Amoureux et al. BMC Cancer 2010, 10:91 http://www.biomedcentral.com/1471-2407/10/91 the response to treatment and relapse in a large variety of cancer including medulloblastoma [28], neuroblas- toma [29], rhabdomyosarcoma [30] and small cell lung carcinoma [31]. PSA-NCAM in non-small cell lung can- cer biopsies was correlated with tumor progression and was an independent prognosis factor [32]. NCAM expression has also been evaluated in glioma [20], and other tumor types [31], but NCAM immunoreactivity does not differentiate polysialylated from non polysialy- lated NCAM. Interpretations of NCAM expression results have therefore been limited due to the omitted consideration of NCAM polysialylation, post-transla- tional modification that affects dramatically NCAM binding properties and intermembrane repulsion [15]. In gliomas, PSA-NCAM has been detected in GBM explants [33] and on biopsies more frequently in diffuse astrocytoma cells, which spread extensively [20]. It has also been shown to confer invasive properties to glioma cells in animal models [20]. However, although some studies have reported biomarkers of different grades of glioma [34,35], investigations showing the prognosis value of molecular factors by multivariate analysis, speci- fically in the GBM subgroup, have been limited, and most used semi-quantitative methods or mRNA analysis [36,37]. Therefore, the methodology developed here and the finding of PSA-NCAM as a prognosis marker in GBM appears significant. We found that 70% of biopsies expressed PSA-NCAM at levels above the level set up as background, with some variability. Moreover, GBM showed considerably lower levels than MB. A likely explanation for this dif- ference is that MB cells are all in the same differentia- tion state, engaged in a neuronal phenotype, whereas in GBM, cells from very immature to differentiated pheno- type can be observed (personal observations). The con- trasted low PSA levels in GBM versus high levels in MB could also explain the highly metastatic versus non metastatic behavior of MB versus GBM, respectively. The content of PSA-NCAM in GBM biopsies might result from at least two phenomena: the number of cells expressing PSA-NCAM and the amount of PSA-NCAM expressed by individual cells. The different patterns of PSA-NCAM expression observed by immunohistochem- istry in GBM are in keeping with these hypotheses as some show a rather low level on many cells spread over the tissue whereas for others high expression is exhib- ited only by islets of cells. However, since the tumor is not strictly homogeneous, the different staining patterns that can be observed cannot be assumed to be respre- sentative of the entire tumor of a given patient. Cells expressing PSA-NCAM could be either progenitors and/ or cells exhibiting an altered differentiation process due to transformation, although we cannot exclude that in some cases PSA-NCAM positive cells are cells from the Page 9 of 12 subventricular zone attracted by the tumor [38]. PSA expression is under transcriptional control, a mechanism that can be perturbed following oncogenic transforma- tion, and the enzymes polysialyltransferases that transfer PSA to NCAM represent obvious targets. In addition, several post-translational mechanisms that have been shown to regulate the expression dynamics could be at play [39,40]. Despite variations of expression, PSA-NCAM expres- sion was correlated with poor prognosis for both OS and DFS. Although at this stage whether PSA-NCAM molecule itself plays a causal role or is a downstream consequence of changes in tumorigenesis is not known, some hypotheses may be formulated to explain a nega- tive role of PSA-NCAM in survival. First, PSA-NCAM may be carried by undifferentiated cells in the tumor capable of cancer initiation and resistance to therapy [7]. Indeed, cumulative studies suggest that persistence of PSA-NCAM could prevent differentiation. During development, a defined spatial and temporal window of expression of PSA-NCAM illustrates that this molecule constitutes a very effective cue when plasticity and pre- cise timing of differentiation is required [40]. A promi- nent role of PSA in differentiation is also supported by its capacity to delay oligodendrocyte maturation events such as differentiation and myelinating potential [19,41,42] or neuronal differentiation [43,44]. Moreover, PSA-NCAM is an attractive candidate to be expressed by CIC since it is characterized by a strong and ubiqui- tous expression during embryonic development in mul- tipotent or lineage restricted precursors, and a stem cell niche marker in the adult CNS, mainly in the SVZ and hippocampus producing neuroblasts throughout life. Polysialylation could therefore support the maintenance of an immature phenotype. Transplantation studies with PSA+ and PSA- GBM cell populations will be required to answer whether PSA-NCAM defines cell populations with CIC properties. Second, PSA-NCAM could favor infiltration of cells in the surrounding healthy tissue and be responsible for earlier relapse, which may subsequently lead to decreased OS as disseminated tumor cells play a critical role in GBM recurrence. This PSA-NCAM enhancing effect on migration was indeed demonstrated in healthy tissue and in disease models such as rhabdomyosarcoma metastasis mouse model [27] and after grafting of PSA- expressing C6 glioma cells in mouse brain [20]. Third, PSA-NCAM might trigger proliferation and enhance GBM growth. This could occur via an increased sensitivity of PSA-NCAM positive cells to growth factors such as PDGF, as shown for oligodendro- cytes [45], or GDNF [17]. Interestingly PDGF receptor expression was required for oligodendrocytes to gener- ate gliomas [46]. An alternative could be the prevention