Spatial association of apoptosis-related gene expression and cellular death in clinical neuroblastoma

Abstract

Summary Several unique features of neuroblastoma (NB), including the capacity for spontaneous regression and maturation to benign pathology, suggest that genes that regulate cellular proliferation, survival and differentiation may be involved in directing clinical tumour aggressiveness. The in situ expression of Bcl-2, Rb, p21, p53 and Bax proteins, as well as the proliferation marker proliferating cell nuclear antigen (PCNA) were examined immunocytochemically in a selection of 38 stage-and outcome-identified NB tumours. Apoptotic cells were identified morphologically and by a DNA fragmentation labelling technique (TUNEL). Although the tumour cell density of Bcl-2, p53, Bax, PCNA and TUNEL positivity correlated with patient survival, a spatially organized expression pattern was further recognized in stroma-poor differentiating tumours. Immature tumour cells adjacent to thin fibrovascular stroma are proliferating, as evidenced by PCNA positivity, and often express Bcl-2. At increasing distance from this fibrovascular stroma, intermediately differentiated tumour cells express Rb, while with more advanced differentiation, proliferation ceases and Bcl-2 immunoreactivity is lost. The most differentiated tumour cells, which often express p53, and occasionally p21 and Bax, lie adjacent to TUNEL-positive, morphologically apoptotic cells. This spatial organization in favourable outcome NB tumours suggests that physiological regulation of differentiation and apoptosis may be involved in tumour regression.

Induction of ID2 Expression by Hypoxia-inducible Factor-1

“…Depending on the differentiation stage of the tumor cells at diagnosis, the clinical behavior can be predicted, with immature tumors being more aggressive and having a poor prognosis (16,17). Neuroblastoma derives from immature sympathetic neural precursors, often with remaining neural crest traits (14,15,18). We have previously found that hypoxic neuroblastoma tumors and cells exposed to hypoxia (1% O 2 ) down-regulate SNS marker genes, including the * This work was supported by grants from the Swedish Cancer Society, the Children's Cancer Foundation of Sweden, Åke Wiberg's Foundation, HKH Kronprinsessan Lovisas förening för barnasjukvård, Hans von Kantzow's Foundation, Ollie and Elof Ericsson's foundation, the Crafoord Foundation, and Malmö University Hospital Research Funds.…”

“…Neuroblastoma (NB), the most common extracranial solid pediatric tumor, arises where sympathetic nervous system (SNS) tissue forms (14,15). Depending on the differentiation stage of the tumor cells at diagnosis, the clinical behavior can be predicted, with immature tumors being more aggressive and having a poor prognosis (16,17).…”

“…Depending on the differentiation stage of the tumor cells at diagnosis, the clinical behavior can be predicted, with immature tumors being more aggressive and having a poor prognosis (16,17). Neuroblastoma derives from immature sympathetic neural precursors, often with remaining neural crest traits (14,15,18). We have previously found that hypoxic neuroblastoma tumors and cells exposed to hypoxia (1% O 2 ) down-regulate SNS marker genes, including the neuronal transcription factors HASH-1 and dHAND (19), as well as the gene coding for the E-protein E2-2 (20).…”

ID2 expression in neuroblastoma does not correlate to MYCN levels and lacks prognostic value

“…These data, obtained in two independent laboratories, challenge the previously proposed ID2-MYCN relation. Oncogene (2003Oncogene ( ) 22, 456-460. doi:10.1038 Keywords: ID2; MYC; MYCN; neuroblastoma; prognosis Neuroblastoma is a childhood tumor derived from sympathetic nervous system precursor cells (Hoehner et al, 1996(Hoehner et al, , 1998. Detailed cytogenetic characterization indicates that neuroblastoma can be divided into subgroups based on their genetic aberrations, but the molecular events leading to malignant transformation of these neural crest-derived precursor cells are not known in any detail.…”

ASK1 resistant neuroblastoma is deficient in activation of p38 kinase

“…4 ± 7 Apoptosis also takes place within the primary neuroblastoma as the tumour cells move away from the fibrovascular stroma. 8 Positive correlations have been observed between frequency of apoptotic cells and favourable outcome of patient. 9 The mechanism behind the spontaneous regression of neuroblastoma is unknown, but one hypothesis suggests it was due to apoptosis.…”