Polysialic Acid Directs Tumor Cell Growth by Controlling Heterophilic Neural Cell Adhesion Molecule Interactions

Institut für Zoologie (220), Universität Hohenheim, 70593 Stuttgart, Germany.
Molecular and Cellular Biology (Impact Factor: 4.78). 09/2003; 23(16):5908-18. DOI: 10.1128/MCB.23.16.5908-5918.2003
Source: PubMed


Polysialic acid (PSA), a carbohydrate polymer attached to the neural cell adhesion molecule (NCAM), promotes neural plasticity
and tumor malignancy, but its mode of action is controversial. Here we establish that PSA controls tumor cell growth and differentiation
by interfering with NCAM signaling at cell-cell contacts. Interactions between cells with different PSA and NCAM expression
profiles were initiated by enzymatic removal of PSA and by ectopic expression of NCAM or PSA-NCAM. Removal of PSA from the
cell surface led to reduced proliferation and activated extracellular signal-regulated kinase (ERK), inducing enhanced survival
and neuronal differentiation of neuroblastoma cells. Blocking with an NCAM-specific peptide prevented these effects. Combinatorial
transinteraction studies with cells and membranes with different PSA and NCAM phenotypes revealed that heterophilic NCAM binding
mimics the cellular responses to PSA removal. In conclusion, our data demonstrate that PSA masks heterophilic NCAM signals,
having a direct impact on tumor cell growth. This provides a mechanism for how PSA may promote the genesis and progression
of highly aggressive PSA-NCAM-positive tumors.

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    • "It was demonstrated that the migratory effect is NCAM-dependent, but independent of FGF receptor activity (84). Removal of PSA from the cell-surface led to reduced proliferation and neuronal differentiation (82). In vivo studies indicate that PSA-NCAM reduces the adhesiveness of tumor cells and promotes dissemination, and its expression is also closely associated with tumor invasion and metastasis (85). "
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    ABSTRACT: Neuroblastoma (NB), accounting for 10% of childhood cancers, exhibits aberrant cell-surface glycosylation patterns. There is evidence that changes in glycolipids and protein glycosylation pathways are associated to NB biological behavior. Polysialic acid (PSA) interferes with cellular adhesion, and correlates with NB progression and poor prognosis, as well as the expression of sialyltransferase STX, the key enzyme responsible for PSA synthesis. Galectin-1 and gangliosides, overexpressed and actively shedded by tumor cells, can modulate normal cells present in the tumor microenvironment, favoring angiogenesis and immunological escape. Different glycosyltransferases are emerging as tumor markers and potential molecular targets. Immunotherapy targeting disialoganglioside GD2 rises as an important treatment option. One anti-GD2 antibody (ch14.18), combined with IL-2 and GM-CSF, significantly improves survival for high-risk NB patients. This review summarizes our current knowledge on NB glycobiology, highlighting the molecular basis by which carbohydrates and protein-carbohydrate interactions impact on biological behavior and patient clinical outcome.
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    • "A further important role for the polySia glycan is its support of dynamic changes associated with peripheral nerve regeneration [21]. Due to its polyanionic charge, the polySia chains that modify N-linked glycans on NCAM prevents both the homophilic and heterophilic binding interactions between NCAM expressing cells [9] [22]. In this context, polySia functions as an anti-adhesive glycotope preventing cell adhesion and cell migration. "
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    ABSTRACT: During brain development, polysialylated (polySia) neural cell adhesion molecules (polySia-NCAMs) modulate cell-cell adhesive interactions involved in synaptogenesis, neural plasticity, myelination, and neural stem cell (NSC) proliferation and differentiation. Our findings show that polySia-NCAM is expressed on NSC isolated from adult guinea pig spiral ganglion (GPSG), and in neurons and Schwann cells after differentiation of the NSC with epidermal, glia, fibroblast growth factors (GFs) and neurotrophins. These differentiated cells were immunoreactive with mAb's to polySia, NCAM, β-III tubulin, nestin, S-100 and stained with BrdU. NSC could regenerate and be differentiated into neurons and Schwann cells. We conclude: (1) polySia is expressed on NSC isolated from adult GPSG and on neurons and Schwann cells differentiated from these NSC; (2) polySia is expressed on neurons primarily during the early stage of neuronal development and is expressed on Schwann cells at points of cell-cell contact; (3) polySia is a functional biomarker that modulates neuronal differentiation in inner ear stem cells. These new findings suggest that replacement of defective cells in the inner ear of hearing impaired patients using adult spiral ganglion neurons may offer potential hope to improve the quality of life for patients with auditory dysfunction and impaired hearing disorders.
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    • "The mRNA expression of PST enzyme was found to be increased in TCE treated cells, suggesting that downregulation of NCAM expression itself may be the main cause of reduced glycosylation resulting in lower expression of PSA-NCAM. NCAM is widely expressed during embryogenesis, down-regulated in the course of differentiation to be re-expressed during progression of some tumors [75,76]. Apart from adhesion activity, NCAM moiety is highly involved in GDNF mediated signaling in cell migration and axonal outgrowth and play important role during development and injury [77]. "
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