Sialyltransferase STX (ST8SiaII): A novel molecular marker of metastatic neuroblastoma

Abstract

Polysialic acid (PSA) is highly expressed in many human cancers, including neuroblastoma (NB), and is critical for cellular adhesion, neuronal migration and tumor metastasis. The key enzyme responsible for PSA synthesis is sialyltransferase STX (ST8SiaII). Using quantitative RT-PCR we (i) studied STX expression in 39 NB tumors and 8 cell lines and (ii) examined its potential clinical utility as an early response marker in the bone marrows of the entire cohort of 136 high-risk NB patients treated with an immunotherapy protocol utilizing anti-GD2 antibody 3F8 and GM-CSF. Based on the quantitation of 24 normal marrow and peripheral blood samples, a normalized STX transcript value below the mean 1 2SD was defined as negative. Sensitivity of this assay was 1 NB cell in 10 6 normal mononuclear cells. STX expression was high among NB tumors of all stages, as well as NB cell lines of different phenotypes. Evaluation for early (2.5 months from protocol entry) marrow response by univariate Cox model indicated that STX marker status (positive versus negative) was strongly associated with both progression-free and overall survival (p < 0.0005 for both). Similarly, the STX transcript level of posttreatment marrows was also highly prognostic of outcome (PFS, p 5 0.001; OS, p < 0.0005). We conclude that STX mRNA has potential clinical utility as a molecular marker of metastatic NB. ' 2006 Wiley-Liss, Inc.

Expression of the neural cell adhesion molecule and polysialic acid in human neuroblastoma cell lines

“…Comparing polySia-NCAM and ST8SiaII expression of the associated primary tumours, LAN-1 and LAN-5 tumours showed a high polySia-NCAM and ST8SiaII expression. This result supports the current model that expression of polySia-NCAM reduces the adhesiveness of tumour cells, contributes to cellular dissemination and may promote metastasis (21,33). Cells from neuroblastomas, which are positive for polySia-NCAM disseminate and emigrate as single cells in the parenchyma of the lung, whereas cells of tumours without or with weak polySia-NCAM expression leave the primary tumour and adhere as cell clusters to the vascular vessel but do not transmigrate or do so very slowly, respectively.…”

“…Polysialylation of NCAM is crucial for NCAM-mediated regulation of tumour growth (31). In clinical studies high polySia serum levels were associated with poor prognosis and polySia and ST8SiaII were suggested as molecular prognostic markers (15,16,21,32). PolySia is thought to abrogate homophilic binding properties of NCAM and to reduce cell adhesion important in cell migration and invasion.…”

“…ST8SiaII is described as the predominant form in embryonic and early postnatal brain, whereas ST8SiaIV was found to be the major form in adult brain (18)(19)(20). Expression of ST8SiaII mRNA was recently shown to be a potential molecular marker of metastatic neuroblastoma (21).…”

Polysialyltransferase expression is linked to neuronal migration in the developing and adult zebrafish

“…Based on their differential expression PSA synthesis during embryogenesis has mainly been attributed to STX, whereas adult PSA synthesis is thought to be mediated preferentially by PST (Becker et al, 1996;Hildebrandt et al, 1998;Ong et al, 1998). The expression and function of these polysialyltransferases has attracted increasing biomedical interest for several reasons: (1) high PSA levels as well as STX expression can serve as diagnostic markers for neuroblastomas with poor prognostic outcome (Cheung et al, 2006;Seidenfaden et al, 2003); (2) polysialyltransferase activity promotes metastasis formation and, thus, represents an interesting pharmaceutical target; (3) the migration promoting activity of either STXor PST-mediated PSA synthesis in genetically engineered Schwann cells significantly supports regeneration by increasing axon outgrowth and Schwann cell-mediated remyelination (Lavdas et al, 2006;Zhang et al, 2007).…”

Polysialic Acid Bioengineering of Cancer and Neuronal Cells by N-Acyl Sialic Acid Precursor Treatment

“…The limited expression of PSA in normal adult tissue increases its potential as a cancer determinant where it has been found in abundance in such malignancies as Wilm's tumor (9), small cell and non-small cell lung cancer (10;11), neuroblastoma (12), and rhabdomyosarcoma (13). Several lines of evidence further implicate the anti-adhesive nature of PSA with primary tumor shedding and metastasis (14)(15)(16), where its expression is negatively associated with favourable prognoses (10).…”