Nuclear expression of Survivin in paediatric ependymomas and choroid plexus tumours correlates with morphologic tumour grade

Abstract

Survivin is a gene that is widely expressed throughout the development of the normal mammalian embryo. Subcellular localisation of Survivin to both the nucleus and cytoplasm has suggested multiple functional roles, including inhibition of cell death, especially as demonstrated within a variety of malignant cell types, as well as regulation of the mitotic spindle checkpoint. The expression of Survivin has been associated with an adverse clinical outcome in a large number of malignancies. However, nuclear Survivin expression has been described as an independent variable of favourable prognosis in two large clinical studies of breast and gastric carcinomas. Reports of Survivin expression in normal postnatal, differentiated tissues have been restricted to cell types with high proliferative capacities, including vascular endothelium, endometrium, colonic epithelium, and activated lymphocytes. Prior to this report, expression within the normal human brain had not been characterised. Here, we analyse the expression of Survivin in human brain sections obtained from perinatal and paediatric autopsy cases. We report a strikingly high level of expression of Survivin within normal ependyma and choroid plexus (CP). Analysis of corresponding neoplastic tissue in paediatric ependymomas and CP tumours shows that expression of the nuclear form of Survivin correlates with morphologic tumour grade, with a loss of nuclear expression associated with progressive cytologic anaplasia. This pattern of expression supports a hypothesis that Survivin plays a functional role in normal ependymal growth and/or neural stem cell differentiation, and that abnormally low levels of expression of the nuclear form of this protein may be a marker of more aggressive disease and/or higher morphologic grade in ependymal and CP tumours.

Figure 1

Survivin expression in normal brain tissue using the sc-10811 antisera (A–D) and the NB-500-201K3 antisera (E–H). (A) choroid plexus, (B) ependyma-fourth ventricle, (C) Purkinje neuron, (D) choroid plexus cyst; (E) choroid plexus, (F) ependyma-fourth ventricle, (G) Purkinje neurons, and (H) choroid plexus cyst. The sc-10811 antisera stain the nuclear form, while the NB-500-201K3 antisera stain the cytoplasmic form of Survivin.

Figure 2

Survivin expression in ependymomas using the sc-10811 antisera: (A) myxopapillary ependymoma, (B) grade II ependymoma, (C) grade II ependymoma, and (D) anaplastic ependymoma.

Figure 3

Survivin expression in choroid plexus tumours using the sc-10811 antisera: (A) papilloma grade I, (B) atypical papilloma grade I–II (low magnification), (C) atypical papilloma grade I–II (high magnification), and (D) choroid plexus carcinoma.

Figure 4

Survivin and β-actin protein expression in normal human ependyma and cortex.

Figure 5

Genomic structure of the three known isoforms of Survivin: Survivin-ΔEx3, Survivin, and Survivin-2B (adapted from The UCSC Genome Browser Database).