oligosaccharides and decreased GalNAc-/GlcNAc-residues are of particular functional and prognostic importance for PCa progression.
[1] Lange T, Ullrich S, Müller I, et al. Human Prostate Cancer in a Clinically Relevant Xenograft Mouse Model: Identification of ß(1,6)-branched Oligosaccharides as a Marker of Tumor Progression. Clin Cancer Res 2012; 18: 1364-73.
